Abstract
Children represent a vulnerable population in which management of nociceptive pain is complex. Drug responses in children differ from adults due to age-related differences. Moreover, therapeutic choices are limited by the lack of indication for a number of analgesic drugs due to the challenge of conducting clinical trials in children. Furthermore the assessment of efficacy as well as tolerance may be complicated by children’s inability to communicate properly. According to the World Health Organization, weak opioids such as tramadol and codeine, may be used in addition to paracetamol and ibuprofen for moderate nociceptive pain in both children and adults. However, codeine prescription has been restricted for the last 5 years in children because of the risk of fatal overdoses linked to the variable activity of cytochrome P450 (CYP) 2D6 which bioactivates codeine. Even though tramadol has been considered a safe alternative to codeine, it is well established that tramadol pharmacodynamic opioid effects, efficacy and safety, are also largely influenced by CYP2D6 activity. For this reason, the US Food and Drug Administration recently released a boxed warning regarding the use of tramadol in children. To provide safe and effective tramadol prescription in children, a personalized approach, with dose adaptation according to CYP2D6 activity, would certainly be the safest method. We therefore recommend this approach in children requiring chronic or recurrent nociceptive pain treatment with tramadol. In case of acute inpatients nociceptive pain management, prescribing tramadol at the minimal effective dose, in a child appropriate dosage form and after clear instructions are given to the parents, remains reasonable based on current data. In all other situations, morphine should be preferred for moderate to severe nociceptive pain conditions.
Highlights
Effective pain management in children is essential but various factors make it difficult to achieve
Unlike the European Medicines Agency (EMA), the FDA recently released a boxed warning regarding the use of tramadol in children who are obese, or have obstructive sleep apnea or severe lung disease, and made recommendations not to use tramadol in children younger than 12 years and in children younger than 18 years after ear-noseand-throat (ENT) surgery (US Food and Drug Administration, 2017)
It has been shown that CYP2D6 poor metabolizers (PM) have up to two times lower analgesic response rate (Pedersen et al, 2006; Stamer et al, 2007) and higher tramadol and/or rescue medication consumption after surgery (Stamer et al, 2003, 2007; Slanar et al, 2012)
Summary
Effective pain management in children is essential but various factors make it difficult to achieve. His M1 concentration (24 μg/mL) was higher than expected (Vandenbossche et al, 2015, 2016), and genotyping showed that he was an UM for CYP2D6 (Orliaguet et al, 2015) Both tramadol and codeine are prodrug opioids bioactivated by CYP2D6 to exert their opioid analgesic effect, and changes in CYP2D6 activity (drug–drug interactions or genetic polymorphisms) have been shown to significantly alter the efficacy and safety of tramadol. This will, not always be sufficient to ensure safe and effective pain management and two alternative scenarios should be currently considered: (1) a personalized approach, which implies to identify patients at risk for “over or under response” and to adapt the dose according to CYP2D6 activity in order to preserve safe and effective use of tramadol; and (2) the choice of an alternative analgesic molecule.
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