Methadone

A systematic review and meta-analysis quantified the incidence during methadone maintenance treatment.supported

Systematic review and meta-analysis quantifying incidence of QTc prolongation and TdP in methadone maintenance treatment. md.0000000000045304

Additive respiratory depression is confirmed experimentally for the diazepam/methadone combinationsupported

Diazepam/methadone combination produces additive respiratory depression in rats. j.drugalcdep.2012.12.020

The mechanism is direct hERG (IKr) potassium channel blockade (IC₅₀ = 4.8 μM), confirmed in iPSC-derived cardiomyocytes where methadone also inhibits L-type calcium current (ICaL) and late sodium current (INaL)partially supported

Methadone IC50 for hERG inhibition = 4.8 microM. s12012-010-9074-y

The mechanism is direct hERG (IKr) potassium channel blockade (IC₅₀ = 4.8 μM), confirmed in iPSC-derived cardiomyocytes where methadone also inhibits L-type calcium current (ICaL) and late sodium current (INaL)supported

Methadone inhibited hERG (IhERG), ICaL, and INaL at clinically relevant concentrations; caused delayed repolarization in iPSC-CMs. journal.pone.0241362

The American Heart Association's scientific statement on drug-induced arrhythmias specifically names methadone among drugs capable of QTc prolongation and TdPsupported

AHA scientific statement on drug-induced arrhythmias. Methadone specifically mentioned as capable of prolonging QT interval and provoking torsades de pointes. cir.0000000000000905

Claim in safety — inconclusiveinconclusiveworking →

Risk factors include: doses exceeding 100 mg/day, co-administration of other QT-prolonging drugs, hypokalemia and hypomagnesemia, pre-existing cardiac disease, female sex, and CYP inhibition raising S-methadone levelssupported

AHA scientific statement on drug-induced arrhythmias. Methadone specifically mentioned as capable of prolonging QT interval and provoking torsades de pointes. cir.0000000000000905

Risk factors include: doses exceeding 100 mg/day, co-administration of other QT-prolonging drugs, hypokalemia and hypomagnesemia, pre-existing cardiac disease, female sex, and CYP inhibition raising S-methadone levelssupported

CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135

Claim in safety — inconclusiveinconclusiveworking →

Respiratory depression is the primary mechanism of fatal methadone overdosesupported

Co-ingested CNS depressants more critical than tolerance reduction. j.forsciint.2015.01.004

The induction phase — the first weeks of treatment — carries the highest mortality risk.supported

Largest proportion of deaths during induction phase. pmid:21158011

The induction phase — the first weeks of treatment — carries the highest mortality risk.supported

Mortality drops sharply in first 4 weeks of treatment. bmj.j1550

Forensic data: a systematic review of methadone-related deaths found median postmortem blood concentration of 503 ng/mL (IQR 300–933 ng/mL) in adultssupported

Median blood methadone concentration in adults at death: 503 ng/mL (IQR 300-933). s00414-025-03620-0

In 176 Kentucky methadone fatalities, mean blood concentration was 0.535 mg/L (range 0.02–4.0 mg/L), and only 6.25% had methadone as the sole detected drugsupported

176 Kentucky methadone fatalities 2000-2004. Mean blood concentration 0.535 mg/L (range 0.02-4.0). Only 6.25% had methadone as sole detected drug. pmid:18093068

Co-detected substances included antidepressants (39.8%), benzodiazepines (32.4%), other opioids (27.8%), cannabinoids (28.4%), and cocaine (21.9%)partially supported

Antidepressants (39.8%), benzodiazepines (32.4%), other opioids (27.8%) co-detected. pmid:18093068

Polydrug combinations — especially with benzodiazepines — constitute the overwhelming context for methadone fatalities.supported

Extensive benzodiazepine co-use in all subgroups. Co-ingested CNS depressants more critical than tolerance reduction. j.forsciint.2015.01.004

The CYP2B6 poor metabolizer phenotype (especially the CYP2B6*6 allele) significantly elevates blood methadone concentrations and is independently associated with fatal outcomessupported

CYP2B6*6 allele associated with high methadone concentrations in fatalities. pmid:21158011

The CYP2B6 poor metabolizer phenotype (especially the CYP2B6*6 allele) significantly elevates blood methadone concentrations and is independently associated with fatal outcomessupported

CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135

OPRM1 variants also influence methadone treatment outcomes and may modify dose requirements.supported

Study of OPRM1 and CYP2B6 genetic variants and methadone treatment outcomes in 1,172 patients. journal.pone.0261201

The overlap between therapeutic and fatal blood concentrations implies a narrow therapeutic index, particularly in opioid-naive individuals and CYP2B6 poor metabolizerssupported

Median blood methadone concentration in adults at death: 503 ng/mL (IQR 300-933), overlapping with therapeutic concentrations. s00414-025-03620-0

Dependence and compulsive use: Methadone is classified as having high abuse potential (DEA Schedule II). Psychological dependence develops alongside physical dependence.supported

Reviews neurobiology of addiction including opioid use disorder. nejmra1511480

Opioid tolerance develops through mu-opioid receptor desensitization, phosphorylation, uncoupling, and internalization — a cascade involving β-arrestin recruitment that reduces receptor density and signaling efficiencysupported

Review of opioid receptor desensitization mechanisms including phosphorylation, receptor uncoupling, internalization, and post-endocytic fate. Links receptor desensitization to clinical tolerance development. fphar.2014.00280

Methadone's β-arrestin-biased agonism may alter the kinetics of this desensitization relative to G-protein-biased agonists like morphine, though clinical confirmation is incomplete.supported

Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist. 1744806916654146

In vivo evidence for this is limited — spinal electrophysiology shows the NMDA component is modest and partially naloxone-reversible.supported

d-Methadone inhibitory effects on dorsal horn neurons are naloxone-reversible, suggesting predominantly opioid mechanism in vivo despite NMDA antagonist activity in vitro. pmid:10833552

Claim in safety — not_supportednot supportedworking →

Methadone maintenance treatment deliberately harnesses physical dependence therapeutically: the Cochrane meta-analysis confirms MMT retains patients and suppresses heroin use more effectively than non-opioid treatmentssupported

Methadone maintenance was first widely used ORT for heroin dependence. Retains patients better and decreases heroin use better than non-opioid treatments. 14651858.cd002209.pub2

The mortality benefit is substantial — all-cause mortality of 11.3 per 1,000 person-years during treatment versus 36.1 out of treatment.supported

All-cause mortality 11.3 vs 36.1 per 1000 person-years in vs out of methadone treatment. bmj.j1550

benzodiazepines and alcohol facilitate GABA-A-mediated inhibition, synergizing with methadone's mu-opioid respiratory depression through convergent but pharmacologically distinct pathwayssupported

Benzodiazepines and alcohol facilitate GABA inhibition; alcohol also decreases glutamate excitation at NMDA receptors. pmid:10707430

Benzodiazepines are the most prevalent co-detected substance in methadone fatalities.supported

Extensive benzodiazepine co-use in all subgroups. j.forsciint.2015.01.004

Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported

Methadone inhibits SERT in HEK293 cells transfected with human SERT. Supports pharmacological class as SNRI-type activity. s00204-018-2244-6

Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported

Methadone confirmed as SERT and NET inhibitor. Link to clinical reports of serotonin syndrome. bph.14105

Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported

Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6

Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported

High-risk combinations (e.g., MAOIs with tramadol/methadone) must be avoided. s00482-015-1512-0

Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported

Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6

Methadone's SERT and NET inhibition creates clinically significant serotonin syndrome risk in combination with MAOIs (high risk, potentially lethal), SSRIs, SNRIs, and TCAs (moderate risk). tramadol poses dual risk: it inhibits SERT/NET and is a weak mu-opioid agonist, producing both serotonin syndrome and enhanced respiratory depression simultaneously.supported

Combined with serotonergic drugs, can provoke serotonin syndrome. High-risk combinations (e.g., MAOIs with tramadol/methadone) must be avoided. s00482-015-1512-0

CYP inhibitors (fluconazole, paroxetine, grapefruit juice) elevate methadone levels, increasing both opioid and cardiac risksupported

Grapefruit juice (intestinal CYP3A inhibitor) investigated for effect on steady-state methadone PK. pmid:15229464

Claim in safety — inconclusiveinconclusiveworking →

The stereoselective metabolism means some interactions preferentially alter S- or R-methadone levels, with different clinical consequences.supported

CYP2B6 preferentially metabolizes S-methadone; CYP2C19 preferentially metabolizes R-methadone; CYP3A4 no stereoselectivity. pmid:14628297

Methadone functions as an independent risk factor for life-threatening arrhythmias.supported

Methadone specifically mentioned as capable of prolonging QT interval and provoking torsades de pointes. cir.0000000000000905

Concurrent MAOI use: High risk of lethal serotonin syndrome via methadone's SERT inhibition.supported

Methadone inhibits SERT in HEK293 cells transfected with human SERT. s00204-018-2244-6

Concurrent MAOI use: High risk of lethal serotonin syndrome via methadone's SERT inhibition.supported

High-risk combinations (e.g., MAOIs with tramadol/methadone) must be avoided. s00482-015-1512-0

QT-prolonging conditions or medications: Significant TdP risk; ECG monitoring required at initiation and dose changes.supported

Systematic review and meta-analysis quantifying incidence of QTc prolongation and TdP in methadone maintenance treatment. md.0000000000045304

QT-prolonging conditions or medications: Significant TdP risk; ECG monitoring required at initiation and dose changes.supported

Methadone specifically mentioned as capable of prolonging QT interval and provoking torsades de pointes. cir.0000000000000905

CYP2B6 poor metabolizer phenotype (especially *6/*6 genotype): Elevated blood levels; dose reduction and enhanced monitoring required.supported

CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135

CYP2B6 poor metabolizer phenotype (especially *6/*6 genotype): Elevated blood levels; dose reduction and enhanced monitoring required.supported

CYP2B6*6 allele associated with high methadone concentrations in fatalities. pmid:21158011

Concurrent benzodiazepine use: Additive respiratory depression; if unavoidable, dose reduction and respiratory monitoring are essential.supported

Extensive benzodiazepine co-use in all subgroups. Co-ingested CNS depressants more critical than tolerance reduction. j.forsciint.2015.01.004

Claim in pharmacology — inconclusiveinconclusiveworking →

Methadone has been characterized as a β-arrestin-biased μ-opioid receptor agonist, pharmacodynamically distinct from morphine and fentanyl in discriminative stimulus assays and in vitro measures of MOR internalization and β-arrestin recruitmentsupported

Investigates pharmacological profile of methadone vs fentanyl and morphine. Measures discriminative stimulus, NMDA receptor binding, mu-opioid receptor internalization, and beta-arrestin recruitment. 1744806916654146

Both enantiomers bind to the non-competitive (MK-801) site of the NMDA receptor in rat forebrain and spinal cord, with affinity in the low micromolar range comparable to dextromethorphan, while lacking affinity at the competitive (CGS-19755) sitesupported

dl-Methadone and d- and l-isomers exhibited low micromolar affinities for [3H]MK-801-labeled non-competitive NMDA site in rat forebrain and spinal cord. Ki values similar to dextromethorphan. No affinity at competitive site. pmid:9058409

Racemic methadone binds the MK-801-labeled site with Ki = 0.85 μMsupported

Methadone Ki for [3H]MK-801 binding = 0.85 microM. pmid:7624018

Functional inhibition of all rat NMDA receptor subtypes occurs at low micromolar IC₅₀ values that overlap with clinically achievable plasma concentrations, with NR1/2A and NR1/2B subtypes more sensitive than NR1/2C and NR1/2D; R(−)-methadone shows preferential selectivity for NR1/2Asupported

Racemic methadone inhibited all subtypes of rat NMDA receptors with IC50 in low micromolar range; concentrations overlap with clinically achievable levels. NR1/2A and NR1/2B more sensitive than NR1/2C and NR1/2D. Noncompetitive mechanism. R(-) methadone highly selective for NR1/2A. pmid:14980914

The mechanism is non-competitive channel block, reducing maximum NMDA-stimulated currents without shifting EC₅₀.supported

Noncompetitive mechanism. pmid:14980914

Methadone has been characterized alongside ketobemidone as a weak non-competitive NMDA antagonist with potential utility in neuropathic pain via combined opioid and NMDA mechanismssupported

Methadone, ketobemidone, and dextropropoxyphene demonstrated to be weak noncompetitive NMDA receptor antagonists in addition to being opioid agonists. Discusses structure-activity relationships and clinical relevance for neuropathic pain. pmid:9783723

Despite these in vitro findings, in vivo spinal cord electrophysiology in rats demonstrated that methadone's antinociceptive effects are predominantly opioid-receptor mediated and naloxone-reversible, with the NMDA antagonist component playing a lesser role than in vitro data might suggestsupported

d-Methadone inhibitory effects on dorsal horn neurons are naloxone-reversible, suggesting predominantly opioid mechanism in vivo despite NMDA antagonist activity in vitro. pmid:10833552

Methadone inhibits the human serotonin transporter (SERT) in HEK293 cells and shows interaction with 5-HT₂A receptorssupported

Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6

Norepinephrine transporter (NET) inhibition has also been quantified, confirming SERT and NET inhibitory activity at therapeutic concentrationssupported

Systematic in vitro study of opioid effects on SERT and NET. Methadone confirmed as SERT and NET inhibitor. bph.14105

Methadone directly blocks the cardiac hERG (IKr) potassium channel with an IC₅₀ of 4.8 μM — approximately 100-fold more potent than heroin at this targetsupported

Methadone IC50 for hERG inhibition = 4.8 microM; heroin IC50 = 427 microM. Methadone ~100-fold more potent than heroin at blocking hERG currents. s12012-010-9074-y

In iPSC-derived cardiomyocytes, methadone also inhibits L-type calcium current (ICaL) and late sodium current (INaL) at clinically relevant concentrations, causing delayed repolarizationsupported

Methadone inhibited hERG (IhERG), ICaL, and INaL at clinically relevant concentrations; caused delayed repolarization in iPSC-CMs. journal.pone.0241362

Methadone's pharmacokinetics are defined by high oral bioavailability (~75%, range 36–100%), slow absorption (Tmax 2.5–4 hours), extensive tissue distribution (Vd ~4 L/kg), and a long, highly variable elimination half-life (mean ~22 hours, range 5–130 hours)supported

Methadone bioavailability mean ~75% (range 36-100%). Peak plasma at 2.5-4 hours. Mean half-life ~22 hours (range 5-130h). Volume of distribution ~4 L/kg. pmid:12405865

Interindividual variability in blood concentration can reach 17-fold for a given dose, driven primarily by CYP enzyme polymorphismssupported

17-fold interindividual variation in blood concentration. CYP3A4 and CYP2D6 metabolism. pmid:12405865

Metabolism proceeds via N-demethylation to the inactive metabolite EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), with CYP2B6 as the primary enzyme, CYP2C19 as secondary, and CYP3A4 as tertiarysupported

CYP2B6 has highest Vmax/Km for EDDP formation from methadone. Hierarchy: CYP2B6 > CYP2C19 >= CYP3A4. pmid:14628297

Metabolism proceeds via N-demethylation to the inactive metabolite EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), with CYP2B6 as the primary enzyme, CYP2C19 as secondary, and CYP3A4 as tertiarysupported

CYP2B6 identified as principal methadone metabolizing enzyme (more recent data). journal.pone.0231467

Sustained MOR occupancy during maintenance treatment reduces the neurobiological drive for exogenous opioid seeking, though it simultaneously suppresses endogenous peptide tone — contributing to the dependence and withdrawal syndrome observed upon discontinuation.supported

Reviews neurobiology of addiction including opioid use disorder. Discusses how brain disease model has led to effective treatments including methadone maintenance. nejmra1511480

Methadone maintenance stabilizes the allostatic set point by providing consistent MOR agonism, reducing the between-dose withdrawal cycles that drive further allostatic shift.supported

Reviews neurobiology of addiction including opioid use disorder. Discusses how brain disease model has led to effective treatments including methadone maintenance. nejmra1511480

Does β-arrestin-biased agonism at MOR meaningfully alter clinical tolerance and respiratory depression? Methadone's β-arrestin bias predicts distinct downstream signaling, but whether this translates to clinically relevant differences in tolerance kinetics or overdose risk versus G-protein-biased agonists remains unresolved.supported

Characterization of methadone as a β-arrestin-biased μ-opioid receptor agonist. 1744806916654146

Can pharmacogenomic-guided dosing reduce methadone-related mortality? CYP2B6 and OPRM1 variants predict treatment outcomes and fatality risk, but prospective implementation studies of genotype-guided methadone dosing are lacking.supported

Study of OPRM1 and CYP2B6 genetic variants and methadone treatment outcomes in 1,172 patients. journal.pone.0261201

Can pharmacogenomic-guided dosing reduce methadone-related mortality? CYP2B6 and OPRM1 variants predict treatment outcomes and fatality risk, but prospective implementation studies of genotype-guided methadone dosing are lacking.supported

CYP2B6*6 allele associated with high methadone concentrations in fatalities. OPRM1 A118G allele correlated with benzodiazepine co-detection. pmid:21158011

Can pharmacogenomic-guided dosing reduce methadone-related mortality? CYP2B6 and OPRM1 variants predict treatment outcomes and fatality risk, but prospective implementation studies of genotype-guided methadone dosing are lacking.supported

CYP2B6 SNPs rs3745274 and rs8192719 enhanced in fatality group. CYP2B6 poor metabolizers at elevated fatality risk. bkw135

This circuit mediates the reinforcing and euphoric effects of all mu-opioid agonistssupported

Reviews neurobiology of addiction including opioid use disorder. nejmra1511480

The additional NMDA receptor antagonism at spinal and supraspinal sites may provide supplementary antinociceptive activity, though in vivo evidence assigns a dominant role to opioid receptors.supported

d-Methadone inhibitory effects on dorsal horn neurons are naloxone-reversible, suggesting predominantly opioid mechanism in vivo despite NMDA antagonist activity in vitro. pmid:10833552

Methadone's non-competitive NMDA antagonism (Ki = 0.85 μM at the MK-801 site) may counteract central sensitization and wind-up, providing a mechanistic basis for its reported utility in neuropathic pain and opioid rotation settings where tolerance to other opioids has developed.partially supported

Methadone, ketobemidone, and dextropropoxyphene demonstrated to be weak noncompetitive NMDA receptor antagonists. Discusses clinical relevance for neuropathic pain. pmid:9783723

Claim in neuroscience — inconclusiveinconclusiveworking →

What is the quantitative contribution of NMDA antagonism to methadone's clinical analgesia? In vitro data show functionally relevant NMDA blockade at therapeutic concentrations, but in vivo evidence assigns a dominant role to opioid receptors. The NMDA contribution may be most significant in neuropathic pain states and tolerance attenuation — conditions difficult to isolate in clinical trials.supported

d-Methadone inhibitory effects on dorsal horn neurons are naloxone-reversible, suggesting predominantly opioid mechanism in vivo despite NMDA antagonist activity in vitro. pmid:10833552

Does SERT/NET inhibition contribute meaningfully to methadone's clinical effects? In vitro SERT and NET activity is documented, but no clinical study has isolated the monoaminergic contribution to methadone's analgesic or mood effects independent of MOR agonism.supported

Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6

Methadone (6-(dimethylamino)-4,4-diphenylheptan-3-one) is a synthetic full mu-opioid receptor agonist of the diphenylheptanone class, distinguished from other clinical opioids by its exceptionally long and variable elimination half-life (mean ~22 hours, range 5–130 hours) and oral duration of 10–19 hourssupported

Mean half-life ~22 hours (range 5-130h). pmid:12405865

Claim in summary — inconclusiveinconclusiveworking →

Methadone was added to the WHO Model List of Essential Medicines in 2005 and remains the most extensively studied pharmacotherapy for opioid use disorder.partially supported

In March 2005, methadone and buprenorphine added as 'complementary' medicines to the 14th WHO Model List of Essential Medicines. pmid:16544403

The R(−)-enantiomer drives mu-opioid receptor agonism — characterized as β-arrestin-biased — while both enantiomers block NMDA receptors at the MK-801 site (Ki = 0.85 μM)supported

Investigates pharmacological profile of methadone vs fentanyl and morphine. Measures discriminative stimulus, NMDA receptor binding, mu-opioid receptor internalization, and beta-arrestin recruitment. 1744806916654146

The R(−)-enantiomer drives mu-opioid receptor agonism — characterized as β-arrestin-biased — while both enantiomers block NMDA receptors at the MK-801 site (Ki = 0.85 μM)supported

Methadone Ki for [3H]MK-801 binding = 0.85 microM. pmid:7624018

Additional activity includes serotonin and norepinephrine transporter inhibition and hERG potassium channel blockade (IC₅₀ = 4.8 μM).supported

Methadone inhibits SERT in HEK293 cells transfected with human SERT. Also shows 5-HT2A receptor interaction. s00204-018-2244-6

Additional activity includes serotonin and norepinephrine transporter inhibition and hERG potassium channel blockade (IC₅₀ = 4.8 μM).supported

Methadone confirmed as SERT and NET inhibitor. bph.14105

Additional activity includes serotonin and norepinephrine transporter inhibition and hERG potassium channel blockade (IC₅₀ = 4.8 μM).supported

Methadone IC50 for hERG inhibition = 4.8 microM. s12012-010-9074-y

Methadone carries a narrow therapeutic index: postmortem blood concentrations in fatalities (median 503 ng/mL) overlap substantially with therapeutic levels in tolerant patientssupported

Median blood methadone concentration in adults at death: 503 ng/mL (IQR 300-933), overlapping with therapeutic concentrations. s00414-025-03620-0

QTc prolongation via hERG blockade constitutes an independent cardiac risk rare among opioidssupported

Systematic review and meta-analysis quantifying incidence of QTc prolongation and TdP in methadone maintenance treatment. md.0000000000045304

Physical dependence develops rapidly; tolerance proceeds through mu-opioid receptor desensitization, though NMDA antagonism may attenuate this process relative to pure mu agonistssupported

Review of opioid receptor desensitization mechanisms including phosphorylation, receptor uncoupling, internalization, and post-endocytic fate. Links receptor desensitization to clinical tolerance development. fphar.2014.00280

Interindividual pharmacokinetic variability is extreme — up to 17-fold differences in blood concentration for a given dose — driven primarily by CYP2B6 polymorphismspartially supported

17-fold interindividual variation in blood concentration. CYP3A4 and CYP2D6 metabolism. pmid:12405865

Overdose mortality: 2.6 versus 12.7 per 1,000 person-years in and out of treatment, respectivelysupported

Overdose mortality 2.6 vs 12.7 per 1000 person-years. bmj.j1550

A Cochrane review comparing methadone and buprenorphine maintenance found comparable efficacy overall, with methadone showing superior treatment retention at adequate doses and buprenorphine demonstrating a more favorable safety profile (lower overdose risk)partially supported

Methadone superior to buprenorphine in retaining people in treatment. 14651858.cd002207.pub4

Methadone remains the standard comparator in trials of diamorphine (pharmaceutical heroin) prescribing for treatment-refractory heroin dependence.supported

Supervised injectable heroin treatment as intensive alternative to standard oral methadone maintenance treatment for entrenched heroin users. bjp.bp.114.149195

A Cochrane systematic review confirmed that MMT retains patients in treatment and reduces heroin use significantly more than non-opioid treatments or placebosupported

Retains patients better and decreases heroin use better than non-opioid treatments. 14651858.cd002209.pub2

The induction phase carries the highest mortality risk; mortality rates are elevated in the first four weeks after treatment entry and in the period immediately following treatment cessation.supported

Largest proportion of deaths during induction phase. pmid:21158011

Claim in clinical-evidence — inconclusiveinconclusiveworking →

The CDC's 2022 clinical practice guideline notes methadone's unique risks (QT prolongation, variable pharmacokinetics) and recommends it be prescribed only by clinicians familiar with its specific properties.supported

Updated CDC clinical practice guideline for prescribing opioids for pain. Includes guidance on opioid selection and dosages. mmwr.rr7103a1

A systematic review documented wide variation in published conversion ratios, with the methadone:morphine ratio increasing at higher morphine-equivalent doses (a phenomenon unique to methadone among opioids).supported

Systematic review of methadone conversion methods and dosing ratios for pain treatment. Wide variability in published conversion ratios. j.1526-4637.2008.00461.x

Claim in clinical-evidence — not_supportednot supportedworking →

Claim in clinical-evidence — not_supportednot supportedworking →

All values from the definitive pharmacokinetic review.supported

Methadone bioavailability mean ~75% (range 36-100%). Peak plasma at 2.5-4 hours. Mean half-life ~22 hours (range 5-130h). R-enantiomer mean ~40h. CYP3A4 and CYP2D6 metabolism. 17-fold interindividual variation in blood concentration. pmid:12405865

Up to 17-fold variation in blood concentration for a given oral dose has been documented, primarily attributable to CYP enzyme polymorphismssupported

17-fold interindividual variation in blood concentration. CYP3A4 and CYP2D6 metabolism. pmid:12405865

The stereoselective CYP enzyme hierarchy, confirmed by subsequent population pharmacokinetic modeling:supported

CYP2B6 phenotype determinant of clearance of both R- and S-methadone enantiomers. psp4.12687

The stereoselective CYP enzyme hierarchy, confirmed by subsequent population pharmacokinetic modeling:supported

Comprehensive population PK model for R- and S-methadone and EDDP. Weight and CYP2B6 genotype but not CYP2C19, sex or race as key covariates. Enantiomeric differences in CYP2B6-catalyzed metabolism. cpt.70147

This hierarchy was revised and corroborated by subsequent work, firmly establishing CYP2B6 as the principal enzymesupported

CYP2B6 has highest Vmax/Km for EDDP formation from methadone. Hierarchy: CYP2B6 > CYP2C19 >= CYP3A4. pmid:14628297

This hierarchy was revised and corroborated by subsequent work, firmly establishing CYP2B6 as the principal enzymesupported

CYP2B6 identified as principal methadone metabolizing enzyme (more recent data). journal.pone.0231467

Grapefruit juice: Intestinal CYP3A4 inhibitorsupported

Grapefruit juice (intestinal CYP3A inhibitor) investigated for effect on steady-state methadone PK. pmid:15229464

A Cochrane comparison found methadone superior for treatment retention at adequate doses, while buprenorphine's safety profile (lower overdose risk, reduced QT liability) and office-based prescribing model expand its accessibility.partially supported

Methadone superior to buprenorphine in retaining people in treatment. 14651858.cd002207.pub4

The β-arrestin bias profile of methadone diverges from fentanyl's MOR signaling pattern, though the clinical implications of this difference for overdose risk remain under investigation.supported

Investigates pharmacological profile of methadone vs fentanyl and morphine. Measures discriminative stimulus, NMDA receptor binding, mu-opioid receptor internalization, and beta-arrestin recruitment. 1744806916654146

Methadone's β-arrestin-biased agonism at MOR contrasts with morphine's relatively G-protein-biased profile — a distinction with potential implications for tolerance kinetics and respiratory depression liability, though clinical confirmation is incomplete.supported

Investigates pharmacological profile of methadone vs fentanyl and morphine. Measures mu-opioid receptor internalization and beta-arrestin recruitment. 1744806916654146

Pharmacokinetically, methadone's oral bioavailability (~75%) far exceeds morphine's (~25–30%), and its elimination half-life (mean ~22 hours versus morphine's 2–3 hours) permits once-daily dosingsupported

Methadone bioavailability mean ~75% (range 36-100%). Mean half-life ~22 hours (range 5-130h). pmid:12405865

Equianalgesic conversion is not fixed: the methadone:morphine ratio shifts with increasing morphine-equivalent dose, reflecting methadone's incomplete cross-tolerance and possible NMDA-mediated anti-tolerance effects.supported

Systematic review of methadone conversion methods and dosing ratios for pain treatment. Wide variability in published conversion ratios. j.1526-4637.2008.00461.x

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

Functional inhibition across NMDA receptor subtypes, measured in Xenopus oocytes expressing recombinant rat receptors, revealed a selectivity gradient: NR1/2A and NR1/2B subtypes are significantly more sensitive to methadone than NR1/2C and NR1/2Dsupported

Racemic methadone inhibited all subtypes of rat NMDA receptors with IC50 in low micromolar range. NR1/2A and NR1/2B more sensitive than NR1/2C and NR1/2D. pmid:14980914

R(−)-methadone: Higher mu-opioid receptor affinity; accounts for virtually all analgesic activity; longer elimination half-life (~40 hours); preferential selectivity for NR1/2A NMDA subtype.partially supported

R-enantiomer mean ~40h. pmid:12405865

S(+)-methadone: Weaker mu agonist; preferentially metabolized by CYP2B6; accumulates in CYP2B6 poor metabolizers; disproportionately responsible for QT prolongation.partially supported

CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135

Claim in chemistry — inconclusiveinconclusiveworking →

S(+)-methadone: a weaker mu-opioid agonist, preferentially metabolized by CYP2B6. Elevated S-methadone plasma concentrations are associated with QT prolongation and cardiotoxicity.partially supported

CYP2B6 poor metabolizers at elevated fatality risk. SNP rs3211371 associated with higher blood methadone concentrations. bkw135

Claim in history — inconclusiveinconclusiveworking →