Codeine Risk In Children, Especially Those With Sleep Apnea

Although the initial FDA warnings about potentially fatal overdose from codeine in children were released in 2012, I’m recently discovered that a few of my surgeon and nursing colleagues were still unaware of the potential risks. Therefore I thought it might be helpful to bring up the topic so people can remind their own colleagues of the risks of codeine in children.

Codeine must be used with extreme caution, if at all, in young children or pregnant women because of variants in the enzymes some patient’s use to metabolize the drug.

Treating Pediatric Pain:Always A Challenge

Treating pain in infants and children has always been challenging. We all know that central nervous system immaturity, combined with relative lack of exposure to drugs, can cause respiratory depression and apnea even in older children. Children often become very sleepy, and perhaps apneic, with even small doses of pain medications.

The fact that the youngest ones are non-verbal and can’t tell us when they are in pain makes it very easy to over medicate with pain meds. It’s hard to tell the difference between a child crying from pain and one crying from fear. But it’s easy to overdose to try to calm the child.

Liver function is comparatively immature in young children, with decreased function of hepatic enzymes. This means that barbiturates, other sedatives, and opioids have a longer duration of action.

Making things even more challenging is the fact that metabolism of codeine, one of the most commonly used pain medications in health care, varies significantly in some patients.

Illustration showing how the immature liver of a child increases respiratory risks, including with codeine overdose. (copyright C Whitten MD)

Illustration showing how the immature liver of a child increases respiratory risks. (copyright C Whitten MD)

Codeine Must be Metabolized To Work

Codeine is often used for mild to moderate acute and chronic pain, both alone and in combinations with either acetaminophen or aspirin. It’s even used in some cough syrups with other medications to suppress coughing. However, codeine itself is an inactive drug. To work, codeine must be metabolized in the liver into the active form of morphine.

Cytochrome P450 2D6 is a liver enzyme that transforms many drugs, including the conversion of codeine to the active analgesic morphine. There are multiple enzyme variants of P450. The 2D6 variant is more rapid and results in more complete conversion, and therefore results in a much higher-than-normal blood level of morphine. High levels of morphine may result in respiratory depression, which can be fatal.

Incidence of Ultra Rapid Metabolizers of Codeine

The incidence of rapid metabolizers has been estimated to lie between 1 and 7 per 100 people — but can be as high as 28/100 people in certain ethnic groups, such as those with Ethiopian heritage.

chart showing prevalence of ultra rapid metabolizers of codeine in different populations from http://www.fda.gov/Drugs/DrugSafety/ucm313631.htm

From http://www.fda.gov/Drugs/DrugSafety/ucm313631.htm

This means there are a large number of potential patients out there at risk. The main problem is that there is no easy way to identify these people ahead of time. Children, of course, may be seeing a medication for the first time and therefore have no history of problems.

Highest Risk Patients

Adults as well as children have this genetic variant, but the margin for safe dosing in infants and young children is so narrow that children with this variant have sometimes suffered fatal overdose. This is of such concern that the FDA issued a black box warning in 2012 for use of codeine in children having tonsillectomies or adenoidectomies.

Children undergoing tonsillectomy and adenoidectomy are at particular risk. Many of these children already suffered from sleep apnea from their hypertrophied tonsils. Of note, disturbed patterns of breathing such as sleep apnea do not always immediately resolve after T&A, but take time. Although 70% to 80% of children undergoing T&A for sleep apnea improve their apnea long term, many children’s respiratory conditions worsen immediately after surgery. Patients with obstructive sleep apnea are also more sensitive to opioids as sleep deprivation is common.

In addition, children with recurrent hypoxic episodes from sleep apnea have more sensitive respiratory centers, placing them at increased risk of apnea with opioids. It’s important to identify children with higher risk of sleep apnea from their history.

Decreasing Risk Of Pediatric Respiratory Depression

There is a movement away from using codeine in children. Since codeine is excreted in milk, prescribing codeine to nursing mothers is also a concern. Options include:

Use Local Anesthetics When You Can

Can your surgeon use long acting local anesthetic at the surgical site? This can provide long lasting relief. The most painful time after surgery is the immediate few hours when inflammation is highest. Think of hitting your thumb with hammer. Those first few hours are terrible, after that you know you’re hurt but its not as bad as your body’s own endorphins and healing process kick in.

Bupivicaine (max. dose) 2.5 mg/kg can last 4-8 hours, sometimes more. Since bupivicaine 0.25% has 2.5 mg per kg, an easy way to calculate maximum dosage when using 0.25% is to recognize that the maximum safe total volume is the same as the  weight of the child. A 10 kg child has a maximum dose of 25 mg (2.5 mg/kg X 10 kg) which equals 10 ml of local anesthetic.

Consider Non-Opioid Anti-Inflammatory Medications.

Non opioid medications often work very well as primary analgesics in children — especially if local anesthetic has been used by the surgeon. Consider:

  • Acetaminophen
    • single dose: 10-15 mg/kg IV/PO, not to exceed 5 doses in 24 hours (or 2.6 gm whichever is less)
  • NSAIDs (depending on the surgery and the risk of postop bleeding)
    • toradol: 0.5 mg/kg IM/IV q6h up to 72h; Alt: 1 mg/kg IM/IV q6h up to 24-48h; Max: 30 mg/dose IM; 15 mg/dose IV; Info: use lowest effective dose, shortest effective tx duration. Renal impairment decrease by 50%
    • ibuprofen: 4-10 mg/kg/dose. Give PO every 6-8 hours. Maximum single dose is 400 mg/dose, and maximum daily dose is 40 mg/kg/day up to 1200 mg/day

Dexamethasone: 0.25 mg/kg IV can be used as an additional adjuvant to decrease inflammation and decrease nausea risk.

Consider Alternative Oral Pain Medications

My hospital is moving toward use of liquid oxycodone for use in small children. The pediatric dose of oxycodone is 0.05-0.2 mg oxycodone/kg/dose every 4-6 hours as needed. May titrate up to 5 mg/dose oxycodone every 4-6 hours.

Whatever narcotic is chosen, prescribe the smallest effective dose. Always start low and go slow. Some studies show children with sleep apnea can be managed well with 50% of the average starting dose and that larger doses may risk apnea spells.

Prescribe As Needed — Not Around The Clock Dosing

Infants and young children should be dosed with opioids on an as needed bases- not around the clock. metabolism of all drugs will be slower than in adults, tolerance will be less. Also, when prescribing codeine the risk of overdosing from undiscovered hyper-metabolism is lessened when doses as needed.

Use Parents As Your Safety Monitors

Educate the parents to monitor their child for symptoms of overdose (good advice for any opioid):

  • Unusual sleepiness, such as being difficult to wake up
  • Disorientation or confusion
  • Labored or noisy breathing, such as breathing shallowly with a “sighing” pattern of breathing or deep breaths separated by abnormally long pauses
  • Blueness on the lips or around the mouth
  • Parents should stop giving the opioid and bring the child in to emergency or call 911 if the child is having breathing problems.

Consider Postoperative Admission

Children with sleep apnea are at higher risk of persistent transient disturbed respiratory patterns and obstruction, even after corrective tonsillectomy and adenoidectomy. You should consider overnight admission in the small child who has been diagnosed with severe sleep apnea or who has signs and symptoms suggestive of sleep apnea, especially if obesity is present.

Don’t Forget Codeine Under-Metabolizers

Before we leave the subject of codeine, it’s worth noting that some people have a different variant of this enzyme that does a very poor job of converting codeine to morphine. Without the conversion, there is poor analgesia. They will have poorly relieved pain after taking codeine and will want more pain medications. Don’t just assume this is drug-seeking behavior. If your patient tells you that codeine just doesn’t work for them or do anything for their pain, they might very well be right.

Summary

Untreated pain can lead to respiratory compromise. However, treating pain in infants and young children must take into account the facts that their immature nervous system and livers place them at higher risk of respiratory depression. Add to that an at risk population such as those undergoing airway surgery such as tonsillectomy in the setting of pre-existing sleep apnea and the risk is high. You must observe children carefully when medicating and titrate slowly to effect (for a clinical example click here). Respiratory depression can lead to cardiac arrest. Dose low and go slow. And consider alternatives to codeine in this high risk population.

May The Force Be  With You!

Christine Whitten MD, author Anyone Can Intubate, 5th Edition
and
Pediatric Airway Management: A Step by Step Guide

 

Further Reading

  1. http://www.fda.gov/Drugs/DrugSafety/ucm313631.htm
  2. http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm
  3. Morris LGT, Lieberman SM, Reitzen SD. Characteristics and outcomes of malpractice claims after tonsillectomy. Otolaryngology Head and Neck Surgery 2008;138:315-320
  4. Kelly LE, Rieder M, et al. More Codeine Fatalities After Tonsillectomy in North American Children. Pediatrics May 2012, VOLUME 129 / ISSUE 5
  5. Ye J, Liu H, Zhang GH, et al. Outcome of adenotonsillectomy for obstructive sleep apnea syndrome in children. Ann Otol Rhinol Laryngol. 2010;119(8):506–513pmid:20860275
  6. Cote CJ, Posner KL, and Domino KB. Death or Neurologic Injury After Tonsillectomy in Children with a Focus on Obstructive Sleep Apnea: Houston, We Have a Problem! Anesth Analg. 2014 Jun;118(6):1276-83. doi: 10.1213/ANE.0b013e318294fc47.

 

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