Introduction and History of Opioid Tolerance

Information regarding opioid tolerance in the pediatric population is limited, and the information for treating pediatric opioid tolerance is extrapolated from the adult population (Shapiro et al. 1995). The majority of the literature on withdrawal syndromes and tolerance comes from the adult literature and is associated with opioidaddicted patients (Collett 1998; Anand and Arnold 1994). Opioid dependence and withdrawal was first described in the pediatric literature after babies were born to drug-addicted mothers in the late 1970s and early 1980s (Tobias 2000a; Landau 2006; Margas et al. 2007; Zhang et al. 2005; Finnegan et al. 1975). It was these initial findings and description of Neonatal Abstinence Syndrome (NAS) that led to valuable information still used today in our treatment of children requiring longterm opioid therapy for pain management or sedation (Finnegan et al. 1975). The origin of scoring systems to quantify symptoms of withdrawal and the pharmacologic treatment of children experiencing physiological withdrawal came from these early papers (Finnegan et al. 1975). It was not until 1990 that problems associated with dependency and withdrawal were identified in the PICU population in 37 neonates requiring extracorporeal membrane oxygenation (ECMO) for profound respiratory failure (Tobias 2000a; Arnold et al. 1991; Tobias 2005). These babies were on long-term intravenous fentanyl for sedation and pain management. Although the study goal was to look for signs and symptoms of NAS, upon examining these babies’ requirements for adequate sedation; the criteria for adequate sedation being that the child could be aroused, but was sedate otherwise; it was observed that the fentanyl dose requirement dramatically increased throughout their clinical course. Thus, tolerance was first described in the pediatric literature. Their mean fentanyl requirements rose from 11.6 ± 6.9 mcg/ kg/h on day 1 to 52.5 ± 19.4 mcg/kg/h on day 8 of their opioid therapy. In this same study, plasma fentanyl levels were measured in five babies, this revealed an increase in plasma fentanyl levels to maintain the same desired level of sedation. Tolerance was labeled as a pharmacodynamic process based on this information and the risk factors for development of tolerance, physical Sarah E. Rebstock, Jill M. Eckert, and Claude Abdallah