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Neuropharmacology Nov 2023Buprenorphine (BUP) and methadone (MTD) are used for medication-assisted treatment (MAT) in opioid use disorder. Although both medications show improved maternal and...
Buprenorphine (BUP) and methadone (MTD) are used for medication-assisted treatment (MAT) in opioid use disorder. Although both medications show improved maternal and neonatal outcomes compared with illicit opioid use during pregnancy, BUP has exhibited more favorable outcomes to newborns than MTD. The underlying cellular and molecular mechanisms for the difference between BUP and MTD are largely unknown. Here, we examined the growth and neuronal activity in human cortical organoids (hCOs) exposed to BUP or MTD. We found that the growth of hCOs was significantly restricted in the MTD-treated but not in the BUP-treated hCOs and BUP attenuated the growth-restriction effect of MTD in hCOs. Furthermore, a κ-receptor agonist restricted while an antagonist alleviated the growth-restriction effect of MTD in hCOs. Since BUP is not only a μ-agonist but a κ-antagonist, the prevention of this growth-restriction by BUP is likely due to its κ-receptor-antagonism. In addition, using multielectrode array (MEA) technique, we discovered that both BUP and MTD inhibited neuronal activity in hCOs but BUP showed suppressive effects only at higher concentrations. Furthermore, κ-receptor antagonist nBNI did not prevent the MTD-induced suppression of neuronal activity in hCOs but the NMDA-antagonism of MTD (that BUP lacks) plays a role in the inhibition of neuronal activity. We conclude that, although both MTD and BUP are μ-opioid agonists, a) the additional κ-receptor antagonism of BUP mitigates the MTD-induced growth restriction during neurodevelopment and b) the lack of NMDA antagonism of BUP (in contrast to MTD) induces much less suppressive effect on neural network communications.
Topics: Infant, Newborn; Humans; Buprenorphine; Methadone; Analgesics, Opioid; N-Methylaspartate; Opioid-Related Disorders; Receptors, Opioid, kappa; Organoids; Brain; Narcotic Antagonists
PubMed: 37543137
DOI: 10.1016/j.neuropharm.2023.109683 -
Pharmacogenomics Sep 2017Current treatments of opioid addiction include primarily maintenance medications such as methadone. Chronic exposure to opiate and/or long-lasting maintenance treatment... (Review)
Review
Current treatments of opioid addiction include primarily maintenance medications such as methadone. Chronic exposure to opiate and/or long-lasting maintenance treatment induce modulations of gene expression in brain and peripheral tissues. There is increasing evidence that epigenetic modifications underlie these modulations. This review summarizes published results on opioid-induced epigenetic changes in animal models and in patients. The epigenetic modifications observed with other drugs of abuse often used by opiate abusers are also outlined. Specific methadone maintenance treatment induced epigenetic modifications at different treatment stages may be combined with the ones resulting from patients' substance use history. Therefore, research comparing groups of addicts with similar history and substances use disorders but contrasting for well-characterized treatment phenotypes should be encouraged.
Topics: Animals; Cell Line; DNA Methylation; Epigenesis, Genetic; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pharmacogenetics
PubMed: 28841113
DOI: 10.2217/pgs-2017-0040 -
Molecules (Basel, Switzerland) Apr 2022In this article, we studied physicochemical and microbiological stability and determined the beyond-use date of two oral solutions of methadone in three storage...
In this article, we studied physicochemical and microbiological stability and determined the beyond-use date of two oral solutions of methadone in three storage conditions. For this, two oral solutions of methadone (10 mg/mL) were prepared, with and without parabens, as preservatives. They were packed in amber glass vials kept unopened until the day of the test, and in a multi-dose umber glass bottle opened daily. They were stored at 5 ± 3 °C, 25 ± 2 °C and 40 ± 2 °C. pH, clarity, and organoleptic characteristics were obtained. A stability-indicating high-performance liquid chromatography method was used to determine methadone. Microbiological quality was studied and antimicrobial effectiveness testing was also determined following European Pharmacopoeia guidelines. Samples were analyzed at days 0, 7, 14, 21, 28, 42, 56, 70, and 91 in triplicate. After 91 days of storage, pH remained stable at about 6.5-7 in the two solutions, ensuring no risk of methadone precipitation. The organoleptic characteristics remained stable (colorless, odorless, and bitter taste). The absence of particles was confirmed. No differences were found with the use of preservatives. Methadone concentration remained within 95-105% in all samples. No microbial growth was observed. Hence, the two oral methadone solutions were physically and microbiologically stable at 5 ± 3 °C, 25 ± 2 °C, and 40 ± 2 °C for 91 days in closed and opened amber glass bottles.
Topics: Amber; Chromatography, High Pressure Liquid; Drug Compounding; Drug Stability; Drug Storage; Methadone; Solutions
PubMed: 35566167
DOI: 10.3390/molecules27092812 -
JAMA Network Open Jul 2022The opioid crisis has been exacerbated by the COVID-19 pandemic in the US, with concerns over major disruptions to medication treatment of opioid use disorder.
IMPORTANCE
The opioid crisis has been exacerbated by the COVID-19 pandemic in the US, with concerns over major disruptions to medication treatment of opioid use disorder.
OBJECTIVE
To investigate whether the COVID-19 pandemic was associated with disruption of buprenorphine and methadone supplies in the US.
DESIGN, SETTING, AND PARTICIPANTS
This repeated cross-sectional study used ARCOS (Automated Reports and Consolidated Ordering System) data, which monitor the flow of controlled substances in the US, from January 1, 2012, through June 30, 2021. Manufacturers and point of sale or distribution at the dispensing or retail level, including hospitals, retail pharmacies, clinicians, midlevel clinicians, and teaching institutions, were included in the analysis.
EXPOSURES
COVID-19 pandemic.
MAIN OUTCOMES AND MEASURES
Quarterly supplies of buprenorphine and methadone per capita in milligrams.
RESULTS
The per capita supply of methadone dropped from 13.2 mg in the first quarter of 2020 to 10.5 mg in the second quarter of 2020, whereas the per capita supply of buprenorphine increased from 3.6 mg to 3.7 mg in the same period. The per capita supply of methadone declined 20% (-2.7 mg) in the second quarter of 2020 compared with the first quarter of 2020, and the supply had not returned to 2019 levels as of June 2021, whereas the supply of buprenorphine per person increased consistently during the same period. There were considerable state disparities in the reduction of the methadone supply during the pandemic, with many states experiencing pronounced per capita supply decreases, including reductions as great as 50% in New Hampshire and Florida. These decreases in per capita methadone supply were not compensated by proportional increases in the per capita buprenorphine supply (linear fit, 0.17 [95% CI, -0.43 to 0.76]; P = .47).
CONCLUSIONS AND RELEVANCE
This cross-sectional study of buprenorphine and methadone supplies during the COVID-19 pandemic found a pronounced decline in the methadone supply but no disruption to the buprenorphine supply. Future research is needed to explain the pronounced state disparities in the methadone supply.
Topics: Buprenorphine; Cross-Sectional Studies; Humans; Methadone; Opiate Substitution Treatment; Pandemics; COVID-19 Drug Treatment
PubMed: 35881394
DOI: 10.1001/jamanetworkopen.2022.23708 -
Neuroscience and Biobehavioral Reviews Feb 2017There is a presumption that neurocognition is commonly impaired in chronic methadone exposed individuals (CM) when compared with healthy controls (HP). Additionally, it... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
There is a presumption that neurocognition is commonly impaired in chronic methadone exposed individuals (CM) when compared with healthy controls (HP). Additionally, it remains unclear if short term (<1year) abstinence (AP) is associated with an altered cognitive profile when compared with CM.
METHOD
A random effect model approach was used on data assembled into the Comprehensive Meta-Analysis programme. Cohen's d effect sizes and a significance levels of p<0.01 were calculated for each domain.
RESULTS
Data from a total cohort of 1063 CM, 412 AP and 879 HP participants, from 23 independent studies indicate global impairments in neurocognitive function in CM relative to HP participants. The smaller body of evidence comparing CM to AP participants is inconclusive.
CONCLUSION
Methodological issues such as small sample sizes, heterogeneity and poor quality limited the interpretation of the results and does not address whether the observed impairments reflect co-morbid functioning, methadone-related sedation and/or other factors. Only higher quality longitudinal studies will permit confident interpretation of the results observed in this meta-analysis.
Topics: Humans; Longitudinal Studies; Methadone
PubMed: 27913280
DOI: 10.1016/j.neubiorev.2016.11.008 -
Hematology/oncology Clinics of North... Jun 2018Methadone is a valuable opioid in the management of patients who have cancer with pain. Methadone is a mu-, kappa-, and delta-opioid agonist, and an N-methyl-D-aspartate... (Review)
Review
Methadone is a valuable opioid in the management of patients who have cancer with pain. Methadone is a mu-, kappa-, and delta-opioid agonist, and an N-methyl-D-aspartate receptor antagonist. These mechanisms of action make methadone an attractive option for complex pain syndromes. It is critically important that providers consider a patient's risk status before beginning methadone. Careful consideration must be given to dosing methadone in both opioid-naïve and opioid-tolerant patients, with vigilant monitoring for therapeutic effectiveness and potential toxicity until the patient achieves steady state.
Topics: Half-Life; Humans; Inappropriate Prescribing; Methadone; Neoplasms; Pain
PubMed: 29729777
DOI: 10.1016/j.hoc.2018.01.004 -
Journal of Addictive Diseases 2021Investigations proposed that genetic polymorphisms within proteins in methadone pharmacokinetic and pharmacodynamics are critical factors in determination of methadone...
BACKGROUND
Investigations proposed that genetic polymorphisms within proteins in methadone pharmacokinetic and pharmacodynamics are critical factors in determination of methadone dose in methadone maintenance therapy (MMT).
OBJECTIVE
This study aimed to assess the associations between two polymorphisms, (rs2740574) and (rs1799971), with dose of methadone in Iranian patients undergoing MMT.
METHODS
A total of 124 Iranian male subjects aged 18-65 years old who were confirmed to be addicted by the addiction diagnostic tests and underwent MMT were assessed. Patients were divided into three groups of low (less than 40 mg/day), moderate (more than 40 mg/day and less than 110 mg/day) and high (more than 110 mg/day) methadone dose consumption. DNAs of included patients were extracted from their blood samples and were assessed for and polymorphisms.
RESULTS
Results showed that there was no significant association between the studied polymorphisms and methadone dose in Iranian addicted patients underwent MMT (P > 0.05).
CONCLUSIONS
and single variations cannot explain variability in methadone dosage in MMT. Studying the interactions of more genetic factors in larger samples may elucidate factors influencing the required dose of methadone and better individualized therapy.
Topics: Adult; Cytochrome P-450 CYP3A; Genotype; Humans; Iran; Male; Methadone; Middle Aged; Opiate Substitution Treatment; Opioid-Related Disorders; Polymorphism, Genetic; Receptors, Opioid, mu
PubMed: 33682628
DOI: 10.1080/10550887.2021.1886566 -
Journal of Neuroimmune Pharmacology :... Sep 2016Neuroimaging techniques to measure the function and biochemistry of the human brain such as positron emission tomography (PET), proton magnetic resonance spectroscopy... (Review)
Review
Neuroimaging techniques to measure the function and biochemistry of the human brain such as positron emission tomography (PET), proton magnetic resonance spectroscopy ((1)H MRS), and functional magnetic resonance imaging (fMRI), are powerful tools for assessing neurobiological mechanisms underlying the response to treatments in substance use disorders. Here, we review the neuroimaging literature on pharmacological and behavioral treatment in substance use disorder. We focus on neural effects of medications that reduce craving (e.g., naltrexone, bupropion hydrochloride, baclofen, methadone, varenicline) and that improve cognitive control (e.g., modafinil, N-acetylcysteine), of behavioral treatments for substance use disorders (e.g., cognitive bias modification training, virtual reality, motivational interventions) and neuromodulatory interventions such as neurofeedback and transcranial magnetic stimulation. A consistent finding for the effectiveness of therapeutic interventions identifies the improvement of executive control networks and the dampening of limbic activation, highlighting their values as targets for therapeutic interventions in substance use disorders.
Topics: Clinical Trials as Topic; Cognitive Behavioral Therapy; Craving; Humans; Methadone; Naltrexone; Neurofeedback; Neuroimaging; Substance-Related Disorders; Treatment Outcome
PubMed: 27184387
DOI: 10.1007/s11481-016-9680-y -
Expert Opinion on Drug Metabolism &... Jul 2016People who inject drugs (PWID) and other individuals with opioid use disorders have a dramatically higher prevalence of hepatitis C virus (HCV) infection than the... (Review)
Review
INTRODUCTION
People who inject drugs (PWID) and other individuals with opioid use disorders have a dramatically higher prevalence of hepatitis C virus (HCV) infection than the general population. The availability of novel direct acting antivirals (DAAs) for the treatment of HCV infection with very high efficacy, improved tolerability and shortened treatment durations have led to global efforts to ramp up treatment for all HCV-infected individuals to prevent or delay complications of the disease. Individuals with opioid use disorders, including those on medication-assisted therapy such as methadone or buprenorphine, are a key demographic group that can benefit from HCV treatment given their high HCV prevalence; however, pharmacokinetic and pharmacodynamic drug interactions could blunt their utility.
AREAS COVERED
We performed a comprehensive literature review of published and unpublished data from PubMed database, relevant conference abstracts/proceedings and FDA approved drug package inserts, to review the pharmacokinetic (PK) profile and drug interactions between currently approved HCV DAAs and methadone and buprenorphine.
EXPERT OPINION
The paper highlights specific drug combinations which result in altered opioid drug levels including telaprevir/methadone, daclatasvir/buprenorphine, and Abbvie 3D combination regimen (paritaprevir, ritonavir, ombitasvir and dasabuvir)/buprenorphine. However, concurrent pharmacodynamics assessments did not reveal significant signs and symptoms of opioid withdrawal or toxicity that would preclude concurrent administration.
Topics: Animals; Antiviral Agents; Buprenorphine; Drug Interactions; Hepatitis C; Humans; Methadone; Opioid-Related Disorders; Substance Abuse, Intravenous
PubMed: 27140427
DOI: 10.1080/17425255.2016.1183644 -
Journal of Forensic Sciences May 2021The paper presents a method for the determination of methadone, EDDP, and EMDP in postmortem biological materials using liquid-liquid extraction with ethyl acetate (pH9)...
The paper presents a method for the determination of methadone, EDDP, and EMDP in postmortem biological materials using liquid-liquid extraction with ethyl acetate (pH9) and UHPLC-MS/MS technique. Methadone-d and EDDP-d were used as the internal standards. The method validation results for blood and urine were as follows: linearity: 0.5-1000 ng/ml; R > 0.9993 for methadone, EDDP and R > 0.9944 for EMDP. Intra- and inter-day precision: 0.1%-7.5% and 0.3%-8.6%, respectively; intra- and inter-day accuracy: -11.8% to 13.9% and -9.3 to 14.8%, respectively; recovery: 91.5%-123.0%; matrix effect: 83.5%-123.9%. This study also describes 18 postmortem cases, where methadone concentrations ranged 2.3-1180 ng/ml in blood (n = 17), from 11.0 to >10,000 ng/ml in urine (n = 13) and 135.2-409.0 in vitreous humor (VH, n = 3). EDDP concentrations ranged from not detectable to 180 ng/mL in blood, from 42.4 to >10,000 ng/ml in urine and 18.3-36.5 in VH. EMDP concentrations were found in four cases in blood from below LLOQ to 1.8 ng/ml and in seven cases in urine, ranged 2.1-243.0 ng/ml. EMDP was not detected in VH samples. The EDDP/methadone ratios and blood/urine ratios for methadone and EDDP in EMDP-positive and negative cases were performed. The paper presents mass spectra of other methadone metabolites, than EDDP and EMDP (ring hydroxylated methadone, ring hydroxylated EDDP, ring hydroxylated EMDP, methadol, and DDP). Simultaneous determination of methadone and its metabolites in order to unequivocally interpret the results of toxicological tests seems to be useful in cases related to prescription/illicit use of methadone.
Topics: Analgesics, Opioid; Chromatography, High Pressure Liquid; Forensic Toxicology; Humans; Liquid-Liquid Extraction; Mass Spectrometry; Methadone; Pyrrolidines
PubMed: 33512019
DOI: 10.1111/1556-4029.14674