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Translational Psychiatry May 2023Opioid use disorder (OUD) among pregnant women has become an epidemic in the United States. Pharmacological interventions for maternal OUD most commonly involve...
Opioid use disorder (OUD) among pregnant women has become an epidemic in the United States. Pharmacological interventions for maternal OUD most commonly involve methadone, a synthetic opioid analgesic that attenuates withdrawal symptoms and behaviors linked with drug addiction. However, evidence of methadone's ability to readily accumulate in neural tissue, and cause long-term neurocognitive sequelae, has led to concerns regarding its effect on prenatal brain development. We utilized human cortical organoid (hCO) technology to probe how this drug impacts the earliest mechanisms of cortico-genesis. Bulk mRNA sequencing of 2-month-old hCOs chronically treated with a clinically relevant dose of 1 μM methadone for 50 days revealed a robust transcriptional response to methadone associated with functional components of the synapse, the underlying extracellular matrix (ECM), and cilia. Co-expression network and predictive protein-protein interaction analyses demonstrated that these changes occurred in concert, centered around a regulatory axis of growth factors, developmental signaling pathways, and matricellular proteins (MCPs). TGFβ1 was identified as an upstream regulator of this network and appeared as part of a highly interconnected cluster of MCPs, of which thrombospondin 1 (TSP1) was most prominently downregulated and exhibited dose-dependent reductions in protein levels. These results demonstrate that methadone exposure during early cortical development alters transcriptional programs associated with synaptogenesis, and that these changes arise by functionally modulating extra-synaptic molecular mechanisms in the ECM and cilia. Our findings provide novel insight into the molecular underpinnings of methadone's putative effect on cognitive and behavioral development and a basis for improving interventions for maternal opioid addiction.
Topics: Humans; Female; Pregnancy; Infant; Methadone; Analgesics, Opioid; Opioid-Related Disorders; Substance Withdrawal Syndrome; Brain; Opiate Substitution Treatment
PubMed: 37147277
DOI: 10.1038/s41398-023-02397-3 -
BMC Medical Imaging Jan 2020Accidental ingestion or consumption of supra-therapeutic doses of methadone can result in neurological sequelae in humans. We aimed to determine the neurological... (Review)
Review
BACKGROUND
Accidental ingestion or consumption of supra-therapeutic doses of methadone can result in neurological sequelae in humans. We aimed to determine the neurological deficits of methadone-poisoned patients admitted to a referral poisoning hospital using brain magnetic resonance (MR) and diffusion weighted (DW) imaging.
METHODS
In this retrospective study, brain MRIs of the patients admitted to our referral center due to methadone intoxication were reviewed. Methadone intoxication was confirmed based on history, congruent clinical presentation, and confirmatory urine analysis. Each patient had an MRI with Echo planar T1, T2, FLAIR, and DWI and apparent deficient coefficient (ADC) sequences without contrast media. Abnormalities were recorded and categorized based on their anatomic location and sequence.
RESULTS
Ten patients with abnormal MRI findings were identified. Eight had acute- and two had delayed-onset encephalopathy. Imaging findings included bilateral confluent or patchy T2 and FLAIR high signal intensity in cerebral white matter, cerebellar involvement, and bilateral occipito-parietal cortex diffusion restriction in DWI. Internal capsule involvement was identified in two patients while abnormality in globus pallidus and head of caudate nuclei were reported in another. Bilateral cerebral symmetrical confluent white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both patients with delayed-onset encephalopathy.
CONCLUSIONS
Acute- and delayed-onset encephalopathies are two rare adverse events detected in methadone-intoxicated patients. Brain MRI findings can be helpful in detection of methadone-induced encephalopathy.
Topics: Adolescent; Adult; Brain Diseases; Child; Child, Preschool; Diffusion Magnetic Resonance Imaging; Disease Progression; Female; Humans; Male; Methadone; Radiographic Image Interpretation, Computer-Assisted; Retrospective Studies; White Matter; Young Adult
PubMed: 31952488
DOI: 10.1186/s12880-020-0410-9 -
The International Journal on Drug Policy Dec 2022The coronavirus pandemic resulted in many changes which had the potential to impact mortality related to opioid agonist therapy (OAT; methadone, buprenorphine),...
BACKGROUND
The coronavirus pandemic resulted in many changes which had the potential to impact mortality related to opioid agonist therapy (OAT; methadone, buprenorphine), including changes in the prescribing and dispensing of OAT and patterns of drug availability and use. We aimed to assess the impact of the first lockdown (initiated March 23rd 2020) on methadone- and buprenorphine-related deaths in England in people both prescribed and not prescribed OAT using data from the National Programme on Substance Abuse Deaths.
METHODS
This was a retrospective post-mortem toxicology study of OAT-related deaths which occurred in the 3-month period March 23rd to June 22nd in the years 2016-2020. Provisional data regarding numbers accessing treatment for opioid use disorder was provided by the National Drug Treatment Monitoring System.
RESULTS
We found a 64% increase in methadone-related deaths in March to June 2020 compared to March to June 2019 (2019 n = 96; 2020 projected n = 157). There were increases in the mortality rate of both in-treatment decedents (22% increase; 2019 n = 45; an exponential smoothing model of the 2016-19 trend [α=0.5] predicted 44 deaths in 2020, 55 were reported) and decedents not prescribed methadone (74% increase; 2019 n = 46; 2016-19 trend predicted 43 deaths in 2020, 80 were reported). There was no increase in buprenorphine-related deaths (2019 n = 9/529; 2020 n = 11/566). There were no changes in the numbers of deaths where other opioids or multiple substances were detected, or in methadone levels detected. Numbers of people accessing treatment for opioid use disorder in 2020 did not decrease relative to previous years (p >0.05).
CONCLUSIONS
Methadone-related deaths in non-prescribed individuals, but not prescribed individuals, increased considerably above the annual trend forecast for 2020 during the first COVID-19 lockdown in England. Further studies are thus needed to understand this difference.
Topics: Humans; Buprenorphine; Methadone; Analgesics, Opioid; Opiate Substitution Treatment; Retrospective Studies; Pandemics; COVID-19; Communicable Disease Control; Opioid-Related Disorders
PubMed: 36265326
DOI: 10.1016/j.drugpo.2022.103877 -
American Journal of Public Health Apr 2022
Topics: COVID-19; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders
PubMed: 35349324
DOI: 10.2105/AJPH.2021.306654 -
Developmental Medicine and Child... Sep 2021To examine the developmental outcomes of children born to opioid-dependent females enrolled in methadone maintenance and identify pre- and postnatal factors that place...
AIM
To examine the developmental outcomes of children born to opioid-dependent females enrolled in methadone maintenance and identify pre- and postnatal factors that place these children at developmental risk.
METHOD
Ninety-nine methadone-maintained females and their 100 infants (42 females, 58 males, mean gestational age 38.8wks) were recruited during pregnancy/at birth and studied to age 2 years alongside a regionally representative comparison group of 108 non-methadone-maintained females and their 110 infants (62 females, 48 males, mean gestational age 39.2wks). Information about perinatal exposure was collected from medical records, maternal urine and infant meconium toxicological analysis, maternal interviews (at birth and at 18mo), and a home visit (at 18mo). At age 2 years, child neuromotor function, cognition, language, and emotional/behavioral dysregulation were assessed.
RESULTS
Opioid-exposed children achieved lower motor, cognitive, and language scores and had poorer self, emotional, eating/feeding, and sensory processing regulation than unexposed children. After adjustment for maternal education and other substance use in pregnancy, between-group differences in child motor, cognitive, and overall dysregulation remained. Postnatal parental and family factors explained a further 40% to 52% of between-group differences in child outcomes.
INTERPRETATION
These children and families are extremely high-risk and need antenatal and postnatal support. Children exposed to opioids during pregnancy have pervasive developmental difficulties by age 2 years. These challenges are largely explained by adverse pregnancy and socio-environmental exposures, emphasizing the importance of specialist prenatal care and postnatal intervention support. What this paper adds Children born to opioid-dependent females are at high risk of pervasive developmental problems. These problems span a range of functional domains, including motor, cognitive, language, and behavioral/emotional dysregulation. Contributing factors include other adverse pregnancy exposures, postnatal environmental factors, and the direct effects of prenatal opioid exposure.
Topics: Adult; Child Development; Child, Preschool; Confounding Factors, Epidemiologic; Female; Humans; Infant; Infant, Newborn; Male; Maternal Exposure; Methadone; Mothers; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Young Adult
PubMed: 33462809
DOI: 10.1111/dmcn.14808 -
Molecules (Basel, Switzerland) Aug 2022The abuse of buprenorphine and methadone has grown into a rising worldwide issue. After their consumption, buprenorphine, methadone and their metabolites can be found in... (Review)
Review
The abuse of buprenorphine and methadone has grown into a rising worldwide issue. After their consumption, buprenorphine, methadone and their metabolites can be found in the human organism. Due to the difficulty in the assessment of these compounds by routine drug screening, the importance of developing highly sensitive analytical approaches is undeniable. Liquid chromatography tandem mass spectrometry is the preferable technique for the determination of buprenorphine, methadone and their metabolites in biological matrices including urine, plasma, nails or oral fluids. This research aims to review a critical discussion of the latest trends for the monitoring of buprenorphine, methadone and their metabolites in various biological specimens.
Topics: Buprenorphine; Chromatography, Liquid; Humans; Methadone; Tandem Mass Spectrometry
PubMed: 36014451
DOI: 10.3390/molecules27165211 -
Substance Use & Misuse 2022Illicit opioid use in pregnancy is associated with adverse maternal, neonatal, and childhood outcomes. Opioid substitution is recommended, but whether methadone or... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Illicit opioid use in pregnancy is associated with adverse maternal, neonatal, and childhood outcomes. Opioid substitution is recommended, but whether methadone or buprenorphine is the optimal agent remains unclear.
METHODS
We searched EMBASE, PubMed, Web of Science, Scopus, Open Gray, CINAHL and the Cochrane Central Registry of Controlled Trials (CENTRAL) from inception to April 2020 for randomized controlled trials (RCTs) and cohort studies comparing methadone and buprenorphine treatment for opioid-using mothers. Included studies assessed maternal and or neonatal outcomes. We used random-effects meta-analyses to estimate summary measures for outcomes and report these separately for RCTs and cohort studies.
RESULTS
Of 408 abstracts screened, 20 papers were included (4 RCTs, 16 cohort, 223 and 7028 participants respectively). All RCTs (4/4) had a high risk of bias and median (IQR) Newcastle Ottawa Scale for cohort studies was 7.5 (6-9). In both RCTs and cohort studies, buprenorphine was associated with; greater offspring birth weight (weighted mean difference [WMD] 343 g (95% CI: 40-645 g) in RCT and 184 g (95% CI: 121-247 g) in cohort studies); body length at birth (WMD 2.28 cm (95% CI: 1.06-3.49 cm) in RCTs and 0.65 cm (95% CI: 0.31-0.98 cm) in cohort studies); and reduced risk of prematurity (risk ratio [RR] 0.41 (95% CI: 0.18-0.93) in RCTs and 0.63 [95% CI: 0.53-0.75] in cohort studies) when compared to methadone. All other clinical outcomes were comparable.
CONCLUSIONS
Compared to methadone, buprenorphine was consistently associated with improved birthweight and gestational age, however given potential biases, results should be interpreted with caution.
Topics: Analgesics, Opioid; Buprenorphine; Child; Female; Humans; Infant, Newborn; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy
PubMed: 35758300
DOI: 10.1080/10826084.2022.2083174 -
The Journal of Pain Mar 2021Adequate analgesia can be challenging, as pharmacological options are not necessarily effective for all types of pain and are associated with adverse effects. Methadone...
Adequate analgesia can be challenging, as pharmacological options are not necessarily effective for all types of pain and are associated with adverse effects. Methadone is increasingly being considered in the management of both cancer-related and noncancer-related pain. The purpose of this article is to provide a narrative review of all available randomized controlled trials (RCTs) investigating the effectiveness of methadone in the management of pain, in relation to a comparison drug. The primary outcome was analgesic effectiveness, and the secondary outcomes were side effects and cost. A search of PubMed, Medline, Embase, and Google Scholar databases was conducted to identify eligible RCTs and methodologic quality was assessed. A total of 40 RCTs were included in this review. The majority compared methadone to morphine or fentanyl. Analgesic effectiveness of methadone was demonstrated in different types of pain, including postprocedural, cancer-related, nociceptive, and neuropathic pain. The evidence demonstrates that the use of methadone in postprocedural pain and in cancer-related pain may be dependent on the procedure and cancer type, respectively. Side effects experienced were generally similar to the comparison drug, and lower cost was a benefit to using methadone. Methadone may also be useful as an adjunctive analgesic for adequate pain control, as well as in patients with renal impairment. Additional high-quality, large-scale RCT evidence is needed to establish its role as monotherapy or as an adjunctive medication. Future research should also aim to standardize reported outcomes for measuring analgesic effectiveness to permit for pooled analysis across studies. PERSPECTIVE: This article presents a systematic review, which includes a summary of published RCTs investigating the effectiveness of methadone in the management of pain. This is important for determining its analgesic utility and for identifying gaps in existing knowledge.
Topics: Analgesics, Opioid; Cancer Pain; Humans; Methadone; Neuralgia; Nociceptive Pain; Outcome Assessment, Health Care; Pain Management; Randomized Controlled Trials as Topic
PubMed: 32599153
DOI: 10.1016/j.jpain.2020.04.004 -
CPT: Pharmacometrics & Systems... Oct 2021Methadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well-defined....
Methadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well-defined. The pharmacokinetics (PKs) of methadone is highly variable due to the variability in alpha-1 acid glycoprotein (AAG) and genotypic differences in drug-metabolizing enzymes. Additionally, the R and S enantiomers of methadone have unique PK and pharmacodynamic properties. This study aims to describe the PKs of R and S methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in pediatric surgical patients and to identify sources of inter- and intra-individual variability. Children aged 8-17.9 years undergoing orthopedic surgeries received intravenous methadone 0.1 mg/kg intra-operatively followed by oral methadone 0.1 mg/kg postoperatively every 12 h. Pharmacokinetics of R and S methadone and EDDP were determined using liquid chromatography tandem mass spectrometry assays and the data were modeled using nonlinear mixed-effects modeling in NONMEM. R and S methadone PKs were well-described by two-compartment disposition models with first-order absorption and elimination. EDDP metabolites were described by one compartment disposition models with first order elimination. Clearance of both R and S methadone were allometrically scaled by bodyweight. CYP2B6 phenotype was a determinant of the clearance of both the enantiomers in an additive gene model. The intronic CYP3A4 single-nucleotide polymorphism (SNP) rs2246709 was associated with decreased clearance of R and S methadone. Concentrations of AAG and the SNP of AAG rs17650 independently increased the volume of distribution of both the enantiomers. The knowledge of these important covariates will aid in the optimal dosing of methadone in children.
Topics: Adolescent; Analgesics, Opioid; Biological Variation, Individual; Biological Variation, Population; Child; Female; Humans; Intraoperative Care; Male; Methadone; Orthopedic Procedures; Pain Management; Pain, Postoperative; Pharmacogenomic Variants; Postoperative Care; Pyrrolidines; Stereoisomerism
PubMed: 34435753
DOI: 10.1002/psp4.12687 -
Paediatric Anaesthesia Mar 2023Postoperative pain control is essential to optimizing patient outcomes, improving satisfaction, and allowing patients to resume their baseline functional activities.... (Review)
Review
Postoperative pain control is essential to optimizing patient outcomes, improving satisfaction, and allowing patients to resume their baseline functional activities. Methadone, a synthetic mu-opioid agonist, has multiple pharmacologic properties that may be optimal for perioperative use. Compared to other opioids, methadone has a longer duration of action, rapid onset, extended dosing intervals, high oral bioavailability, low cost, lack of active metabolites, and action on multiple receptors. The current literature examining the use of methadone in the perioperative care of children and adolescents is limited and most often reported within the context of spine or cardiothoracic surgery. Overall, these studies support the hypothesis that perioperative methadone in pediatric patients may decrease postoperative pain, opioid consumption, length-of-stay, and the incidence of some opioid-related side effects, like constipation and urinary retention. A variety of protocols for the perioperative use of methadone have been described, including a single intraoperative dose as well as multiple small doses within multimodal pain protocols. The superiority of these protocols has not been established. Like all opioids, methadone has a side effect profile which includes nausea, vomiting, reduced GI motility, sedation, and respiratory depression at high doses. There is also a concern that it can cause QTc prolongation in patients. The primary aim of this educational review is to examine the pharmacologic data, published perioperative protocols, dosing considerations, and risks and benefits associated with inclusion of methadone in analgesic regimens for surgical patients. A secondary aim is to introduce opportunities for research around the perioperative use of methadone in children and adolescents. Based on our review, we would prioritize establishing optimal procedure-specific methadone protocols, determining generalizability for use in routine pediatric surgeries, and investigating methadone safety and efficacy prospectively as the primary opioid for pain management in the postanesthesia care unit or postsurgical floors.
Topics: Humans; Child; Adolescent; Methadone; Analgesics, Opioid; Analgesics; Pain, Postoperative; Pain Management; Drug-Related Side Effects and Adverse Reactions
PubMed: 36281540
DOI: 10.1111/pan.14584