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Journal of the American Heart... Jun 2022Background Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K...
Background Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K current () the principal mechanism of drug-associated arrhythmia. Congenital defects of inward rectifier K current () have been linked to increased U-wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of , contributing to delayed repolarization and manifesting on surface ECGs as augmented U-wave integrals. Methods and Results Using a whole-cell voltage clamp, methadone inhibited both recombinant and native with a half-maximal inhibitory concentration IC50) of 1.5 μmol/L, similar to that observed for block (half-maximal inhibitory concentration of 2.9 μmol/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal repolarization at low concentrations. At higher concentrations, action potential duration at 90% repolarization lengthening was abolished, but its effect on terminal repolarization rose steadily and correlated with increased fluctuations of diastolic membrane potential. In parallel, patient ECGs were analyzed before and after methadone initiation, with 68% of patients having a markedly increased U-wave integral compared with premethadone (lead V3; mean +38%±15%, =0.016), along with increased QT and T to T intervals, likely reflective of block. Conclusions Methadone is a potent inhibitor that causes augmentation of U waves on surface ECG. We propose that increased membrane instability resulting from block may better explain methadone's arrhythmia risk beyond inhibition alone. Drug-induced augmentation of U waves may represent evidence of blockade of multiple repolarizing ion channels, and evaluation of the effect of that agent on may be warranted.
Topics: Action Potentials; Arrhythmias, Cardiac; Electrocardiography; Humans; Methadone; Myocytes, Cardiac; Potassium
PubMed: 35658478
DOI: 10.1161/JAHA.121.023482 -
Equine Veterinary Journal Jul 2019Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses.
BACKGROUND
Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses.
OBJECTIVES
To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses.
STUDY DESIGN
Randomised, placebo-controlled, blinded, crossover.
METHODS
Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 μg/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 [MLD], 5 [MMD] or 10 [MHD] μg/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) [1].
RESULTS
Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra-additive (partial antagonism) effect for HHAG (α = -1.33), VAS (α = -0.98) and GIM (α = -1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (α = 0.78).
MAIN LIMITATIONS
This is a small experimental study.
CONCLUSIONS
Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations.
Topics: Analgesics, Opioid; Animals; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Horses; Hypnotics and Sedatives; Imidazoles; Methadone; Random Allocation
PubMed: 30298682
DOI: 10.1111/evj.13031 -
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 -
The Canadian Veterinary Journal = La... Nov 2023Opioid analgesics are routinely used during the perioperative period, to provide analgesia and reduce anesthetics doses required to maintain a surgical plane of... (Review)
Review
Opioid analgesics are routinely used during the perioperative period, to provide analgesia and reduce anesthetics doses required to maintain a surgical plane of anesthesia in companion animals. Acting on receptors in the brain, spinal cord, and peripheral nervous system, opioids provide reliable and consistent analgesia; however, they are not without adverse effects. Methadone, a mu agonist opioid analgesic, was recently licensed for veterinary use in Canada. In addition to its action on opioid receptors, methadone contributes to analgesia through other pathways, including inhibition of N-methyl-D-aspartate (NMDA) receptors. It has physiologic effects similar to other mu opioid agents, but fewer adverse gastrointestinal effects. This review discusses methadone's mechanism of action, pharmacologic characteristics, and clinical effects in dogs and cats. Current recommendations for using methadone in companion animals are also provided.
Topics: Animals; Cats; Dogs; Methadone; Pets; Cat Diseases; Dog Diseases; Analgesics, Opioid; Anesthesia; Pain
PubMed: 37915778
DOI: No ID Found -
The Cochrane Database of Systematic... May 2016Withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment.
OBJECTIVES
To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists compared with placebo, reducing doses of methadone, symptomatic medications, or an alpha2-adrenergic agonist regimen different to the experimental intervention, for the management of the acute phase of opioid withdrawal. Outcomes included the withdrawal syndrome experienced, duration of treatment, occurrence of adverse effects, and completion of treatment.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to November week 2, 2015), EMBASE (January 1985 to November week 2, 2015), PsycINFO (1806 to November week 2, 2015), Web of Science, and reference lists of articles.
SELECTION CRITERIA
Randomised controlled trials comparing alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS
We included 26 randomised controlled trials involving 1728 participants. Six studies compared an alpha2-adrenergic agonist with placebo, 12 with reducing doses of methadone, four with symptomatic medications, and five compared different alpha2-adrenergic agonists. We assessed 10 studies as having a high risk of bias in at least one of the methodological domains that were considered.We found moderate-quality evidence that alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.18 to 0.57; 3 studies; 148 participants). We found moderate-quality evidence that completion of treatment was significantly more likely with alpha2-adrenergic agonists compared with placebo (RR 1.95, 95% CI 1.34 to 2.84; 3 studies; 148 participants).Peak withdrawal severity may be greater with alpha2-adrenergic agonists than with reducing doses of methadone, as measured by the likelihood of severe withdrawal (RR 1.18, 95% CI 0.81 to 1.73; 5 studies; 340 participants; low quality), and peak withdrawal score (standardised mean difference (SMD) 0.22, 95% CI -0.02 to 0.46; 2 studies; 263 participants; moderate quality), but these differences were not significant and there is no significant difference in severity when considered over the entire duration of the withdrawal episode (SMD 0.13, 95% CI -0.24 to 0.49; 3 studies; 119 participants; moderate quality). The signs and symptoms of withdrawal occurred and resolved earlier with alpha2-adrenergic agonists. The duration of treatment was significantly longer with reducing doses of methadone (SMD -1.07, 95% CI -1.31 to -0.83; 3 studies; 310 participants; low quality). Hypotensive or other adverse effects were significantly more likely with alpha2-adrenergic agonists (RR 1.92, 95% CI 1.19 to 3.10; 6 studies; 464 participants; low quality), but there was no significant difference in rates of completion of withdrawal treatment (RR 0.85, 95% CI 0.69 to 1.05; 9 studies; 659 participants; low quality).There were insufficient data for quantitative comparison of different alpha2-adrenergic agonists. Available data suggest that lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine.
AUTHORS' CONCLUSIONS
Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. We detected no significant difference in efficacy between treatment regimens based on clonidine or lofexidine and those based on reducing doses of methadone over a period of around 10 days, but methadone was associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.
Topics: Acute Disease; Adrenergic alpha-2 Receptor Agonists; Clonidine; Controlled Clinical Trials as Topic; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome
PubMed: 27140827
DOI: 10.1002/14651858.CD002024.pub5 -
Drug and Alcohol Dependence Oct 2016To quantify gender, age-group and quantity of methadone prescribed as risk factors for drugs-related deaths (DRDs), and for methadone-specific DRDs, in Scotland's...
AIM
To quantify gender, age-group and quantity of methadone prescribed as risk factors for drugs-related deaths (DRDs), and for methadone-specific DRDs, in Scotland's methadone-prescription clients.
DESIGN
Linkage to death-records for Scotland's methadone-clients with one or more Community Health Index (CHI)-identified methadone prescriptions during July 2009 to June 2013.
SETTING
Scotland's Prescribing Information System and National Records of Scotland.
MEASUREMENTS
Covariates defined at first CHI-identified methadone prescription, and person-years at-risk (pys) thereafter until the earlier of death-date or 31 December 2013. Methadone-specific DRDs were defined as: methadone implicated but neither heroin nor buprenorphine. Hazard ratios (HRs) were assessed using proportional hazards regression.
FINDINGS
Scotland's CHI-identified methadone-prescription cohort comprised 33,128 clients, 121,254 pys, 1,171 non-DRDs and 760 DRDs (6.3 per 1,000 pys), of which 362 were methadone-specific. Irrespective of gender, methadone-specific DRD-rate, per 1,000 pys, was higher in the 35+ age-group (4.2; 95% CI: 3.6-4.7) than for younger clients (1.9; 95% CI: 1.5-2.2). For methadone-specific DRDs, age-related HRs (e.g., 2.9 at 45+ years; 95% CI: 2.1-3.9) were steeper than for all DRDs (1.9; 95% CI: 1.5-2.4); there was no hazard-reduction for females; no gender by age-group interaction; and, unlike for all DRDs, the highest quintile for quantity of prescribed methadone at cohort-entry (>1960mg) was associated with increased HR (1.8; 95% CI: 1.3-2.5).
CONCLUSION
Higher methadone-specific DRD rates in older clients, irrespective of gender, call for better understanding of methadone's pharmaco-dynamics in older, opioid-dependent clients, many with progressive physical or mental ill-health.
Topics: Adult; Age Factors; Analgesics, Opioid; Cause of Death; Female; Heroin Dependence; Humans; Male; Methadone; Middle Aged; Opiate Substitution Treatment; Risk Factors; Scotland; Suicide; Young Adult
PubMed: 27593969
DOI: 10.1016/j.drugalcdep.2016.08.627 -
Drug Metabolism and Pharmacokinetics Dec 2022Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid...
Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d-methadone. The pharmacokinetic profiles of d-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD value for a single intravenous dose of d-methadone was 2.1-fold higher than that for methadone. Moreover, d-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.
Topics: Male; Animals; Mice; Methadone; Analgesics, Opioid; Blood-Brain Barrier; Kinetics; Brain
PubMed: 36368298
DOI: 10.1016/j.dmpk.2022.100477 -
Substance Abuse Treatment, Prevention,... Sep 2023The US federal regulations allow pharmacy administration and dispensing of methadone for opioid use disorder (PADMOUD) to increase the capability of opioid treatment...
BACKGROUND
The US federal regulations allow pharmacy administration and dispensing of methadone for opioid use disorder (PADMOUD) to increase the capability of opioid treatment programs (OTPs) in providing methadone maintenance treatment (MMT) for opioid use disorder (OUD) as part of a medication unit. However, there is a lack of research data from both pharmacy and OTP staff to inform the implementation of PADMOUD.
METHODS
Staff of a pharmacy (n = 8) and an OTP (n = 9) that participated in the first completed US trial on PADMOUD through electronic prescribing for methadone (parent study) were recruited to participate in this qualitative interview study to explore implementation-related factors for PADMOUD. Each interview was recorded and transcribed verbatim. NVivo was used to help identify themes of qualitative interview data. The Promoting Action on Research Implementation in Health Services (PARIHS) framework was used to guide the coding and interpretation of data.
RESULTS
Six pharmacy staff and eight OTP staff (n = 14) completed the interview. Results based on PARIHS domains were summarized, including evidence, context, and facilitation domains. Participants perceived benefits of PADMOUD for patients, pharmacies, OTPs, and payers. PADMOUD was considered to increase access for stable patients, provide additional patient service opportunities and revenues for pharmacies/pharmacists, enhance the capability of OTPs to treat more new patients, and reduce patients' cost when receiving medication at a pharmacy relative to an OTP. Both pharmacy and OTP staff were perceived to be supportive of the implementation of PADMOUD. Pharmacy staff/pharmacists were perceived to need proper training on addiction and methadone as well as a protocol of PADMOUD to conduct PADMOUD. Facilitators include having thought leaders to guide the operation, a certification program to ensure proper training of pharmacy staff/pharmacist, having updated pharmacy service software or technology to streamline the workflow of delivering PADMOUD and inventory management, and reimbursement for pharmacists.
CONCLUSION
This study presents the first findings on perspectives of PADMOUD from both staff of a community pharmacy and an OTP in the US. Finding on barriers and facilitators are useful data to guide the development of strategies to implement PADMOUD to help address the US opioid crisis.
Topics: Humans; Pharmacies; Analgesics, Opioid; Pharmacists; Methadone; Pharmacy; Pharmaceutical Services; Pharmacy Administration; Opioid-Related Disorders
PubMed: 37697326
DOI: 10.1186/s13011-023-00563-w -
Substance Abuse Treatment, Prevention,... Dec 2014Concomitant cocaine use is a major problem in clinical practice in methadone maintenance treatment (MMT) and may interfere with successful treatment. Data from European...
BACKGROUND
Concomitant cocaine use is a major problem in clinical practice in methadone maintenance treatment (MMT) and may interfere with successful treatment. Data from European methadone populations is sparse. This register-based study sought to explore the association between prescribed methadone dose and concomitant cocaine and heroin use in the methadone population of Basel City.
METHODS
The study included 613 methadone patients between April 1, 2003 and March 31, 2004. Anonymized data was taken from the methadone register of Basel City. For analysis of the prescribed methadone dose distribution, the patient sample was split into three methadone dosage groups: a low dose group (LDG) (n = 200; < 60 mg/day), a medium dose group (MDG) (n = 273; 60 to 100 mg/day), and a high dose group (HDG) (n = 140; > 100 mg/day). Concomitant drug use was based on self-report.
RESULTS
Analysis showed a significant difference in self-reported cocaine use between groups (p < 0.001). Patients in the LDG reported significantly fewer cocaine consumption days compared to the MDG (p < 0.001) and the HDG (p < 0.05). Patients in the HDG reported significantly fewer heroin consumption days than those in the LDG (p < 0.01) and the MDG (p < 0.001). In logistic regression analysis, cocaine use was significantly associated with heroin use (OR 4.9).
CONCLUSIONS
Cocaine use in methadone patients may be associated with heroin use, which indicates the importance of prescribing appropriate methadone dosages in order to indirectly reduce cocaine use.
Topics: Adult; Cocaine-Related Disorders; Dose-Response Relationship, Drug; Female; Heroin Dependence; Humans; Male; Methadone; Middle Aged; Narcotics; Opiate Substitution Treatment; Opioid-Related Disorders; Surveys and Questionnaires; Switzerland; Young Adult
PubMed: 25472871
DOI: 10.1186/1747-597X-9-46 -
Evaluation and Program Planning Jun 2022The purpose of this study is to identify the relative strengths of association of medication and health and social services in comprehensive substance use disorder (SUD)...
BACKGROUND
The purpose of this study is to identify the relative strengths of association of medication and health and social services in comprehensive substance use disorder (SUD) treatment.
OBJECTIVES
The study uses a novel variance decomposition method to assess the relative strength of association of six active ingredients of comprehensive SUD treatment: methadone medication, access services, SUD counseling, matched service ratio, client-provider relationship, and treatment duration.
METHODS
The study uses data from the National Treatment Improvement Evaluation Study (1992-1997), a dataset with an unusual number of services and service strategies measured. The data include 3012 clients from 45 SUD treatment programs. Linear mixed models are used to assess the relation of service variables to the outcome of posttreatment substance use. Variance decomposition methods are used to assess the relative importance of the ingredients in the treatment model.
RESULTS
Along with a random intercept and background variables, receipt of methadone accounted for the greatest relative strength of association at 35.4%, compared with 23.8% for treatment duration, 15.4% for client-provider relationship, and 11.2% for matched service ratio. Access and SUD counseling accounted for modest strengths of association at 1% and 3% each.
CONCLUSION
Findings indicate somewhat greater strength of association of methadone compared with other services and service strategies and overall, reinforce the importance of both medication and services and service strategies in the design and development of effective models of service delivery.
SIGNIFICANCE
This study, among the first to evaluate the relative importance of specific services and service strategies of comprehensive SUD treatment, provides insights relevant to the development of effective models of service delivery.
Topics: Humans; Methadone; Program Evaluation; Social Work; Substance-Related Disorders
PubMed: 35247677
DOI: 10.1016/j.evalprogplan.2022.102060