The effect of chronic methadone treatment on intra-uterine growth of the Cynomolgus monkey (Macaca fascicularis)

Hein, P.R.; Schatorjé, J.S.J.O.; Frencken, H.J.A.A.M.

doi:10.1016/s0028-2243(88)80014-5

Cited by 13 publications

(4 citation statements)

References 17 publications

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“…However, in the pregnant rat, methadone metabolism is rapid (terminal half-life: 3-5 hours) and once-daily dosing can result in daily maternal and offspring withdrawal [ 163 ]. To achieve clinically relevant blood levels (150-500 ng/ml) [ 101 , 135 ] in rats, a daily oral dose of approximately 12.5 mg/kg is required [ 166 ]. However, in most studies (Table 2 ), a daily dose of 5 mg/kg of methadone was administered maternally, indicating an apparent “under-dosing”.…”

Section: Animal Studiesmentioning

confidence: 99%

“…Decreased birthweights found in humans are consistent with animal studies which report that gestational methadone exposure reduces growth [ 99 , 166 , 256 , 410 ]. An early study on maternally administered methadone (10-13 mg/kg/day) in primates showed significantly reduced birthweights in the offspring [ 135 ]. In rat, a number of deleterious effects are associated with perinatal methadone exposure including increased mortality of mothers [ 167 ] and offspring [ 34 , 166 , 408 ], as well as low birthweights and growth retardation [ 41 , 166 , 257 , 408 ].…”

Section: Animal Studiesmentioning

confidence: 99%

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The Effects of Maternally Administered Methadone, Buprenorphine and Naltrexone on Offspring: Review of Human and Animal Data

Farid¹,

Dunlop

Tait³

et al. 2008

137

144

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Most women using heroin are of reproductive age with major risks for their infants. We review clinical and experimental data on fetal, neonatal and postnatal complications associated with methadone, the current "gold standard", and compare these with more recent, but limited, data on developmental effects of buprenorphine, and naltrexone. Methadone is a -opioid receptor agonist and is commonly recommended for treatment of opioid dependence during pregnancy. However, it has undesired outcomes including neonatal abstinence syndrome (NAS). Animal studies also indicate detrimental effects on growth, behaviour, neuroanatomy and biochemistry, and increased perinatal mortality. Buprenorphine is a partial -opioid receptor agonist and a -opioid receptor antagonist. Clinical observations suggest that buprenorphine during pregnancy is similar to methadone on developmental measures but is potentially superior in reducing the incidence and prognosis of NAS. However, small animal studies demonstrate that low doses of buprenorphine during pregnancy and lactation lead to changes in offspring behaviour, neuroanatomy and biochemistry. Naltrexone is a non-selective opioid receptor antagonist. Although data are limited, humans treated with oral or sustained-release implantable naltrexone suggest outcomes potentially superior to those with methadone or buprenorphine. However, animal studies using oral or injectable naltrexone have shown developmental changes following exposure during pregnancy and lactation, raising concerns about its use in humans. Animal studies using chronic exposure, equivalent to clinical depot formulations, are required to evaluate safety. While each treatment is likely to have maternal advantages and disadvantages, studies are urgently required to determine which is optimal for offspring in the short and long term.

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Section: Animal Studiesmentioning

confidence: 99%

Section: Animal Studiesmentioning

confidence: 99%

The Effects of Maternally Administered Methadone, Buprenorphine and Naltrexone on Offspring: Review of Human and Animal Data

Farid¹,

Dunlop

Tait³

et al. 2008

137

144

View full text Add to dashboard Cite

show abstract

“…This is concerning because the endogenous opioid system plays a key role in neurobiological development (Sargeant et al, 2008). Previous animal studies have shown that exposure to opioids during fetal or early life affects the migration and survival of neurons, leading to an overall inhibition of brain growth and development (Zagon and McLaughlin, 1977;Wu et al, 2001;Bajic et al, 2013), which may cause acute effects (Hutchings et al, 1979;Hein et al, 1988;Kunko et al, 1996) and longlasting neurobiological changes. Indeed, exposure to methadone or buprenorphine during development has caused impaired learning and memory (Zagon et al, 1979;Van Wagoner et al, 1980;Chen et al, 2015), anxiety and depression (Daly et al, 2012;Hung et al, 2013;Chen et al, 2015), and altered pain thresholds in adolescent and adult Fig.…”

Section: Discussionmentioning

confidence: 99%

High Accumulation of Methadone Compared with Buprenorphine in Fetal Rat Brain after Maternal Exposure

Kongstorp

Bogen

Stiris

et al. 2019

J Pharmacol Exp Ther

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Experimental animal studies are valuable in revealing a causal relationship between prenatal exposure to opioid maintenance treatment (OMT) and subsequent effects; however, previous animal studies of OMT during pregnancy have been criticized for their lack of clinical relevance because of their use of high drug doses and the absence of pharmacokinetic data. Hence, the aim of this study was to determine blood and brain concentrations in rat dams, fetuses, and offspring after continuous maternal exposure to methadone or buprenorphine during gestation and to examine the offspring for neonatal outcomes and withdrawal symptoms. Female rats were implanted with a 28-day osmotic minipump delivering methadone (10 mg/kg per day), buprenorphine (1 mg/kg per day) or vehicle 5 days before mating. Continuous exposure to methadone or buprenorphine induced stable blood concentrations in the dams of 0.25 6 0.02 mM and 5.65 6 0.16 nM, respectively. The fetal brain concentration of methadone (1.89 6 0.35 nmol/g) was twice as high as that in the maternal brain, whereas the fetal brain concentration of buprenorphine (20.02 6 4.97 pmol/g) was one-third the maternal brain concentration. The opioids remained in the offspring brain several days after the exposure ceased. Offspring prenatally exposed to methadone, but not buprenorphine, displayed reduced body weight and length and increased corticosterone levels. No significant changes in ultrasonic vocalizations were revealed. Our data in rat fetuses and neonates indicate that OMT with buprenorphine may be a better choice than methadone during pregnancy. SIGNIFICANCE STATEMENT Concern has been raised about the use of opioid maintenance treatment during pregnancy because of the important role of the endogenous opioid system in brain development. Here, we show that the methadone concentration in the fetal rat brain was twice as high as that in the maternal brain, whereas the buprenorphine concentration was one-third the maternal concentration. Furthermore, buprenorphine allowed more favorable birth outcomes, suggesting that buprenorphine may be a better choice during pregnancy.

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“…Low birth weight persists even controlling for maternal nutrition, antenatal care and additional drugs and appears to be a direct opiate effect [15]. Women using methadone as their sole drug of use are reported to have higher birth weight babies than women using heroin, but these in fact are still of lower birth weight than those born to drug-free mothers [16].…”

Section: Pharmacology O F Drugmentioning

confidence: 99%

Pregnancy and Drug Abuse: Complications and Management Issues

Gerada¹

1995

Eur Addict Res

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In the UK notification of male opiate use has increased by 200% over the last two decades and that for female opiate use by 500%. As the number of women using drugs increases so does the number becoming pregnant, too. It beholds all health professionals to be able to identify and help the pregnant drug user wherever she presents for care. This article reviews the complications of and management issues related to drug use in pregnancy.

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The effect of chronic methadone treatment on intra-uterine growth of the Cynomolgus monkey (Macaca fascicularis)

Cited by 13 publications

References 17 publications

The Effects of Maternally Administered Methadone, Buprenorphine and Naltrexone on Offspring: Review of Human and Animal Data

The Effects of Maternally Administered Methadone, Buprenorphine and Naltrexone on Offspring: Review of Human and Animal Data

High Accumulation of Methadone Compared with Buprenorphine in Fetal Rat Brain after Maternal Exposure

Pregnancy and Drug Abuse: Complications and Management Issues

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