Most neonatologists caring for passively opiate-addicted children are faced with the problem of preventing morbidity and mortality due to spontaneous withdrawal after birth (or in utero). Better antenatal care and prudent use of methadone in maintenance programs, better nutrition of the pregnant addicts and gradual withdrawal of neonates appears to minimize risk of severe complications but an expanding preclinical literature suggests that neurochemical and/or functional (e.g. behavioral) deficits may attend opiate exposure during development. We believe that many of these preclinical studies with methadone are flawed by experimental designs which have not taken into account such factors as acute toxicity (respiratory depression, postural rigidity, even death) and endocrinological dysfunction in pregnant subjects (usually rats) treated for the first time shortly before or after pregnancy is initiated. Inadequate dosing schedules (usually once per day) of methadone in rodents conveys neither tolerance to the toxic effects or stable dependence wherein pregnant subjects (and/or fetuses) do not experience intermittent withdrawal between doses. Our studies with 1-Alpha-acetylmethadol (LAAM) or its active metabolities indicates that prenatal and/or postnatal toxicity or withdrawal may be more responsible for congenital changes than is continued maintenance on otherwise nontoxic, dependence-inducing opiate treatment. We propose to continue our studies with LAAM and compare and contrast them with subjects exposed or withdrawn from various methadone treatment schedules, some used by other laboratories and a schedule developed in my laboratory which I believe will more closely resemble a model for clinical methadone maintenance exposure of pregnant subjects and their offspring. Neurochemical (RNA, DNA, ornithine, decarboxylase, transmitters, receptors) endocrinological (pituitary-adrenal) and behavioral (unconditioned and conditioned) variables will be assessed in offspring exposed to various treatment and withdrawal schedules, including withdrawl of neonates treated with clonidine or mianserin. These studies will allow us to determine which effects are directly attributable to opiate maintenance, toxicity or withdrawal. It will allow us to more assuredly interpret the preclinical and clinical literature and give us some insight into the potential benefits or risks associated with treating spontaneously withdrawing neonates with supplemental opiate therapy, clonidine both of which have been used clinically, or mianserin the latter without knowledge of its potential effects upon developing organisms.
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