2 approach usually follows with the aim to titrate medication to an optimal level at which symptoms are controlled. Once eﬀective levels are reached, a weaning process follows which can last from a few days to several months. 3. Duration of Opiate Treatment for Neonatal Withdrawal Length of pharmacological treatment for weaning depends on several factors, such as the maximum dose required or individual withdrawal patterns. It also varies, quite signiﬁcantly, with the type of weaning strategy employed. For example, rapid weaning involves dose reduction several times per week depending on tight and frequent assess- ments for withdrawal symptoms. Rapid weaning is generally performed in hospital and can be quite work intensive for nursing staﬀ, parents and carers. On the other hand, slow weaning has become a more frequent practice, with a weekly or fortnightly dose reduction occurring in the home setting. Slow weaning is often used with the rationale of minimising the disruption to maternal-infant bonding by allowing a more gradual reduction of opiates in the home environment, as well as the advantage of reduced costs. The downside of slow weaning, however, is the potential for more prolonged exposure to either opiates or barbiturates and increased cumulative doses in early infancy. From our own review of 232 cases, the average length of treatment was 49 days for those patients managed in the home setting versus 23 days for in patient weaning. It is important to note that this increased postnatal pharmacological exposure is in addition to the already prolonged exposure to opiates or other illicit drugs whilst in utero. At this stage, there is no data to guide choice of one strategy over another (i.e., rapid versus slow weaning). Therefore, choice of weaning strategy remains subject to the resources and services available at diﬀerent centres [25, 33]. As a result, the risks of prolonged and increased total cumulative pharmacological exposure to opiates require some attention, particularly given the growing body of evidence that argues against opiates as an inert substance for neurodevelopment. 4. Effects of Opiates on the Developing Central Nervous System Opiates exhibit signiﬁcant eﬀects on the growing brain. This includes direct dose-dependent eﬀects on reduc- tion in brain size and weight, protein, DNA, RNA, and neurotransmitters—possibly as a direct consequence of a number of opiate-mediated systems that inﬂuence neural cell diﬀerentiation, proliferation, and apoptosis [32]. The animal evidence also suggests that these adverse eﬀects on central nervous system development translate into abnormalities in later animal neurodevelopment and behaviour [34–39]. More speciﬁcally opiates appear to interfere with the GABAergic system. While in the mature brain the primary role of the GABAergic system is inhibition, in the immature brain the GABAergic system is predominantly excitatory, a International Journal of Pediatrics function required for normal brain development. Chronic opiate exposure in utero and in the perinatal period can interfere with normal GABA system development and inﬂu- ence brain excitability and seizure susceptibility [35, 40]. Excessive excitation of brain cells—excitotoxicity—is a well established mechanism of cell injury and death, resulting from an imbalance between excitatory and inhibitory signals. Furthermore, the switch in GABA function is regulated by certain transporter proteins, which have been implicated in excessive excitation and opiate addiction [41]. Superimposed on an already excitatory and compro- mised environment, prolonged treatment with medications that enhance inhibition in a mature brain could para- doxically lead to potentially damaging levels of excitation in a developing newborn brain. Some evidence of poten- tial adverse eﬀects due to enhanced GABAergic activation includes recent association with impaired cognitive function at 3 years and in utero exposure to valproic acid—an agent that directly targets the GABA system [42]. 5. Clinical Evidence for Adverse Effects of Opiates in Early Life Although animal data strongly suggests adverse neurode- velopmental outcomes due to opiate exposure in early life, clinical data in humans remains insuﬃcient, conﬂicting, and inconclusive [28, 43–48]. So far there is little clinical evidence to support either harmful or benign long-term eﬀects of opiate exposure in utero or the perinatal period. However, the great challenge here is to diﬀerentiate between harms directly due to opiates [32, 46, 47, 49] and indirect eﬀects associated with the medical and social complications that cooccur with illicit drug use [2, 43–45, 50, 51]. Many studies do not control for social variables, such as socioeconomic status, early childhood education, maternal education level, and income, home social and psychological environment or family stressors [49, 52–54]. Given the enormous social challenges that face children raised in a drug-exposed environment, it is not possible to draw any meaningful conclusion about the relationship between opiate exposure and harm without controlling for these variables. Some studies attempted to eliminate the social variables by matching children on social environment— for example, by comparing drug-exposed children raised in foster care to non-drug-exposed children [5, 49, 52–56]. However, this introduces additional confounders of foster parents who may be more educated and provide greater support to help overcome the initial adversity faced by the drug-exposed child [55]. In addition to social variables, there are numerous other potential maternal and neonatal confounders to match or statistically control for in order to make valid comparisons between exposed and nonexposed groups [44, 46, 47, 57– 59]. This includes, but is not limited to, confounders such as, maternal age, nutrition status, IQ and psychiatric history, neonatal birth weight, gestational age, perinatal compli- cations and congenital and developmental anomalies, and sources of bias, such as selection bias, for example, selecting children who are already suspected of developmental delay