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The New England Journal of Medicine Nov 2023
Topics: Humans; Methadone; Neoplasms; Opiate Substitution Treatment; Opioid-Related Disorders
PubMed: 38009604
DOI: 10.1056/NEJMp2310123 -
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 -
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 -
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 -
Balkan Medical Journal Aug 2020The opioid epidemic has emerged as a major health and social problem over the last few decades. An increasing number of patients with opioid use disorder are presenting... (Review)
Review
The opioid epidemic has emerged as a major health and social problem over the last few decades. An increasing number of patients with opioid use disorder are presenting for perioperative management. These patients are either on buprenorphine or methadone for the maintenance and treatment of opioid addiction or chronic pain. In the settings of acute pain, the optimal management of patients with opioid use disorder is challenging, and recovery can be jeopardized secondary to the unique pharmacology of these agents. The purpose of this narrative review is to summarize the existing studies on the perioperative management of patients who are using buprenorphine and methadone and provide guidance for the management of patients with opioid use disorder during the perioperative period.
Topics: Buprenorphine; Humans; Methadone; Pain Management; Perioperative Care
PubMed: 32407063
DOI: 10.4274/balkanmedj.galenos.2020.2020.5.2 -
The Journal of Clinical Psychiatry 2017Methadone is a standard treatment for opioid dependence in pregnancy; however, its impact on maternal corrected QT interval (QTc) has not been evaluated. We studied the...
BACKGROUND
Methadone is a standard treatment for opioid dependence in pregnancy; however, its impact on maternal corrected QT interval (QTc) has not been evaluated. We studied the association between methadone dose and enantiomer-specific plasma concentrations and QTc among pregnant and postpartum women and newborns. We assessed the relevance of QTc screening guidelines for pregnant women and infants.
METHODS
From 2006 to 2008, plasma methadone concentrations were measured during pregnancy, postpartum, and in cord blood in women treated for opioid dependence at a single treatment program. Electrocardiograms (ECGs) were obtained at peak methadone concentrations in mothers and within 48 hours of birth for infants. Pearson correlations were performed at each time point for QTc and R-methadone, S-methadone, and total methadone concentrations and ratio of R-methadone/S-methadone concentrations.
RESULTS
Mean (SD) daily methadone dose for the 25 women was 94.2 (39.1) mg during pregnancy and 112.5 (46.6) mg postpartum. During the third trimester, higher methadone dose and R-methadone concentration correlated with longer QTc (Pearson r = 0.67, P < .001 and Pearson r = 0.49, P = .02, respectively), while S-methadone concentration, R-methadone/S-methadone concentration ratio, and total methadone concentration did not. Postpartum, QTc did not significantly correlate with dose or enantiomer concentrations. Infant QTc did not correlate with maternal dose at delivery or enantiomer-specific cord methadone concentrations. In pregnant and postpartum women, 13% and 17%, respectively, had QTc ≥ 450 ms, as did 19% of infants.
CONCLUSIONS
QTc correlated with dose and R-methadone concentration during the third trimester. However, longer QTc was common among women during and after pregnancy. Given the relatively high rate of QTc > 450 ms, an ECG before and after methadone initiation is advisable for pregnant and postpartum women.
Topics: Adult; Dose-Response Relationship, Drug; Drug Monitoring; Electrocardiography; Female; Fetal Blood; Half-Life; Humans; Infant, Newborn; Long QT Syndrome; Methadone; Narcotics; Opiate Substitution Treatment; Opioid-Related Disorders; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Third; Statistics as Topic; United States
PubMed: 28994902
DOI: 10.4088/JCP.16m11318 -
Neuropsychopharmacology : Official... Nov 2022The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However,...
The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However, methadone has undesirable effects that limit its clinical efficacy. Intermediate efficacy MOR agonists may treat OUD with fewer undesirable effects. We compared the effects of methadone with the intermediate efficacy MOR agonist TRV130 (oliceridine) on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats. Male rats (n = 20) were trained under a fentanyl-vs.-food choice procedure. Rats were then provided extended fentanyl (3.2 µg/kg/infusion) access (6 p.m.-6 a.m.) for 10 days to produce opioid dependence/withdrawal. Rats were treated with vehicle (n = 7), TRV130 (3.2 mg/kg; n = 8), or methadone (3.2 mg/kg; n = 5) three times per day after each extended-access session (8:30 a.m., 11 a.m., 1:30 p.m.). Withdrawal sign scoring (1:55 p.m.) and choice tests (2-4 p.m.) were conducted daily. Vehicle, TRV130, and methadone effects on fentanyl choice were redetermined in post-opioid-dependent rats. Vehicle-, TRV130-, and methadone-treated rats had similar fentanyl intakes during extended access. Vehicle-treated rats exhibited increased withdrawal signs and decreased bodyweights. Both methadone and TRV130 decreased these withdrawal signs. TRV130 was less effective than methadone to decrease fentanyl choice and increase food choice in opioid-dependent rats. Neither methadone nor TRV130 decreased fentanyl choice in post-opioid-dependent rats. Results suggest that higher MOR activation is required to reduce fentanyl choice than withdrawal signs in fentanyl-dependent rats. Additionally, given that TRV130 did not precipitate withdrawal in opioid-dependent rats, intermediate efficacy MOR agonists like TRV130 may facilitate the transition of patients with OUD from methadone to lower efficacy treatments like buprenorphine.
Topics: Analgesics, Opioid; Animals; Buprenorphine; Fentanyl; Male; Methadone; Narcotics; Opioid-Related Disorders; Rats; Receptors, Opioid; Spiro Compounds; Substance Withdrawal Syndrome; Thiophenes
PubMed: 35906489
DOI: 10.1038/s41386-022-01393-3 -
Minerva Anestesiologica 2005Methadone is a synthetic opioid analgesic that is used as an alternate to morphine and hydromorphone for patients with severe pain. It is increasingly being used in... (Review)
Review
UNLABELLED
Methadone is a synthetic opioid analgesic that is used as an alternate to morphine and hydromorphone for patients with severe pain. It is increasingly being used in opioid rotation schedules. Methadone has an asymmetric carbon atom resulting in 2 enantiomeric forms, the d and l isomers. The racemic mixture (dl-methadone) is the form commonly used clinically. Recent studies have revealed the pharmacological activity of the d-methadone isomer. We found that the d isomer of methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity both in vitro and in vivo. Studies were designed to examine the ability of d-methadone to attenuate the development of morphine tolerance and to modify NMDA-induced hyperalgesia in rats. Repeated dosing with intrathecal morphine produced a 38-fold increase in the morphine ED50 value. This decrease in the potency of morphine was completely prevented by the coadministration of intrathecal d-methadone at 160 microg/rat. In addition, the decrease in thermal paw withdrawal latency induced by the intrathecal administration of 1.64 microg/rat NMDA was completely blocked by pretreatment with 160 microg/rat d-methadone. Thus, the same dose of intrathecal d-methadone that attenuates the development of spinal morphine tolerance blocks NMDA-induced hyperalgesia in rats. These results support the
CONCLUSIONS
that d-metha-done affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.
Topics: Analgesics, Opioid; Animals; Drug Tolerance; Humans; Isomerism; Methadone; Rats; Receptors, N-Methyl-D-Aspartate
PubMed: 16012416
DOI: No ID Found -
Therapeutic Drug Monitoring Jun 2012Methadone is the recommended pharmacotherapy for opioid-dependent pregnant women. The primary aims of this study were to determine whether a dose-concentration...
INTRODUCTION
Methadone is the recommended pharmacotherapy for opioid-dependent pregnant women. The primary aims of this study were to determine whether a dose-concentration relationship exists between cumulative maternal methadone dose, methadone and metabolite concentrations in maternal hair during pregnancy and whether maternal hair methadone and metabolite concentrations predict neonatal outcomes.
MATERIALS AND METHODS
Hair specimens were collected monthly from opioid-dependent mothers enrolled in methadone treatment and 4 of their infants. Hair specimens were segmented (3 cm), washed (maternal hair only), and analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and 2-ethyl-5-methyl-3,3-diphenylpyrroline by liquid chromatography tandem mass spectrometry.
RESULTS
There was large intersubject variability and no dose-concentration relationship for cumulative methadone dose and methadone, EDDP, 2-ethyl-5-methyl-3,3-diphenylpyrroline, or total concentrations in hair. For individual women, a positive trend was noted for cumulative methadone dose and methadone and EDDP concentrations in hair. There was a positive linear trend for cumulative methadone dose and EDDP/methadone ratio in maternal hair, perhaps reflecting methadone's induction of its own metabolism. Maternal methadone concentrations were higher than those in infant hair, and infant EDDP hair concentrations were higher than those in maternal hair. Maternal methadone dose, and methadone and EDDP hair concentrations were not correlated with peak infant neonatal abstinence syndrome (NAS) scores, days to peak NAS, duration of NAS, time to NAS onset, birth length, head circumference, or amount of neonatal morphine pharmacotherapy. Maternal cumulative third trimester methadone dose was positively correlated with infant birth weight.
CONCLUSIONS
Methadone and EDDP in pregnant women's hair are markers of methadone exposure and do not predict total methadone dose, nor neonatal outcomes from in utero methadone exposure.
Topics: Adolescent; Adult; Female; Hair; Humans; Infant, Newborn; Methadone; Neonatal Abstinence Syndrome; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Young Adult
PubMed: 22495425
DOI: 10.1097/FTD.0b013e3182512b26 -
Stem Cell Research Dec 2020Prenatal opioids exposure can lead to both neonatal abstinence syndrome in newborns and neurological deficits later in life. Although opioids have been well studied in...
Prenatal opioids exposure can lead to both neonatal abstinence syndrome in newborns and neurological deficits later in life. Although opioids have been well studied in general, the cellular and molecular mechanisms by which opioids affect human fetal brain development has not been well understood. In this work, we have taken advantage of a human 3D-brain cortical organoid (hCO) that facilitated enormously the investigation of early human brain development. Using imaging, immunofluorescence, multi-electrode array (MEA) and patch clamp recording techniques, we have investigated the effect of methadone, a frequently used opioid during pregnancy, on early neural development, including neuronal growth, neural network activity and synaptic transmission in hCOs. Our results demonstrated that methadone dose-dependently halted the growth of hCOs and induced organoid disintegration after a prolonged exposure. In addition, methadone dose-dependently suppressed the firing of spontaneous action potentials in hCOs and this suppression could be reversed upon methadone withdrawal in hCOs treated with lower dosages. Further investigation using patch clamp whole cell configuration revealed that, at clinically relevant concentrations, methadone decreased the frequency and amplitude of excitatory postsynaptic currents in neurons, indicating a critical role of methadone in weakening synaptic transmission in neural networks in hCOs. In addition, methadone significantly attenuated the voltage-dependent Na current in hCOs. We conclude that methadone interrupts neural growth and function in early brain development.
Topics: Action Potentials; Female; Humans; Infant, Newborn; Methadone; Organoids; Patch-Clamp Techniques; Pregnancy; Synaptic Transmission
PubMed: 33137567
DOI: 10.1016/j.scr.2020.102065