We read with interest the recent review on opioid-induced respiratory depression (OIRD) in paediatrics by Niesters and colleagues. We would like to comment on buprenorphine toxicity in children and suggest an additional OIRD pattern to those identified in this review. Buprenorphine is a partial agonist with high affinity and slow dissociation at the µ-opioid receptors. However, despite its ceiling respiratory effects, poisonings with typical opioid syndrome and asphyxia-related fatalities were attributed to intentional and accidental buprenorphine ingestions in children. The incidence of such overdoses is increasing in relation to increased prescriptions and availability and also to the similarity to candy of the current formulations. Although exposures to buprenorphine are generally well tolerated in children, significant OIRD may occur in 7–56% of the cases. Concerns about increased vulnerability of children in comparison with adults has been raised, when linking clinical severity to ingested doses. Consequently, referral to hospital for a minimum of 6 h observation was recommended for any child ingesting >2 mg buprenorphine and any <2-yr-old child ingesting more than a lick or taste. Several opioids are substrates of P-glycoprotein (P-gp), a well-known ATP-binding cassette transporter, that alters their pharmacokinetics and subsequently increase their toxicity. Regarding buprenorphine, P-gp plays a key-protective role against its toxicity by allowing the efflux at the blood–brain barrier of norbuprenorphine, its main metabolite that exhibits a potent respiratory depressant activity. Therefore, decreased P-gp expression or function may represent a risk factor of OIRD. Consistently, a developmental age-related increase in P-gp activity was reported in newborns and infants Such a mechanism and additional P-gp gene polymorphism or inhibition related to drug–drug interactions may explain children's vulnerability to opioids as suggested for buprenorphine and assessed for loperamide used to treat diarrhoea. In conclusion, we support Niesters and colleagues' approach to describe patterns of opioid toxicity in paediatrics, in order to improve OIRD prevention. Based on increasing published data, P-gp's role in opioid toxicity should be acknowledged and its altered activity considered as an additional pattern leading to OIRD in paediatrics, like for instance with buprenorphine
British Journal of Anaesthesia.
2013.
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