June 1, 2014
by Michelle Wong, DDS
Codeine is the second-most widely used narcotic analgesic after morphine worldwide.1 Its use for over 200 years,2 availability of this medicine as an over-the-counter remedy for cough, acute and chronic mild-to-moderate pain, its reputation as a weak opioid, and use in pediatrics has fueled a perception of safety. Its recommended use as an analgesic in pediatrics has been debated,3 but now Health Canada and health professional experts no longer advocate it for pediatric practice.2–4
In the 1986 three-step analgesic ladder formulated by the World Health Organization (WHO), codeine constituted the second step for the progressive treatment of increasing pain, where this weak opioid could be used for breakthrough pain when nonsteroidal anti-inflammatories (NSAIDs) and acetaminophen were inadequate.5 In light of recent deaths and greater understanding of pharmacogenetics relating to codeine, agencies including the WHO and various health groups shifted preference from codeine to morphine.
On June 6, 2013, Health Canada released an update stating codeine was no longer recommended for children less than 12 years old based on rare cases of deaths.4 While Health Canada plans to implement new product labelling, changes in the guideline landscape may affect the availability of codeine as a pediatric medicine in the near future.
PHARMACOLOGY OF CODEINE
Codeine or 3-methylmorphine is a natural alkaloid found in the opium poppy Papaver somniferum. Although codeine can be extracted from natural sources, a semisynthetic process is the primary source of codeine for pharmaceutical use. Codeine is a weak opioid with low affinity for the µ-receptor and is 10 times less potent than morphine.2,3 In the body, the drug is metabolized in the liver by three ways: glucuronidation (50-70 percent), N-demethylation to norcodeine by CYP3A4 (10-20 percent) and O-demethylation to morphine by CYP2D6 (5-15 percent).1,5
PHARMACOENETICS AND VARIABILITY IN RESPONSE
The genetic variations or polymorphisms of the cytochrome P450 2D6 system (CYP2D6) account for the potential for the prodrug codeine to be subtherapeutic in poor metabolizers (PM), therapeutic in normal variants, and toxic in extensive (EM) and ultra-rapid metabolizers (UM) at recommended weight-appropriate doses. There is a gene-dose effect As the number of CYP2D6 gene copies increases, the amount of codeine converted to morphine increases.6 A patient with the CYP2D6 UM gene can produce 50 to 75 percent more morphine than a CYP2D6 EM.6 The high morphine serum levels observed in the EM and UM population results in an increased risk of adverse effects including sedation, CNS depression, respiratory depression, and overdose. Unfortunately, the clinical identification of these patients in the population is difficult. Although genetic testing is possible, it is not widely available as a screening tool. It is estimated that 40 percent in North Africa, 26 percent in Oceania, 12 percent in the Middle East, 8 percent in North America, and 3 percent in Europe and 2 percent in East Asia have the CYP2D6 UM genotype.1,2
Recent morbidity and mortality case reports occurring after children received conventional recommended doses of 1 to 3 mg/kg/day are presented in Table 1. These extensive and ultra-rapid metabolizers were found to have morphine serum concentration levels greatly exceeding the therapeutic range of 4.5 +/– 2.1 ng/mL.6 In addition to having elevated morphine levels, these were obstructive sleep apnea (OSA) patients who were prone to increased sensitivity to the respiratory depressant effects of opioids. The mechanism is believed to be the upregulation of µ-receptors secondary to chronic minor hypoxemic events and elevated partial pressures of carbon dioxide in these patients.7
In contrast to ultra-rapid metabolizers being at risk of opioid toxicity, there are poor metabolizers that are reported to be one percent to 30 percent of the population.9 It is estimated that 7-10 percent of Caucasians, 2 percent of Asians, and 1 percent of Arabs are slow metabolizers, meaning codeine is ineffective in these individuals.3
The World Health Organization has revised the analgesic ladder for pediatrics in 2012.9 In these guidelines, they recommend a two-step strategy (Fig. 1). The first step in pediatric pain management addresses mild pain which can be treated with nonopioids: acetaminophen or Ibuprofen. For moderate-to-severe pain, morphine is added to the regimen. Recommended doses are shown in Table 2. Titration of morphine appropriately addresses the spectrum of moderate-to-severe pain. Toronto’s Hospital for Sick Children has adopted this practice and has removed codeine from its formulary.2
Dentists may be wary of prescribing morphine because it has been historically classified as a “strong” opioid. Unlike the prodrug codeine which has uncertain and unpredictable metabolism and response, clinicians must understand that morphine is very predictable in its pharmacokinetic and pharmacodynamics profile.9 Community prescribers can use morphine for breakthrough pain when nonopioids are given round-the-clock. It is recommended to start with low doses and titrate to effect. If pain is not sufficiently addressed in the prescribed regimen, the dosage needs to be increased in steps of no more than 50 percent per 24 hours with possible considerations for sustained-release morphine formulations.9 Treatment with strong opioids needs to be individually adjusted. There is no fixed maximum dosage.9 Opioid use for dental pain is usually of short duration, therefore concerns about physical dependence is unsupported.10 The American Academy of Pediatric Dentistry states that opioids should be considered for moderate-to-severe dental pain.10
Codeine’s role in pediatric practice is diminishing. Recent morbidity and mortality cases resulting from codeine use have led to revised recommendations to use morphine instead. Prescribing morphine at recommended doses yields predictable metabolism and response which will provide adequate analgesia and safety for pediatric dental patients. OH
Dr. Michelle Wong will complete her MSc in dental anaesthesia by September 2014. In addition to joining the teaching staff in the graduate dental anaesthesia program at the University of Toronto, she will provide anaesthesia services in Toronto and the surrounding area. For inquiries, she may be reached at firstname.lastname@example.org
1. Madadi P, Koren G
. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics. 2008;9(9):1267–1284. Available at: http://www.futuremedicine.com/doi/abs/10.2217/14622422.214.171.1247. Accessed October 26, 2013.
2. MacDonald N, MacLeod SM. Has the time come to phase out codeine? CMAJ. 2010;182(17):1825. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2988526&tool=pmcentrez&rendertype=abstract. Accessed October 25, 2013.
3. Tremlett M, Anderson BJ, Wolf A. Pro-con debate: is codeine a drug that still has a useful role in pediatric practice? Pediatr. Anesth. 2010;20(2):183–94. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20059720. Accessed July 19, 2012.
4. Health Canada. Health Canada’s review recommends codeine only be used in patients aged 12 and over–Recalls & alerts–Healthy Canadians Website. 2013. Available at: http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2008/14526a-eng.php.
5. Williams D, Hatch D, Howard R. Codeine phosphate in paediatric medicine. Br. J. Anaesth. 2001;86(3):413–421. Available at: http://web.unife.it/utenti/giampaolo.garani/Sedazione-Farmaci/Articoli Dolore/Codeina/Codeine phosphate in paediatric medicine — Williams et al_ 86 (3) 413 — British Journal of Anaesthesia.pdf. Accessed October 26, 2013.
6. Kelly LE, Rieder M, van den Anker J, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012;129(5):e1343–7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22492761. Accessed October 25, 2013.
7. Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N. Engl. J. Med. 2009;361(8):827–828. Available at: http://www.nejm.org/doi/full/10.1056/NEJMc0904266. Accessed October 26, 2013.
8. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant–an ultra-rapid metabolizer. Paediatr. Anaesth. 2007;17(7):684–7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17564651. Accessed October 25, 2013.
9. World Health Organization. WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses.; 2012:1–172. Available at: http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:WHO+guidelines+on+the+pharmacological+treatment+of+persisting+pain+in+children+with+medical+illnesses#0. Accessed October 25, 2013.
10. American Academy of Pediatric Dentistry. Policy on Pediatric Pain Management. Am. Acad. Pediatr. Dent. 2012:1–4.
11. Coté CJ, Lerman J, Todres ID. A Practice of Anesthesia for Infants and Children. Philadelphia: Elsevier Health Sciences; 2009.