Prenatal Methadone Exposure and Neonatal Neurobehavioral Functioning

Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Pediatric Research (Impact Factor: 2.31). 09/2009; 66(6):704-9. DOI: 10.1203/PDR.0b013e3181bc035d
Source: PubMed


Opioid-exposed infants display a wide and variable range of dysregulated neurobehavioral functioning, but the regulatory difficulties experienced by these infants outside the defined clusters of neonatal abstinence syndrome (NAS) have not been well described and may have implications for the infant's developmental course. This study describes the neurobehavioral functioning of neonates prenatally exposed to methadone, using the NICU Network Neurobehavioral Scale (NNNS), and explores the relationships between maternal factors and infant functioning. The relationship between NNNS measures, NAS severity, and need for pharmacotherapy for NAS was also evaluated. Infants who required pharmacologic treatment for NAS showed more dysregulated behavior and signs of stress and abstinence as indicated by NNNS scores, but NNNS scores were not significantly correlated with maternal methadone dose. The determination of the range of the methadone-exposed infant's neurobehavioral repertoire could guide the optimal treatment of all such infants, particularly those requiring only nonpharmacologic care.

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    • "After birth, approximately half of all infants prenatally exposed to methadone or buprenorphine require medical treatment for neonatal abstinence syndrome (NAS; Jones, O'Grady, Johnson, Velez, & Jansson, 2010), characterized by excessive high-pitched crying, irritability, sleep-wake disturbances, alterations in tone and movement, feeding difficulties, gastrointestinal disturbances, autonomic dysfunction, and failure to thrive (Jansson & Velez, 2012). Infants suffering from NAS commonly display dysregulated behavior, high levels of stress, and have difficulty modulating arousal (Jones et al., 2010; Velez, Jansson, Schroeder, & Williams, 2009). Medical treatment is therefore often essential in order to prevent infant regulatory difficulties and subsequent long-term developmental problems. "
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    ABSTRACT: Although an increasing number of children are born with prenatal methadone or buprenorphine exposure, little is still known about the potential long-term effects of these opioids. The aim of this study was to investigate executive function (EF) in children of women in opioid maintenance therapy (OMT). A total of 66 children (aged 48-57 months) participated in the study, 35 of which had histories of prenatal methadone or buprenorphine exposure. EF was measured using a battery of neuropsychological tests and the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P). Results showed that children of women in OMT perform lower on tasks of short-term memory and inhibition compared to nonexposed children, which was mainly associated with lower maternal education and employment rate. The OMT group scored significantly lower on all EF tasks compared to the nonexposed group, although scores fell within the average range on all measures. The development of these children should be monitored to assess for the possible problem behaviors and to promote optimal outcomes.
    Child Neuropsychology 10/2014; 21(5):1-16. DOI:10.1080/09297049.2014.967201 · 2.42 Impact Factor
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    • "Maintenance treatment with methadone is the current recommended standard of care for opioid-dependent pregnant women, even though the µ-opioid receptor agonist has been shown to predispose the infants to develop symptoms of neonatal abstinence syndrome which is characterized by autonomic and central nervous system hyperactivity, often with associated gastrointestinal tract and respiratory system dysfunction [1], [2]. Buprenorphine, a semisynthetic opioid derivative, which acts as a partial agonist at the µ-opioid receptor and as an antagonist at κ- and δ-opioid receptors [3], was approved by the U.S. Food and Drug Administration in 2002 for the management of opioid dependence in non-pregnant patients, although it has been available for many years to treat pain. "
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    ABSTRACT: Studies indicate that perinatal opioid exposure produces a variety of short- and long-term neurobehavioral consequences. However, the precise modes of action are incompletely understood. Buprenorphine, a mixed agonist/antagonist at the opioid receptors, is currently being used in clinical trials for managing pregnant opioid addicts. This study provides evidence of depression-like consequence following prenatal exposure to supra-therapeutic dose of buprenorphine and sheds light on potential mechanisms of action in a rat model involving administration of intraperitoneal injection to pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days. Results showed that pups at postnatal day 21 but not the dams had worse parameters of depression-like neurobehaviors using a forced swimming test and tail suspension test, independent of gender. Neurobehavioral changes were accompanied by elevation of oxidative stress, reduction of plasma levels of brain-derived neurotrophic factor (BDNF) and serotonin, and attenuation of tropomyosin-related kinase receptor type B (TrkB) phosphorylation, extracellular signal-regulated kinase (ERK) phosphorylation, protein kinase A activity, cAMP response element-binding protein (CREB) phosphorylation, and CREB DNA-binding activity. Since BDNF/serotonin and CREB signaling could orchestrate a positive feedback loop, our findings suggest that the induction of oxidative stress, reduction of BDNF and serotonin expression, and attenuation of CREB signaling induced by prenatal exposure to supra-therapeutic dose of buprenorphine provide evidence of potential mechanism for the development of depression-like neurobehavior.
    PLoS ONE 12/2013; 8(12):e82262. DOI:10.1371/journal.pone.0082262 · 3.23 Impact Factor
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    • "For example, there are concerns regarding the lack of rigorous psychometric testing to establish reliability and validity as well as the lengthy training and administration times required to accurately administer most observer-rated scales (American Academy of Pediatrics, 1998; Jones, 2011; O'Brien et al., 2004). Increasing calls for the development of more objective and sensitive measures of NAS (Jones, 2011; O'Brien et al., 2004; Velez et al., 2009) prompted us to investigate pupil diameter as a potential marker of infant response to opioid administration. "
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    ABSTRACT: Pupil diameter is a frequently assessed objective index of the pharmacodynamic effects of opioids in adults, but to our knowledge has never been examined in infants. Such a measure could improve assessment and treatment of neonates exposed to opioids in utero. The present study examined changes in pupil diameter after opioid administration in opioid-exposed infants who required pharmacological treatment for neonatal abstinence syndrome (NAS) to test the feasibility of using pupil diameter as a measure of opioid effects in these infants. Ten infants (2-7days old) receiving methadone (0.4-0.5mg every 12h) for the treatment of NAS participated. A picture of one of each infant's eyes was taken under controlled illumination conditions with a standard digital camera just prior to dosing and 0-1, 2-4, 5-7, and 8-10h after dosing. The diameters of the pupil and iris were measured and relative pupil diameter (pupil diameter expressed as a percentage of iris diameter) was analyzed. Mean (±SE) relative pupil diameter decreased significantly after dosing from 41±2% to 29±2%. After dosing, a significant increasing linear trend was observed over time, with values of 29±2%, 33±3%, 38±3%, and 41±3% at 0-1, 2-4, 5-7, and 8-10h after dosing. Infant pupils respond to opioid administration in the same sensitive, orderly manner as is commonly observed in adults. Pupil diameter appears to be an objective, sensitive measure of neonatal response to opioids that may be a useful complement to, or perhaps at times a replacement for, observer-rated scale scores.
    Drug and alcohol dependence 06/2012; 126(1-2):268-71. DOI:10.1016/j.drugalcdep.2012.05.006 · 3.42 Impact Factor
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