Normally metabolized into codeine-6-glucuronide (50-70%) and norcodeine (10-15%). Codeine, codeine-6-glucuronide, and norcodeine have low affinity for the μ (mu) receptor.
However, the most active metabolite of codeine is morphine with 200x the affinity for the mu receptor as the codeine derivates. The problem is, people vary in its metabolism from 0-15% of codeine is metabolized to morphine.
Ok, codeine is lame at best, unpredictable at worst.
True. Unless you are hiding a genetic time bomb.
You're an ultra-rapid metabolizer.
Some people have multiple extra copies of the DNA sequence for the CYP2D6 enzyme. Ultra rapid metabolizers funnel a huge proportion of their codeine into morphine metabolism, resulting in a bolus of morphine, ending in apnea.
This combination is no better than placebo -- all of the risks, with no proven benefit. This combination is notoriously abused -- as purple drank or sizzurp. The rapper Pimp C died of this.
Speaking of cough syrups...
The AAP recommends no cough and cold preparations in children under age 6. They have not been adequately studied in young children, and are not recommended for treating the common cold.
What then? You gotta give me something, doctor!
In a study in the Archives of Pediatric and Adolescent Medicine, Dr Paul and colleagues published: Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents. They compared a buckwheat honey, honey-flavored dextromethorphan (DM) and no treatment 30 min before bed for children with upper respiratory tract infections.
Of the three, honey, dextromethorphan, and no treatment – honey scored the best for symptom improvement and cough frequency.
Over age 1? Cough and cold? Honey. There is no concern about accidental overdose, parents are doing something with a proven effect, and compliance is pretty much 100% -- and Grandma approves.
No proven benefit over placebo. Also widely abused, in pill form ("Skittles") and/or liquid form mixed in alcoholic beverage ("robotripping").
Allow the child to speak for himself whenever possible. After acknowledging the parent’s input, perhaps try “I want to make sure I understand how the pain is for you. Tell me more.”
Engage parents and communicate the plan to them. Elicit their expectations, and give them of preview of what to expect in the ED.
Opioids are meant for pain caused by acute tissue injury, for the briefest period of time feasible. Older school-aged children and adolescents are increasingly at risk for opioid dependence and addiction.
Give detailed advice on how to manage pain at home. Set expectations. Let them know you understand and will help them through your good advice that will carry them through this difficult time. Patients and families often just need a plan. Map it out clearly.
Just say no to: codeine, promethazine with codeine, and dextramethorphan.
Dhaliwal G, Hsu D. Tramadol Ultra Rapid Metabolizers at Risk for Respiratory Depression. Pain Physician. 2016; 19(2):E361.
European Medicines Agency. Restriction on the use of codeine for pain relief in children—CMDh endorses PRAC recommendation [press release]. June 28, 2013.
FDA. Most Young Children With a Cough or Cold Don't Need Medicine.
Hartling L et al. How Safe Are Common Analgesics for the Treatment of Acute Pain for Children? A Systematic Review. Pain Res Manag. 2016; 2016: 5346819.
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923.
Jin J. Risks of Codeine and Tramadol in Children. JAMA. 2017 Oct 17;318(15):1514. doi: 10.1001/jama.2017.13534.
Kelly LE et al. More Codeine Fatalities After Tonsillectomy in North American Children. Pediatrics. 2012; 129(5).
Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7(4):257–265
Orliaguet G et al. A Case of Respiratory Depression in a Child With Ultrarapid CYP2D6 Metabolism After Tramadol. Pediatrics. 2015; 135(3).
Poonai N. Analgesia for children in acute pain in the post-codeine era. Curr Pediatr Rev. 2017 Aug 28. doi: 10.2174/157339631366617082911563.1.
This post and podcast are dedicated to Bryan Hayes, PharmD for his practical approach to pharmacologic conundrums and to David Juurlink, MD, PhD for his steadfast dedication to patient safety and clinician education. Check out Bryan's helpful blog and clinical resource, PharmERToxGuy. Check out David anywhere one utters the word Tra-ma-dol.