Neonatal neurobehavior effects following buprenorphine versus methadone exposure. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Management of neonatal abstinence syndrome in neonates born to opioid maintained women. Characteristics of Opioid-Using Pregnant Women Who Accept or Refuse Participation in a Clinical Trial: Screening Results from the MOTHER Study Peripartum pain management in opioid dependent women. A comparison of cigarette smoking profiles in opioid-dependent pregnant patients receiving methadone or buprenorphine. Lessons learned from a comparison of evidence-based research in pregnant opioid-dependent women. Infections and obstetric outcomes in opioid-dependent pregnant women maintained on methadone or buprenorphine. Methadone versus buprenorphine in pregnant addicts: a double-blind, double-dummy comparison study. Acute opioid withdrawal is associated with increased neural activity in reward-processing centers in healthy men: A functional magnetic resonance imaging study. Neonatal abstinence syndrome after methadone or buprenorphine exposure. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial Exercise during pregnancy enhances cerebral maturation in the newborn: A randomized controlled trial
AIM To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior . DESIGN Three sites from the Maternal Opioid Treatment : Human Experimental Research ( MOTHER ) study , a double-blind , double-dummy , r and omized clinical trial participated in this sub study . SETTING Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore , MD , Providence , RI and Vienna , Austria . PARTICIPANTS Thirty-nine full-term infants . MEASUREMENTS The Neonatal Intensive Care Unit ( NICU ) Network Neurobehavioral Scale ( NNNS ) was administered to a subgroup of infants on postpartum days 3 , 5 , 7 , 10 , 14 - 15 and 28 - 30 . FINDINGS While neurobehavior improved for both medication conditions over time , infants exposed in utero to buprenorphine exhibited fewer stress-abstinence signs ( P < 0.001 ) , were less excitable ( P < 0.001 ) and less over-aroused ( P < 0.01 ) , exhibited less hypertonia ( P < 0.007 ) , had better self-regulation ( P < 0.04 ) and required less h and ling ( P < 0.001 ) to maintain a quiet alert state relative to in utero methadone-exposed infants . Infants who were older when they began morphine treatment for withdrawal had higher self-regulation scores ( P < 0.01 ) , and demonstrated the least amount of excitability ( P < 0.02 ) and hypertonia ( P < 0.02 ) on average . Quality of movement was correlated negatively with peak NAS score ( P < 0.01 ) , number of days treated with morphine for NAS ( P < 0.01 ) and total amount of morphine received ( P < 0.03 ) . Excitability scores were related positively to total morphine dose ( P < 0.03 ) . CONCLUSION While neurobehavior improves during the first month of postnatal life for in utero agonist medication-exposed neonates , buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure OBJECTIVES To inform the debate over whether human sleep can be chronically reduced without consequences , we conducted a dose-response chronic sleep restriction experiment in which waking neurobehavioral and sleep physiological functions were monitored and compared to those for total sleep deprivation . DESIGN The chronic sleep restriction experiment involved r and omization to one of three sleep doses ( 4 h , 6 h , or 8 h time in bed per night ) , which were maintained for 14 consecutive days . The total sleep deprivation experiment involved 3 nights without sleep ( 0 h time in bed ) . Each study also involved 3 baseline ( pre-deprivation ) days and 3 recovery days . SETTING Both experiments were conducted under st and ardized laboratory conditions with continuous behavioral , physiological and medical monitoring . PARTICIPANTS A total of n = 48 healthy adults ( ages 21 - 38 ) participated in the experiments . INTERVENTIONS Noctumal sleep periods were restricted to 8 h , 6 h or 4 h per day for 14 days , or to 0 h for 3 days . All other sleep was prohibited . RESULTS Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days result ed in significant cumulative , dose-dependent deficits in cognitive performance on all tasks . Subjective sleepiness ratings showed an acute response to sleep restriction but only small further increases on subsequent days , and did not significantly differentiate the 6 h and 4 h conditions . Polysomnographic variables and delta power in the non-REM sleep EEG-a putative marker of sleep homeostasis -- displayed an acute response to sleep restriction with negligible further changes across the 14 restricted nights . Comparison of chronic sleep restriction to total sleep deprivation showed that the latter result ed in disproportionately large waking neurobehavioral and sleep delta power responses relative to how much sleep was lost . A statistical model revealed that , regardless of the mode of sleep deprivation , lapses in behavioral alertness were near-linearly related to the cumulative duration of wakefulness in excess of 15.84 h ( s.e . 0.73 h ) . CONCLUSIONS Since chronic restriction of sleep to 6 h or less per night produced cognitive performance deficits equivalent to up to 2 nights of total sleep deprivation , it appears that even relatively moderate sleep restriction can seriously impair waking neurobehavioral functions in healthy adults . Sleepiness ratings suggest that subjects were largely unaware of these increasing cognitive deficits , which may explain why the impact of chronic sleep restriction on waking cognitive functions is often assumed to be benign . Physiological sleep responses to chronic restriction did not mirror waking neurobehavioral responses , but cumulative wakefulness in excess of a 15.84 h predicted performance lapses across all four experimental conditions . This suggests that sleep debt is perhaps best understood as result ing in additional wakefulness that has a neurobiological " cost " which accumulates over time Neonates born to opioid-maintained mothers are at risk of developing  neonatal abstinence syndrome ( NAS ) , which often requires pharmacological treatment . This study examined the effect of opioid maintenance treatment on the incidence and timing of NAS , and compared two different NAS treatments ( phenobarbital versus morphine hydrochloride ) . Fifty-three neonates born to opioid-maintained mothers were included in this study . The mothers received methadone ( n=22 ) , slow-release oral morphine ( n=17 ) or buprenorphine ( n=14 ) throughout pregnancy . Irrespective of maintenance treatment , all neonates showed APGAR scores comparable to infants of non-opioid dependent mothers . No difference was found between the three maintenance groups regarding neonatal weight , length or head circumference . Sixty percent ( n=32 ) of neonates required treatment for NAS [ 68 % in the methadone-maintained group ( n=15 ) , 82 % in the morphine-maintained group ( n=14 ) , and 21 % in the buprenorphine-maintained group ( n=3 ) ] . The mean duration from birth to requirement of NAS treatment was 33 h for the morphine-maintained group , 34 h for the buprenorphine-maintained group and 58 h for the methadone-maintained group . In neonates requiring NAS treatment , those receiving morphine required a significantly shorter mean duration of treatment ( 9.9 days ) versus those treated with phenobarbital ( 17.7 days ) . Results suggest that morphine hydrochloride is preferable for neonates suffering NAS due to opioid withdrawal Background : Although concerns arise about the generalizability of results from R and omized Controlled Trials ( RCTs ) , few studies systematic ally examine this issue . Objectives : This study compared the characteristics of 427 opioid-using pregnant women who did ( n = 208 ) and did not consent ( n = 219 ) to enrollment in a multicenter clinical trial of agonist medications ( i.e. , the MOTHER study ) . Methods : Logistic regression models were used to compare consenters and non-consenters to examine the effect of screening variables on the likelihood of consenting . Results : Of nine characteristics examined , most differences did not reach statistical significance . Consenting participants were less likely than non-consenting women to be currently enrolled in a methadone maintenance program ( 74.5 % vs. 84.5 % , p = .01 ) . Conclusion and Scientific Significance : These data show that the recruited sample of drug-dependent pregnant women enrolled in an intensive RCT is representative of the larger population of treated opioid-dependent patients and supports the generalizability of r and omized controlled trials in this population Increased pain sensitivity and the development of opioid tolerance complicate the treatment of pain experiencedby opioid maintained pregnantwomenduring delivery and the perinatal period . The aim of the present study was to investigate differences in pain management of opioid maintained compared to nondependent pregnant women during delivery and the postpartum period . 40 deliveries of 37 opioid dependent women enrolled in a double-blind , double-dummy r and omized controlled trial ( RCT ) examining the safety and efficacy of methadone ( mean dose at the time of delivery = 63.89 mg ) and buprenorphine ( mean dose at the time of delivery = 14.05 mg ) during pregnancy were analyzed and participants were matched to a non-dependent comparison group of 80 pregnant women . Differences in pain management ( opioid and non-opioid analgesic medication ) during delivery and perinatal period were analyzed . Following cesarean delivery opioid maintained women received significantly less  opioid analgesics  ( day of delivery p = 0.038 ; day 1 : p = 0.02 ) ,  NSAIDs  were administered more frequently to opioid dependent patients than to the comparison group during cesarean section and on the third day postpartum . Significantly higher nicotine consumption in the group of opioid dependentwomenhad a strong influence onthe retrieved results , and might be considered as an independent factor of altered pain experience . Differences in pain treatment became evident when comparing opioid maintained women to healthy controls . These differences might be based on psychosocial consequences of opioid addiction along with the lack of an interdisciplinary consensus on pain treatment protocol s for opioid dependent patients INTRODUCTION Little is known about the relationship between cigarette smoking and agonist treatment in opioid-dependent pregnant patients . The objective of this study is to examine the extent to which cigarette smoking profiles differentially changed during the course of pregnancy in opioid-dependent patients receiving either double-blind methadone or buprenorphine .  Patients were participants in the international , r and omized controlled Maternal Opioid Treatment : Human Experimental Research ( MOTHER ) study . METHODS A sample of opioid-maintained pregnant patients ( 18 - 41 years old ) with available smoking data who completed a multisite , double-blind , double-dummy , r and omized controlled trial of  methadone ( n = 67 ) and buprenorphine ( n = 57 ) between 2005 and 2008 . Participants were compared on smoking variables based on opioid agonist treatment condition . RESULTS Overall , 95 % of the sample reported cigarette smoking at treatment entry . Participants in the two medication conditions were similar on pretreatment characteristics including smoking rates and daily cigarette amounts . Over the course of the pregnancy , no meaningful changes in cigarette smoking were observed for either medication condition . The fitted difference in change in adjusted cigarettes per day between the two conditions was small and nonsignificant ( β = -0.08 , SE = 0.05 , p = .132 ) . CONCLUSIONS Results support high rates of smoking with little change during pregnancy among opioid-dependent patients , regardless of the type of agonist medication received . These findings are consistent with evidence that suggests nicotine effects , and interactions may be similar for buprenorphine compared with methadone . The outcomes further highlight that aggressive efforts are needed to reduce/eliminate smoking in opioid-dependent pregnant women OBJECTIVES Lessons learned in research and treatment of opioid dependence demonstrate the need to include pregnant women in clinical trials . METHODS Two double-blind , double-dummy , r and omized controlled trials ( Pilot study , European sample ( † ) of MOTHER-trial ) comparing buprenorphine and methadone in opioid-dependent pregnant women were conducted . In both studies , participants received voucher-based incentives for attendance and completion of study assessment s. In the MOTHER trial , participants additionally received escalating voucher incentives for drug-free urine sample s. Neonatal abstinence syndrome was treated with oral morphine solution based on st and ardized modified Finnegan scores . RESULTS After a mean treatment period of 13.79 weeks in the Pilot study ( PS , n = 18 ) and 20.78 weeks in the MOTHER-trial ( MT , n = 41 ) , respectively ( p < 0.001 ) , PS patients delivered at mean doses of 14.00 mg buprenorphine/52.50 mg methadone and MT participants at 13.44 mg buprenorphine/63.68 mg methadone . Nonsignificant differences regarding dropout rates were found ( 22 % in PS versus 10 % in MT ) , but dropout was significantly earlier in the MT ( p = 0.013 ) . Significantly higher rates of concomitant consumption of opioids and benzodiazepines occurred in the PS compared with the MT ( p < 0.001 ) , however , with no significant differences in neonatal data between both setting s. CONCLUSIONS Early treatment enrolment combined with contingency management contributes to reduced illicit drug use throughout pregnancy , surprisingly without influencing neonatal outcome parameters AIMS To characterize infections and compare obstetric outcomes in opioid-dependent pregnant women who participated in a r and omized clinical trial comparing agonist medications , methadone and buprenorphine .  DESIGN Incidence of infections was identified as part of the screening medical assessment . As part of a planned secondary analysis , analysis of variance and polytomous logistic regressions were conducted on obstetric outcome variables using treatment r and omization condition ( maternal maintenance with either methadone or buprenorphine ) as the predictor variable , controlling for differences between study sites . SETTING Six United States sites and one European site that provided comprehensive treatment to opioid-dependent pregnant women . PARTICIPANTS Pregnant opioid-dependent women ( n = 131 ) who delivered while participating in the Maternal Opioid Treatment : Human Experimental Research ( MOTHER ) study . MEASUREMENTS Obstetric , infectious and other maternal medical complications captured by medical records , physical examination , blood tests and self-report . Neonatal medical complications captured by medical records . FINDINGS Hepatitis C was the most common infection ( 32.3 % ) , followed by hepatitis B ( 7.6 % ) and chlamydia ( 6.1 % ) among participants at study enrollment . Maternal methadone versus buprenorphine maintenance was associated with a higher incidence of preterm labor ( P = 0.04 ) and a significantly higher percentage of signs of respiratory distress in neonates at delivery ( P = 0.05 ) . Other medical and obstetric complications were infrequent in the total sample , as well as in both methadone and buprenorphine conditions . CONCLUSIONS Buprenorphine appears to have an acceptable safety profile for use during pregnancy AIMS To evaluate the efficacy and safety of methadone versus buprenorphine treatment in pregnant opioid-dependent women . DESIGN R and omized , double-dummy , double-blind , flexible-dosing comparison study . SETTING Addiction Clinic at the Medical University of Vienna , Austria . PARTICIPANTS Eighteen women were assigned r and omly to receive either methadone ( n = 9 ) or buprenorphine ( n = 9 ) during weeks 24 - 29 of pregnancy . After dropouts , data were available from 14 cases ( six in the methadone and eight in the buprenorphine group ) . INTERVENTION Sublingual buprenorphine tablets ( 8 - 24 mg/day ) or oral methadone solution ( 40 - 100 mg/day ) , with matched placebos . MEASUREMENTS Mothers : retention in treatment , urine toxicology and nicotine use . Neonates : Routine birth data , neonatal abstinence syndrome ( NAS ) in severity and duration . FINDINGS There was somewhat greater retention in the buprenorphine group but significantly lowered use of additional opioids in the methadone group ( P = 0.047).Neonates : There was earlier onset of NAS in neonates born to the methadone ( mean 60 hours ) than to the buprenorphine groups ( mean 72 hours after last medication ) ; 43 % did not require NAS-treatment with short treatment duration in both groups ( mean 5 days ) . CONCLUSION This preliminary study had limited power to detect differences but the trends observed suggest this kind of research is practicable and that further studies are warranted BACKGROUND Opioid analgesics are frequently prescribed for chronic pain . One expected consequence of long-term opioid use is the development of physical dependence . Although previous resting state functional magnetic resonance imaging ( fMRI ) studies have demonstrated signal changes in reward-associated areas following morphine administration , the effects of acute withdrawal on the human brain have been less well-investigated . In an earlier study by our laboratory , ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal . The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron . METHODS Ten participants were enrolled in this placebo-controlled , r and omized , double-blind , crossover study and attended three acute opioid withdrawal sessions . Participants received either placebo or ondansetron ( 8Ymg IV ) before morphine administration ( 10Ymg/70Ykg IV ) . Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan . Objective and subjective opioid withdrawal symptoms were assessed . RESULTS Imaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions , including the right pregenual cingulate , putamen , and bilateral cau date , and decreased neural activity in networks involved in sensorimotor integration . Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal . CONCLUSIONS This study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal . The fMRI acute opioid withdrawal model may serve as a tool for study ing opioid dependence and withdrawal in human participants BACKGROUND Methadone , a full mu-opioid agonist , is the recommended treatment for opioid dependence during pregnancy . However , prenatal exposure to methadone is associated with a neonatal abstinence syndrome ( NAS ) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction , which often requires medication and extended hospitalization . Buprenorphine , a partial mu-opioid agonist , is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy . METHODS We conducted a double-blind , double-dummy , flexible-dosing , r and omized , controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at eight international sites . Primary outcomes were the number of neonates requiring treatment for NAS , the peak NAS score , the total amount of morphine needed to treat NAS , the length of the hospital stay for neonates , and neonatal head circumference . RESULTS Treatment was discontinued by 16 of the 89 women in the methadone group ( 18 % ) and 28 of the 86 women in the buprenorphine group ( 33 % ) . A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group ( with 58 exposed to buprenorphine and 73 exposed to methadone ) showed that the former group required significantly less morphine ( mean dose , 1.1 mg vs. 10.4 mg ; P<0.0091 ) , had a significantly shorter hospital stay ( 10.0 days vs. 17.5 days , P<0.0091 ) , and had a significantly shorter duration of treatment for the neonatal abstinence syndrome ( 4.1 days vs. 9.9 days , P<0.003125 ) ( P values calculated in accordance with prespecified thresholds for significance ) . There were no significant differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events . CONCLUSIONS These results are consistent with the use of buprenorphine as an acceptable treatment for opioid dependence in pregnant women . ( Funded by the National Institute on Drug Abuse ; Clinical Trials.gov number , NCT00271219 . ) BACKGROUND The ORACLE I trial compared the use of erythromycin and /or amoxicillin-clavulanate ( co-amoxiclav ) with that of placebo for women with preterm rupture of the membranes without overt signs of clinical infection , by use of a factorial r and omised design . The aim of the present study --the ORACLE Children Study I -- was to determine the long-term effects on children of these interventions . METHODS We assessed children at age 7 years born to the 4148 women who had completed the ORACLE I trial and who were eligible for follow-up with a structured parental question naire to assess the child 's health status .  Functional impairment was defined as the presence of any level of functional impairment ( severe , moderate , or mild ) derived from the mark III Multi-Attribute Health Status classification system . Educational outcomes were assessed with national curriculum test results for children resident in Engl and . FINDINGS Outcome was determined for 3298 ( 75 % ) eligible children . There was no difference in the proportion of children with any functional impairment after prescription of erythromycin , with or without co-amoxiclav , compared with those born to mothers who received no erythromycin ( 594 [ 38.3 % ] of 1551 children vs 655 [ 40.4 % ] of 1620 ; odds ratio 0.91 , 95 % CI 0.79 - 1.05 ) or after prescription of co-amoxiclav , with or without erythromycin , compared with those born to mothers who received no co-amoxiclav ( 645 [ 40.6 % ] of 1587 vs 604 [ 38.1 % ] of 1584 ; 1.11 , 0.96 - 1.28 ) . Neither antibiotic had a significant effect on the overall level of behavioural difficulties experienced , on specific medical conditions , or on the proportions of children achieving each level in reading , writing , or mathematics at key stage one . INTERPRETATION The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at 7 years of age . FUNDING UK Medical Research Council ABSTRACT Accumulating research indicates that the regular practice of physical exercise is beneficial to the human brain . From the improvement of academic achievement in children to the prevention of Alzheimer ’s disease in the elderly , exercise appears beneficial across the developmental spectrum . Recent work from animal studies also indicates that a pregnant mother can transfer the benefits of exercise during gestation to her offspring ’s brain . Exercising pregnant rats give birth to pups that have better memory and spatial learning as well as increased synaptic density . To investigate whether this transfer from the pregnant mother to her child also occurs in humans , we conducted a r and omized controlled trial ( n = 18 ) and measured the impact of exercise during pregnancy on the neuroelectric response of the neonatal brain with electroencephalography ( EEG ) . Here we show that , compared to the newborns of mothers who were inactive during their pregnancy , the children of exercising pregnant women are born with more mature brains . This was measured with the infant slow positive mismatch response ( SPMMR ) , an electroencephalographic potential known to decrease in amplitude with age . The SPMMR reflects processes associated with brain maturation via its response to sound discrimination and auditory memory . In this study , the children of the mothers who exercised throughout their pregnancy  have a smaller SPMMR than the children of mothers who remained sedentary ( p = .019 ) . Our results demonstrate the impact regular exercise during pregnancy can have on the development of the human fetal brain
This meta- analysis showed no significant impairments , at a non-conservative significance level of p < 0.05 , for cognitive , psychomotor or observed behavioural outcomes for chronic intra-uterine exposed infants and pre-school children compared to non-exposed infants and children .
However , all domains suggested a trend to poor outcomes in infants/children of opioid using mothers .
Conclusions Chronic intra-uterine opioid exposed infants and pre-school children experienced no significant impairment in neurobehavioral outcomes when compared to non-exposed peers , although in all domains there was a trend to poorer outcomes .
Background It is assumed within the accumulated literature that children born of pregnant opioid dependent mothers have impaired neurobehavioral function as a consequence of chronic intrauterine opioid use .