Codeine

New Guidance on Pregnancy Pain Relief

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Appropriate management of pain during and after pregnancy is essential to minimise the risk of adverse outcomes to mother and baby, but the type and timing of pain relief is important, a new review said.

A team of leading doctors carried out the review for the Royal College of Obstetricians and Gynaecologists (RCOG) following concerns over the use of codeine during breastfeeding.

The scientific impact paper, Antenatal and Postnatal Analgesia , supported the use of appropriate pain relief options, as advised by NHS guidance.

Avoiding Foetal Harm

It recommended that, where possible, all drugs should be avoided during the first trimester because the embryo is most vulnerable to teratogenic effects between 4 to 10 weeks gestation. However, it acknowledged that some would need to be continued to prevent maternal harm.

It found that paracetamol “remains the analgesic of choice” in pregnant and breastfeeding women because of its excellent safety record, although it noted limited associations between the use of paracetamol and adverse outcomes including an increased incidence of childhood asthma, behavioural problems, and a delay in gross motor and communication development in children with long‐term antenatal exposure.

NSAIDS

The review said that nonsteroidal anti-inflammatory drugs (NSAIDS) – such as ibuprofen – should be avoided unless clinically indicated, such as for a severe migraine, within the first trimester and should not be taken after 30 weeks of gestation due to increased risk to the baby.

The reviewing doctors recommended the lowest effective dose for the shortest time because of some evidence that the use of NSAIDS might increase the risk of first-trimester miscarriage.

However, NSAIDS were safe to use during breastfeeding, they said, as the quantity of drug that passed into milk was very small.

Opioids

The guidelines said that opioid analgesics, such as codeine, tramadol, dihydrocodeine (DHC), and morphine should be avoided wherever possible and only administered by a health professional.

However, it highlighted the important difference between codeine and DHC during breastfeeding and emphasised that DHC was safer to take during breastfeeding, whereas codeine should be avoided, because of increased concerns regarding toxicity.

Dr Dina Bisson, a consultant obstetrician who led the review, said: “It is absolutely essential that pain is managed appropriately during pregnancy and breastfeeding. Many women may develop headaches, lower back pain and pelvic pain during pregnancy and breastfeeding, while others may have chronic conditions, where pain management is necessary.

“If pain is not adequately managed, this can have a negative impact on a woman’s physical and mental wellbeing.

“Women should be encouraged to try non-medical treatments, such as adequate rest, hot and cold compresses, massage, physiotherapy, and exercise. But if pain relief drugs are required, it is important that doctors and midwives are able to advise on appropriate medication and hopefully this review will be helpful.”

Influenza Concerns

The RCOG said it was concerned by reports that fewer pregnant women were having a flu vaccine this year. Public Health England said this week that only around 40% of pregnant women have had the vaccine so far this season.

Dr Pat O’Brien, a consultant obstetrician and spokesperson for the RCOG, said: “Flu can occasionally be serious for pregnant women as it increases risk of complications, such as bronchitis, a chest infection that can develop into pneumonia.

“The best way to avoid getting this is to have the flu vaccination. Women who are pregnant should be reassured that current evidence shows the flu vaccine is safe to use.”

Stop Giving Codeine to Children, AAP Says

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The American Academy of Pediatrics (AAP) is now advising against giving codeine to children.

Although codeine is widely used for pain relief, genetic variability in a patient’s drug metabolism causes varied efficacy results, according to a new clinical report from the AAP called “Codeine: Time to Say ‘No.’” Patients’ response to codeine depends on how quickly their body metabolizes the opioid, and patients who are fast metabolizers may exhibit strong reactions.

Children, especially those with sleep-disordered breathing, are at particular risk for opioid sensitivity. Because of this, standard doses of codeine can be fatal in these children. In fact, case reports have consistently linked the use of codeine to life-threatening or fatal respiratory depression in kids.

Despite these well-documented risks, as well as concerns expressed by health care groups that include the AAP, the FDA, and the World Health Organization, codeine is still available without a prescription in OTC cough formulas from outpatient pharmacies in 28 states and the District of Columbia, and it is still frequently prescribed to children as an analgesic and antitussive agent. One study cited in the AAP report revealed that more than 800,000 patients younger than 11 years were prescribed codeine between 2007 and 2011.

A review of data in the FDA’s Adverse Event Reporting System from 1965 to 2015 revealed 64 pediatric cases of codeine-related severe respiratory depression and 24 codeine-related deaths, 21 of which involved children younger than 12 years.

The AAP report uncovered 3 common factors among the codeine-related life-threatening and fatal events that occurred:

1.     The majority of children were relatively young.
2.     The children were put on a postoperative pain regimen of scheduled acetaminophen and codeine.
3.     The children had undergone adenotonsillectomy for sleep-disordered breathing.

According to the AAP, the most effective way to reduce codeine-related adverse effects is to explore alternative medicines for pain relief. The clinical report mentions drugs such as oxycodone, tramadol, and tapentadol as potential avenues for treatment for pediatric patients. Nevertheless, determining a definitive alternative medication that is both safe and effective is difficult and requires further research.

As lead researcher Joseph D. Tobias, MD, FAAP, stated in a press release, “Effective pain management for children remains challenging because children’s bodies process drugs differently than adults do.”

Researchers have shifted their focus to the use of postoperative nonopioid analgesics, such as acetaminophen, and nonsteroidal anti-inflammatory drugs, such as ibuprofen, for acute pain relief in pediatric patients.

In 2015, the FDA recommended that the use of codeine-containing cough medicines should be contraindicated in children younger than 18 years. Final action on this recommendation is pending, and in the meantime, these medicines are still available at outpatient pharmacies for purchase.

According to the AAP, more restrictions on codeine prescribing in the pediatric population is necessary to reduce related risks. Further research on pain relief alternatives, coupled with provider and parental education on nonopioid treatments and the adverse effects of codeine, is key to establishing a safe treatment plan for children.

Codeine risky for kids after certain surgeries, FDA says.

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Children who are given codeine for pain relief after surgery to remove tonsils or adenoids are at risk for overdose and death, U.S. health officials said.

The U.S. Food and Drug Administration said a new boxed warning—the agency’s strongest caution—will be added to the labels of codeine-containing products to warn about this danger.

The FDA strongly recommends against the use of codeine to manage pain in children after surgery to remove tonsils or adenoids, and suggests that doctors use an alternate pain reliever. The agency also said parents and caregivers need to be aware of the risks and ask for a different pain medicine if their children are prescribed codeine after having their tonsils or adenoids removed.

Codeine is an opioid (narcotic) medication used to treat mild to moderate pain and is often prescribed to children after tonsil or adenoid removal. However, some children have died after being given codeine within the recommended dose range.

 

In August 2012, the FDA warned about the danger in children who are “ultra-rapid metabolizers” of codeine, which means their liver converts codeine to morphine in higher-than-normal amounts. High levels of morphine can result in potentially fatal breathing problems.

Since then, a safety review by the FDA identified 10 deaths and three overdosesassociated with codeine that occurred among children in the United States between 1969 and May 2012. Many of these children were recovering from surgery to remove tonsils or adenoids.

All of the children, aged 21 months to 9 years old, received doses of codeine within the normal dose range. Signs of morphine overdose developed within one to two days after the children began taking codeine, the FDA said in an agency news release.

 

Codeine is available by prescription either alone or in combination with acetaminophen and aspirin, and in some cough and cold medications.

When prescribed to treat pain, codeine should not be given on a fixed schedule, but only when a child needs relief from pain. They should never receive more than six doses in a day, the FDA said.

Children receiving codeine for pain should be closely monitored for signs of morphine overdose. These include: unusual sleepiness, such as being difficult to wake up; confusion or disorientation; breathing problems; and blueness on the lips or around the mouth

FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death.

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The U.S. Food and Drug Administration (FDA) is reviewing reports of children who developed serious adverse effects or died after taking codeine for pain relief after tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. Recently, three pediatric deaths and one non-fatal but life-threatening case of respiratory depression were documented in the medical literature1,2 (see Data Summary below). These children (ages two to five) had evidence of an inherited (genetic) ability to convert codeine into life-threatening or fatal amounts of morphine in the body. All children had received doses of codeine that were within the typical dose range.

Facts about codeine
 

 
  • An opioid pain reliever used to treat mild to moderately severe pain
  • Also used, usually in combination with other medications, to reduce coughing
  • Available as a single-ingredient product, or in combination with acetaminophen or  aspirin, and in some cough and cold medications

 

When codeine is ingested, it is converted to morphine in the liver by an enzyme called cytochrome P450 2D6 (CYP2D6). Some people have DNA variations that make this enzyme more active, causing codeine to be converted to morphine faster and more completely than in other people. These “ultra-rapid metabolizers” are more likely to have higher than normal amounts of morphine in their blood after taking codeine. High levels of morphine can result in breathing difficulty, which may be fatal. Taking codeine after tonsillectomy and/or adenoidectomy may increase the risk for breathing problems and death in children who are “ultra-rapid metabolizers.” The estimated number of “ultra-rapid metabolizers” is generally 1 to 7 per 100 people, but may be as high as 28 per 100 people in some ethnic groups (see Table 1 below).

FDA is currently conducting a safety review of codeine to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as post-operative pain following other types of surgery or procedures.

Health care professionals should be aware of the risks of using codeine in children, particularly in those who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. If prescribing codeine-containing drugs, the lowest effective dose for the shortest period of time should be used on an as-needed basis (i.e., not scheduled around the clock).

Parents and caregivers who observe unusual sleepiness, confusion, or difficult or noisy breathing in their child should stop giving their child codeine and seek medical attention immediately, as these are signs of overdose.

FDA will update the public with more information once it has completed its review.

Additional Information for Parents and Caregivers

  • Certain children may be at risk for life-threatening side effects, such as breathing difficulty, or death when taking codeine for pain relief after tonsillectomy or adenoidectomy. This can occur even with use of codeine at recommended doses.
  • Codeine is usually prescribed on an “AS NEEDED” basis. Do not administer codeine to the child on a regular basis UNLESS the child requires the drug. Do not administer more than six (6) doses per day.
  • Signs of serious side effects of codeine in children can include unusual sleepiness, confusion, and difficult or noisy breathing. If your child shows these signs, stop giving your child codeine and seek medical attention immediately by taking your child to the emergency room or calling 911.
  • Talk to your child’s health care professional if you have any questions or concerns about codeine.
  • Report side effects from codeine to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page.

Additional Information for Health Care Professionals 

  • Life-threatening adverse events and death have occurred in certain children who received codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. These children had evidence of being “ultra-rapid metabolizers” of substrates of cytochrome P450 2D6 (CYP2D6), including codeine.
  • If prescribing codeine-containing drugs, use the lowest effective dose for the shortest period of time on an as-needed basis (i.e., not scheduled around the clock).
  • Counsel parents and caregivers on how to recognize the signs of morphine toxicity, and advise them to stop giving the child codeine and to seek medical attention immediately if their child is exhibiting these signs.
  • FDA-cleared tests are available for determining a patient’s CYP2D6 genotype.
  • The estimated number of ultra-rapid metabolizers varies among different racial/ethnic groups (see Table 1below).
  • Consider prescribing alternative analgesics for children undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome.
  • Report adverse events involving codeine to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of this page.

Data Summary

Recently, three deaths and one case of severe respiratory depression were reported in children who received codeine after undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. The children ranged in age from two to five years old. The three deaths occurred in children who had evidence of being “ultra-rapid metabolizers” of substrates of the cytochrome P450 isoenzyme 2D6 (including codeine), and the life-threatening case occurred in a child who was an extensive metabolizer. All children received doses of codeine that were within the typical dose range. In these cases, signs of morphine toxicity developed within one to two days after starting codeine. The post-mortem morphine concentrations in the three children who died1,2 were substantially higher than the typical therapeutic range.3

FDA is conducting a review to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occurred during treatment of other kinds of pain such as post-operative pain following other types of surgery or procedures. FDA will update the public when more information is available.
Table 1. Prevalence of Ultra-rapid Metabolizers in Different Populations

Population UM Genotypes/Phenotypes
(↑ Activity)		 Prevalence %
(UM/Total n)
African/Ethiopian4 UM (active duplicate genes) 29% (35/122)
African American5, 6 UM (three active duplicate genes) 3.4% (3/87)
6.5% (60/919)
Asian7, 8, 9 UM (active duplicate genes) 1.2% (5/400)
2%
Caucasian5, 6 UM (three active duplicate genes) 3.6% (33/919) 6.5% (18/275)
Greek10 CYP2D6*2xN/UM 6.0% (17/283)
Hungarian11 UM (active duplicate genes) 1.9%
Northern European10, 12 UM (active duplicate genes) 1-2%

UM = ultra-rapid metabolizer; CYP2D6 = cytochrome P450 2D6
References

  1. Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med 2009;361:827-8.
  2. Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012;129:e1343-7.
  3. Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br J Anaesth 2002;89:839-45.
  4. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M. Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996;278:441-6.
  5. Kohlrausch FB, Gama CS, Lobato MI, Belmonte-de-Abreu P, Gesteira A, Barros F, et al. Molecular diversity at the CYP2D6 locus in healthy and schizophrenic southern Brazilians. Pharmacogenomics 2009;10:1457-66.
  6. Gaedigk A, Fuhr U, Johnson C, Bérard LA, Bradford D, Leeder JS. CYP2D7-2D6 hybrid tandems: identification of novel CYP2D6 duplication arrangements and implications for phenotype prediction. Pharmacogenomics 2010;11:43-53.
  7. Ji L, Pan S, Marti-Jaun J, Hänseler E, Rentsch K, Hersberger M. Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel *14B allele in mainland Chinese. Clin Chem 2002;48:983-8.
  8. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjöqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452-9.
  9. Lee SY, Sohn KM, Ryu JY, Yoon YR, Shin JG, Kim JW. Sequence-based CYP2D6 genotyping in the Korean population. Ther Drug Monit 2006;28:382-7.
  10. Arvanitidis K, Ragia G, Iordanidou M, Kyriaki S, Xanthi A, Tavridou A, Manolopoulos VG. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Fundam Clin Pharmacol 2007;21:419-26.
  11. Rideg O, Háber A, Botz L, Szücs F, Várnai R, Miseta A, Kovács GL. Pilot study for the characterization of pharmacogenetically relevant CYP2D6, CYP2C19 and ABCB1 gene polymorphisms in the Hungarian population. Cell Biochem Funct 2011;29:562-8.
  12. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5:6-13.

 

Source: http://www.fda.gov/Drugs.com

 

 

New Evidence about an Old Drug — Risk with Codeine after Adenotonsillectomy.

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During the past 10 years, efforts in pharmacogenomics have generated insights into the efficacy and safety of drugs, enhancing our understanding of the safety profile of even some of the oldest drugs, such as codeine sulfate, an opioid analgesic first approved in 1950 for relief of mild or moderate pain. Simultaneously, an increased awareness of the value of both personalized medicine and the reporting of rare adverse outcomes has resulted in the publication of information on adverse events that previously might not have been reported. These developments, in turn, led the Food and Drug Administration (FDA) to reanalyze the safety of — and ultimately restrict — codeine use in patients after adenotonsillectomy.

The activity of codeine depends on its conversion to morphine by the cytochrome P-450 isoenzyme 2D6 (CYP2D6); morphine is subsequently metabolized to the active morphine-6-glucuronide by means of UDP-glucuronosyltransferase 2B7 .The gene encoding CYP2D6 has many genetic variations that affect the amount of codeine that is converted to an active form and that result in the drug’s variable effect. Patients with a normal range of CYP2D6 activity represent 75 to 92% of the population and are called extensive metabolizers. At the low end of the activity spectrum are poor metabolizers (approximately 5 to 10% of the population), who have no functional alleles and therefore receive little to no morphine or analgesia from codeine. At the high end of the CYP2D6 activity spectrum, ultrarapid metabolizers have two or more functional alleles, and their bodies can convert codeine into large amounts of morphine. The prevalence of ultrarapid metabolism varies by ethnic group: it is lower than 1% among Chinese and Japanese patients but potentially higher than 15% among Middle Eastern and North African patients. Clinically significant toxic effects related to opioid excess have been reported in ultrarapid metabolizers, which suggests that the risk of toxic effects from codeine depends, in part, on genotype.1

In April 2012, a case series was published reporting two deaths and one case of respiratory depression in children 3 to 5 years of age who had received typical doses of codeine after tonsillectomy, adenoidectomy, or both performed because of obstructive sleep apnea.2 The two deaths occurred in children who had evidence of being ultrarapid metabolizers, and the postmortem morphine levels in these children were substantially higher than the therapeutic range. The third child was an extensive metabolizer. Signs of morphine toxicity developed within 1 to 2 days after codeine treatment began.

In response to that publication, the FDA initiated an evaluation of the safety of codeine in children. This assessment included a comprehensive review of the literature and case reports that were submitted to the FDA’s Adverse Event Reporting System (AERS, now known as FAERS) between 1969 and May 1, 2012. This search identified 13 cases, including 10 deaths and 3 cases of life-threatening respiratory depression associated with therapeutic codeine use. Seven of these 13 cases (including the 3 from the case series mentioned above) had been reported in the medical literature. Patients ranged in age from 21 months to 9 years. Most of the patients had undergone adenotonsillectomy (eight patients) or had a respiratory tract infection (three patients), and they appeared to receive appropriate doses of codeine. Of the seven children described in the published cases, three were characterized as ultrarapid metabolizers, three as extensive metabolizers, and one as a probable ultrarapid metabolizer. A search of the medical literature and AERS for cases of pediatric death or life-threatening respiratory depression with therapeutic use of hydrocodone, oxycodone, or morphine was also conducted and did not identify robust cases of unexplainable or unconfounded death or life-threatening respiratory depression after the use of these drugs.

In late 2011, the Patient Safety and Quality Improvement Committee of the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) was also becoming concerned about adverse events, particularly respiratory depression, after adenotonsillectomy. Such events have been described informally for decades but rarely reported. In 2012, the committee conducted a nationwide, anonymous survey of otolaryngologists to learn more about these events. When the FDA announced its investigation the committee reached out to share prepublication results with the agency. Limited information was available; however, two children (a 3-year-old and a 12-year-old) with obstructive sleep apnea who died after adenotonsillectomy were confirmed (by genotype) to be ultrarapid metabolizers or suspected (because of high postmortem blood morphine levels) of being ultrarapid metabolizers.3

The only well-documented cases of death or respiratory arrest after codeine treatment in ultrarapid-metabolizing children have involved patients who have just undergone adenotonsillectomy. That does not mean that the risk is not present in other situations, but currently available evidence suggests that the risk is most substantial in children after they have undergone tonsillectomy, adenoidectomy, or both. Many such children have sleep-disordered breathing, and children with sleep-disordered breathing are known to be more sensitive to opioids.4

Therefore, the FDA recently required that the manufacturers of all codeine-containing products add a boxed warning to the labeling of their product that describes the risk posed by codeine after a child has undergone tonsillectomy or adenoidectomy. A contraindication will be added to restrict codeine use in such patients. The “Warnings/Precautions,” “Pediatric Use,” and “Patient Counseling Information” sections of the labeling will also be updated.

Performing routine genotyping before prescribing codeine was not recommended for several reasons. Some of the patients who died or in whom respiratory depression developed were genetically extensive metabolizers, so patients with “normal” genotyping results may still be at risk. Also, since the number that would need to be screened to prevent such a rare toxic effect would be very high, and since preoperative laboratory assessments are not routine before adenotonsillectomy, the practicality of genotyping is questionable.

Although it did not participate in the FDA’s decision process, the AAO-HNS supported the labeling changes because of the increasing evidence that these extremely rare but catastrophic events can be related to codeine use, because codeine is ineffective in some patients (poor metabolizers), and because of emerging clarity that a variety of other drugs (e.g., some nonsteroidal antiinflammatory drugs) are safe to use and do not increase the risk of bleeding.5 The AAO-HNS informally surveyed opinion leaders in academic medicine, private practice, and pediatric otolaryngology and reached a consensus that the availability of other analgesic agents and the risk of catastrophic events outweighed the value of codeine.

Even old and commonly used drugs may cause rare but catastrophic events that will not be recognized without a vigorous effort by the profession to share information in the literature. In the case of codeine, a combination of case reporting and our evolving understanding of genetic influences on drug response has clarified the need to avoid this drug after adenotonsillectomy.

Source: NEJM

 

 

New Evidence about an Old Drug — Risk with Codeine after Adenotonsillectomy.

Posted by

0


During the past 10 years, efforts in pharmacogenomics have generated insights into the efficacy and safety of drugs, enhancing our understanding of the safety profile of even some of the oldest drugs, such as codeine sulfate, an opioid analgesic first approved in 1950 for relief of mild or moderate pain. Simultaneously, an increased awareness of the value of both personalized medicine and the reporting of rare adverse outcomes has resulted in the publication of information on adverse events that previously might not have been reported. These developments, in turn, led the Food and Drug Administration (FDA) to reanalyze the safety of — and ultimately restrict — codeine use in patients after adenotonsillectomy.

The activity of codeine depends on its conversion to morphine by the cytochrome P-450 isoenzyme 2D6 (CYP2D6); morphine is subsequently metabolized to the active morphine-6-glucuronide by means of UDP-glucuronosyltransferase 2B7. The gene encoding CYP2D6 has many genetic variations that affect the amount of codeine that is converted to an active form and that result in the drug’s variable effect. Patients with a normal range of CYP2D6 activity represent 75 to 92% of the population and are called extensive metabolizers. At the low end of the activity spectrum are poor metabolizers (approximately 5 to 10% of the population), who have no functional alleles and therefore receive little to no morphine or analgesia from codeine. At the high end of the CYP2D6 activity spectrum, ultrarapid metabolizers have two or more functional alleles, and their bodies can convert codeine into large amounts of morphine. The prevalence of ultrarapid metabolism varies by ethnic group: it is lower than 1% among Chinese and Japanese patients but potentially higher than 15% among Middle Eastern and North African patients. Clinically significant toxic effects related to opioid excess have been reported in ultrarapid metabolizers, which suggests that the risk of toxic effects from codeine depends, in part, on genotype.1

In April 2012, a case series was published reporting two deaths and one case of respiratory depression in children 3 to 5 years of age who had received typical doses of codeine after tonsillectomy, adenoidectomy, or both performed because of obstructive sleep apnea.2 The two deaths occurred in children who had evidence of being ultrarapid metabolizers, and the postmortem morphine levels in these children were substantially higher than the therapeutic range. The third child was an extensive metabolizer. Signs of morphine toxicity developed within 1 to 2 days after codeine treatment began.

In response to that publication, the FDA initiated an evaluation of the safety of codeine in children. This assessment included a comprehensive review of the literature and case reports that were submitted to the FDA’s Adverse Event Reporting System (AERS, now known as FAERS) between 1969 and May 1, 2012. This search identified 13 cases, including 10 deaths and 3 cases of life-threatening respiratory depression associated with therapeutic codeine use. Seven of these 13 cases (including the 3 from the case series mentioned above) had been reported in the medical literature. Patients ranged in age from 21 months to 9 years. Most of the patients had undergone adenotonsillectomy (eight patients) or had a respiratory tract infection (three patients), and they appeared to receive appropriate doses of codeine. Of the seven children described in the published cases, three were characterized as ultrarapid metabolizers, three as extensive metabolizers, and one as a probable ultrarapid metabolizer. A search of the medical literature and AERS for cases of pediatric death or life-threatening respiratory depression with therapeutic use of hydrocodone, oxycodone, or morphine was also conducted and did not identify robust cases of unexplainable or unconfounded death or life-threatening respiratory depression after the use of these drugs.

In late 2011, the Patient Safety and Quality Improvement Committee of the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) was also becoming concerned about adverse events, particularly respiratory depression, after adenotonsillectomy. Such events have been described informally for decades but rarely reported. In 2012, the committee conducted a nationwide, anonymous survey of otolaryngologists to learn more about these events. When the FDA announced its investigation (www.fda.gov/Drugs/DrugSafety/ucm313631.htm), the committee reached out to share prepublication results with the agency. Limited information was available; however, two children (a 3-year-old and a 12-year-old) with obstructive sleep apnea who died after adenotonsillectomy were confirmed (by genotype) to be ultrarapid metabolizers or suspected (because of high postmortem blood morphine levels) of being ultrarapid metabolizers.3

The only well-documented cases of death or respiratory arrest after codeine treatment in ultrarapid-metabolizing children have involved patients who have just undergone adenotonsillectomy. That does not mean that the risk is not present in other situations, but currently available evidence suggests that the risk is most substantial in children after they have undergone tonsillectomy, adenoidectomy, or both. Many such children have sleep-disordered breathing, and children with sleep-disordered breathing are known to be more sensitive to opioids.4

Therefore, the FDA recently required that the manufacturers of all codeine-containing products add a boxed warning to the labeling of their product that describes the risk posed by codeine after a child has undergone tonsillectomy or adenoidectomy. A contraindication will be added to restrict codeine use in such patients. The “Warnings/Precautions,” “Pediatric Use,” and “Patient Counseling Information” sections of the labeling will also be updated.

Performing routine genotyping before prescribing codeine was not recommended for several reasons. Some of the patients who died or in whom respiratory depression developed were genetically extensive metabolizers, so patients with “normal” genotyping results may still be at risk. Also, since the number that would need to be screened to prevent such a rare toxic effect would be very high, and since preoperative laboratory assessments are not routine before adenotonsillectomy, the practicality of genotyping is questionable.

Although it did not participate in the FDA’s decision process, the AAO-HNS supported the labeling changes because of the increasing evidence that these extremely rare but catastrophic events can be related to codeine use, because codeine is ineffective in some patients (poor metabolizers), and because of emerging clarity that a variety of other drugs (e.g., some nonsteroidal antiinflammatory drugs) are safe to use and do not increase the risk of bleeding.5 The AAO-HNS informally surveyed opinion leaders in academic medicine, private practice, and pediatric otolaryngology and reached a consensus that the availability of other analgesic agents and the risk of catastrophic events outweighed the value of codeine.

Even old and commonly used drugs may cause rare but catastrophic events that will not be recognized without a vigorous effort by the profession to share information in the literature. In the case of codeine, a combination of case reporting and our evolving understanding of genetic influences on drug response has clarified the need to avoid this drug after adenotonsillectomy.

Source: NEJM