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The Cochrane Database of Systematic... May 2017This review replaces an earlier review, "Methadone for chronic non-cancer pain in adults". This review serves to update the original and includes only studies of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This review replaces an earlier review, "Methadone for chronic non-cancer pain in adults". This review serves to update the original and includes only studies of neuropathic pain. Methadone belongs to a class of analgesics known as opioids, that are considered the cornerstone of therapy for moderate-to-severe postsurgical pain and pain due to life-threatening illnesses; however, their use in neuropathic pain is controversial. Methadone has many characteristics that differentiate it from other opioids, which suggests that it may have a different efficacy and safety profile.
OBJECTIVES
To assess the analgesic efficacy and adverse events of methadone for chronic neuropathic pain in adults.
SEARCH METHODS
We searched the following databases: CENTRAL (CRSO), MEDLINE (Ovid), and Embase (Ovid), and two clinical trial registries. We also searched the reference lists of retrieved articles. The date of the most recent search was 30 November 2016.
SELECTION CRITERIA
We included randomised, double-blind studies of two weeks' duration or longer, comparing methadone (in any dose, administered by any route, and in any formulation) with placebo or another active treatment in chronic neuropathic pain.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. There were insufficient data to perform pooled analyses. We assessed the overall quality of the evidence for each outcome using GRADE and created a 'Summary of findings' table.
MAIN RESULTS
We included three studies, involving 105 participants. All were cross-over studies, one involving 19 participants with diverse neuropathic pain syndromes, the other two involving 86 participants with postherpetic neuralgia. Study phases ranged from 20 days to approximately eight weeks. All administered methadone orally, in doses ranging from 10 mg to 80 mg daily. Comparators were primarily placebo, but one study also included morphine and tricyclic antidepressants.The included studies had several limitations related to risk of bias, particularly incomplete reporting, selective outcome reporting, and small sample sizes.There were very limited data for our primary outcomes of participants with at least 30% or at least 50% pain relief. Two studies reported that 11/29 participants receiving methadone achieved 30% pain relief versus 7/29 participants receiving placebo. Only one study presented data in a manner that allowed us to calculate the number of participants with at least 50% pain relief. None of the 19 participants achieved a 50% reduction in pain intensity, either when receiving methadone or when receiving placebo. No study provided data for our other primary outcomes of Patient Global Impression of Change scale (PGIC) much or very much improved (equivalent to at least 30% pain relief) and PGIC very much improved (equivalent to at least 50% pain relief).For secondary efficacy outcomes, one study reported maximum and mean pain intensity and pain relief, and reported statistically significant improvements versus placebo for all outcomes with 20 mg daily doses of methadone, but not with 10 mg daily doses. The second study reported differences in pain reduction between methadone (n = 26) and morphine (n = 38) and found morphine to be statistically superior. The third study reported the number of responders (variously defined) for several pain and functional outcomes and found methadone to be statistically superior to placebo for the outcomes of categorical pain intensity and evoked pain. In the two studies that reported data, 0/29 participants withdrew due to lack of efficacy, whereas 4/29 participants withdrew due to adverse events while taking methadone versus 3/29 while taking placebo.One study reported incidences for several individual adverse events, but found a statistically significant increased incidence for methadone over placebo for only one event, dizziness. The other studies did not report data in a manner that enabled us to analyze adverse events. There were no serious adverse events or deaths reported.We assessed the quality of the evidence as very low for all efficacy and safety outcomes using GRADE, primarily because of the heterogeneity of study designs and populations, short durations, cross-over methodology, and few participants and events.
AUTHORS' CONCLUSIONS
The three studies provide very limited, very low quality evidence of the efficacy and safety of methadone for chronic neuropathic pain, and there were too few data for pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies. No conclusions can be made regarding differences in efficacy or safety between methadone and placebo, other opioids, or other treatments.
Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Humans; Methadone; Neuralgia; Pain Measurement; Patient Dropouts; Randomized Controlled Trials as Topic
PubMed: 28514508
DOI: 10.1002/14651858.CD012499.pub2 -
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 -
British Journal of Clinical Pharmacology Jul 2019Our study aimed to evaluate the impacts of the cytochrome P450 (CYP) 2B6-G516T and CYP2D6 genetic polymorphisms on pharmacokinetic and clinical parameters in patients... (Observational Study)
Observational Study
AIMS
Our study aimed to evaluate the impacts of the cytochrome P450 (CYP) 2B6-G516T and CYP2D6 genetic polymorphisms on pharmacokinetic and clinical parameters in patients receiving methadone maintenance treatment.
METHODS
Opioid PhArmacoLogy (OPAL) was a clinical survey of the sociodemographic characteristics, history and consequences of pathology associated with methadone maintenance treatment response and current addictive comorbidities. A subgroup of 72 methadone patients was genotyped.
RESULTS
When comparing the three CYP2B6 genotype groups, the methadone (R)- and (S)-methadone enantiomer concentrations/doses (concentrations relative to doses) were different (P = .029, P = .0019). The CYP2D6 phenotypes did not seem to be relevant with regard to methadone levels. On multivariate analysis, neither the CYP2B6 genotype nor the CYP2D6 phenotype explained the (R)-methadone concentration/dose values (P = .92; P = .86); the (S)-methadone concentration/dose values (P = .052; P = .95 [although there was a difference between the TT group and GT and GG groups {P = .019}]); or opiate cessation (P = .12; P = .90).
CONCLUSION
The genotyping of CYP2B6 G516T could be an interesting tool to explore methadone intervariability.
Topics: Adult; Cross-Sectional Studies; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Female; Genotype; Humans; Male; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Stereoisomerism
PubMed: 30907440
DOI: 10.1111/bcp.13936 -
Toxicology and Applied Pharmacology Nov 2023The use and/or misuse of opioids by pregnant women would expose the fetuses to these drugs during critical stages of development with serious effects for the newborn,...
The use and/or misuse of opioids by pregnant women would expose the fetuses to these drugs during critical stages of development with serious effects for the newborn, like the neonatal abstinence syndrome (NAS). We have revisited an established chicken model for NAS to describe the distribution of morphine and methadone to the brain and explore its validity as a valuable alternative to rodent models. For this purpose, chicken eggs were injected with a single dose of 10 mg/kg or 20 mg/kg morphine or 20 mg/kg methadone onto the chorioallantoic membrane (CAM) on embryonal day 13. Whole brains and lungs were harvested and the concentrations of morphine, methadone and their subsequent metabolites (morphine-3-glucuronide and EDDP, respectively) determined in the brain and lungs at different time points using LC-MS/MS. Morphine and methadone, as well as their metabolites, were detected both in the brain and lungs, with significantly higher concentrations in the lungs. Pharmacokinetic modelling showed that the distribution of morphine to the brain followed a first-order absorption with transit compartments and linear elimination, with concentrations linearly dependent on dose. Moreover, methadone, but not morphine, reduced μ receptor (the main morphine receptor) binding, which can be of relevance for opioid tolerance. The present study is the first to report the brain distribution of morphine, which can be described by standard pharmacokinetic processes, and methadone in the developing chicken embryo. The present findings supplement the already established model and support the use of this chicken model to study NAS.
Topics: Chick Embryo; Infant, Newborn; Animals; Female; Pregnancy; Humans; Methadone; Morphine; Analgesics, Opioid; Chickens; Chromatography, Liquid; Drug Tolerance; Tandem Mass Spectrometry; Neonatal Abstinence Syndrome; Brain; Receptors, Opioid, mu
PubMed: 37866706
DOI: 10.1016/j.taap.2023.116731 -
Molecules (Basel, Switzerland) Nov 2022(1) Background: Methadone, along with buprenorphine, is the most commonly used drug for the treatment of opioid dependence. This study aimed to analyze methadone and its...
(1) Background: Methadone, along with buprenorphine, is the most commonly used drug for the treatment of opioid dependence. This study aimed to analyze methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenyl pyrrolidine (EDDP), in the urine and plasma of opiate addicts. The study group consisted of drug users voluntarily admitted to the detoxification center C.E.T.T.T. "St. Stelian" of Bucharest. Secondly, the study aimed to identify whether urine or plasma provides better results for the proposed method. (2) Methods: A GC-MS method, using an internal standard (diphenylamine) in the FULL-SCAN and SIM modes of operation and using the m/z = 72 ion for methadone and the m/z = 277 ion for EDDP, combined with a liquid-liquid extraction procedure was performed. (3) Results: The applied procedure allows the detection and quantification of methadone in both urine and plasma samples. EDDP was identified in patients with higher levels of methadone. Higher levels of methadone were detected in urine than in plasma samples. (4) Conclusions: This procedure can be used in clinical laboratories for the rapid determination of methadone levels in urine rather than in plasma. The procedure can be applied for the monitoring of methadone substitution treatment.
Topics: Humans; Methadone; Gas Chromatography-Mass Spectrometry; Buprenorphine; Opioid-Related Disorders; Pyrrolidines
PubMed: 36500452
DOI: 10.3390/molecules27238360 -
Medicina (Kaunas, Lithuania) 2009Methadone is a long-acting synthetic opioid with high affinity for various opioid receptors, especially for m-opioid receptors. Methadone has been used as a successful... (Comparative Study)
Comparative Study Review
Methadone is a long-acting synthetic opioid with high affinity for various opioid receptors, especially for m-opioid receptors. Methadone has been used as a successful pharmacologic intervention for the treatment of heroin dependence and acute and chronic pain. This treatment is effective for opiate addiction, reducing morbidity and mortality associated with heroin use. However, overdosing with methadone has become a growing phenomenon because of the increased availability of this drug. Patients enrolled in a methadone maintenance treatment program may become physically dependent and may experience methadone withdrawal symptoms. In this review article, there are discussed about pharmacokinetic and pharmacodynamic properties of methadone, clinical symptoms of its overdose, dosage problems, detection of methadone in biological samples, treatment, and causes of methadone overdose-related deaths.
Topics: Adult; Analgesics, Opioid; Child, Preschool; Drug Interactions; Drug Overdose; Electrocardiography; Female; Heroin Dependence; Humans; Infant, Newborn; Male; Methadone; Narcotics; Neonatal Abstinence Syndrome; Pain; Pregnancy; Risk Factors; Substance Withdrawal Syndrome; Time Factors
PubMed: 19535889
DOI: No ID Found -
Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease.Pediatric Blood & Cancer Dec 2016Vaso-occlusive episodes (VOEs) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vaso-occlusive episodes (VOEs) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone use for SCD pain. This investigation evaluated methadone pharmacokinetics in children and adults with SCD, with a secondary aim to assess pain relief and opioid consumption.
PROCEDURE
Participants included children (<18 years) and adults with a VOE requiring hospitalization. Patients were randomly assigned to receive standard care (opioid patient-controlled analgesia; control group) or one dose of intravenous methadone (0.1-0.125 mg/kg) in addition to standard care (methadone group). Venous methadone and metabolite concentrations were measured. Pain scores, pain relief scores, and opioid consumption were recorded.
RESULTS
Twenty-four children (12 methadone, 12 controls) and 23 adults (11 methadone, 12 controls) were studied. In children, the half-life of R- and S-methadone enantiomers was 34 ± 16 and 24 ± 9 hr, respectively. In adults, R- and S-methadone half-lives were 52 ± 17 and 38 ± 12 hr, respectively. Pain scores were lower (P = 0.002) and pain relief scores were higher (P = 0.0396) in children receiving methadone versus controls. There was no difference in pain scores and pain relief in adults receiving methadone versus controls. There was no difference in opioid consumption between methadone and control groups, in both adults and children.
CONCLUSIONS
Intravenous methadone disposition in children and adults with SCD was comparable to that in subjects without SCD from prior studies. Methadone produced more pain relief than standard care in children with SCD. Higher methadone doses may be more effective and should be evaluated in both children and adults with SCD.
Topics: Adolescent; Analgesics, Opioid; Anemia, Sickle Cell; Child; Female; Humans; Male; Methadone; Pain
PubMed: 27572136
DOI: 10.1002/pbc.26207 -
Paediatric Anaesthesia Jun 2014The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective...
BACKGROUND
The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP).
METHODS
Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics.
RESULTS
A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) .
CONCLUSIONS
Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.
Topics: Adolescent; Aging; Algorithms; Analgesics, Opioid; Child; Child, Preschool; Computer Simulation; Electrocardiography; Female; Humans; Infant; Infant, Newborn; Male; Methadone; Stereoisomerism
PubMed: 24666686
DOI: 10.1111/pan.12385 -
Journal of Addiction Medicine Apr 2021Methadone regulations have changed minimally since 1974, despite advances in the understanding of the nature of opioid use disorder (OUD) and the role of medications in... (Review)
Review
Methadone regulations have changed minimally since 1974, despite advances in the understanding of the nature of opioid use disorder (OUD) and the role of medications in its treatment. At that time, most patients with OUD were considered to have anti-social personality disorders and the regulations aimed to exert maximal control over medication access. Six- or seven-day clinic attendance is required for months, regardless of distance, or childcare and other social responsibilities. Take home medications are not allowed unless rigid and formulaic conditions are met. Although addiction medicine has rejected the "criminal" paradigm in favor of OUD as a treatable medical disorder, methadone regulations have not kept pace with the science. Pregnancy is characterized by an ultra-rapid metabolic state, but regulations prevent the use of daily divided doses of methadone to maintain stability. This results in repeated episodes of maternal/fetal opioid withdrawal, as well as other fetal physiologic abnormalities. Interference with dose regimen adjustments prevents optimal outcomes. Further, methadone clinics are mostly urban, leaving patients in rural areas without access. This led to excessive morbidity and mortality when the opioid crisis hit. The response of merely expanding capacity in overcrowded urban clinics created a contagion menace when Covid-19 arrived. Pregnant women (and parents with children) were forced to negotiate dosing in dangerous conditions. A revised methadone system must provide treatment that is local, flexible, and limited in size to manage viral contagion risks. This regulatory change can most easily be started by changing regulations that adversely affect pregnant women.
Topics: Analgesics, Opioid; Dose-Response Relationship, Drug; Female; Health Policy; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Pregnancy Complications; United States
PubMed: 32826620
DOI: 10.1097/ADM.0000000000000720 -
Drug and Alcohol Dependence Nov 2021The loosening of U.S. methadone regulations during the COVID-19 pandemic expanded calls for methadone reform. This study examines professional perceptions of methadone...
BACKGROUND
The loosening of U.S. methadone regulations during the COVID-19 pandemic expanded calls for methadone reform. This study examines professional perceptions of methadone take-home dose regulation before and during the COVID-19 pandemic to understand responses to varied methadone distribution policies.
METHODS
Fifty-nine substance use disorder treatment professionals were interviewed between 2017 and 2020 in-person or over video call. An inductive iterative coding process was used to analyze the data. Constructivist grounded theory guided the collection and analysis of in-depth interviews.
RESULTS
Treatment professionals expressed mixed views toward methadone take-home regulations. Participants justified regulation using several arguments: 1) patient care benefitting from supervision, 2) attributing improved patient safety to take-home regulation, 3) fearing liability for methadone-related harms, and 4) relying on buprenorphine as an "escape hatch" for patients who cannot manage MMT policies. Other professionals suggested partial deregulation, while others strongly opposed pre-pandemic take-home regulation, explaining such regulations impede medication access and hinder patient-centered care. Some professionals supported the COVID-19 policy changes and saw these as a test run for broader deregulation, while others framed the changes as temporary and cautiously applied deregulation to their services, at times revoking looser rules for patients they perceived as nonadherent.
CONCLUSION
Treatment professionals working in a range of modalities, including opioid treatment programs, expressed hesitation toward expanded take-home methadone access. While some participants also supported forms of deregulation, post-pandemic efforts to extend looser methadone distribution policies will have to address apprehensive professionals if such policy changes are to be meaningfully adopted in community services.
Topics: COVID-19; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pandemics; Perception; SARS-CoV-2
PubMed: 34600251
DOI: 10.1016/j.drugalcdep.2021.109100