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Electrophoresis Sep 2021The enantioselectivity of the pharmacokinetics of methadone was investigated in anesthetized Shetland ponies after a single intravenous (0.5 mg/kg methadone...
The enantioselectivity of the pharmacokinetics of methadone was investigated in anesthetized Shetland ponies after a single intravenous (0.5 mg/kg methadone hydrochloride; n = 6) or constant rate infusion (0.25 mg/kg bolus followed by 0.25 mg/kg/h methadone hydrochloride; n = 3) administration of racemic methadone. Plasma concentrations of l-methadone and d-methadone and their major metabolites, l- and d-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), respectively, were analyzed by CE with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection from liquid/liquid extracts prepared at alkaline pH. In both trials, the d-methadone concentrations were lower than those of l-methadone and the d-EDDP levels were lower than those of L-EDDP. For the case of a single intravenous bolus injection, the plasma concentration versus time profile of methadone enantiomers was analyzed with a two-compartment pharmacokinetic model. l-methadone showed a slower elimination rate constant, a lower body clearance, and a smaller steady-state volume of distribution than d-methadone. d-methadone and d-EDDP were eliminated faster than their respective l-enantiomers. This is the first study that outlines that the disposition of racemic methadone administered to anesthetized equines is enantioselective.
Topics: Animals; Electrophoresis, Capillary; Horses; Methadone; Pyrrolidines; Stereoisomerism
PubMed: 33978252
DOI: 10.1002/elps.202100115 -
Drug Metabolism Reviews Nov 2016Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the... (Review)
Review
Methadone is a full μ-opioid receptor agonist used in the treatment of heroin addiction. It is commercialized as a racemic mixture with considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile. This review aims to discuss metabolomics of methadone, namely by presenting all major and minor metabolites and pharmacokinetic drug interactions. The main mechanism for methadone metabolism is hepatic through the cytochrome P450, specifically isoenzymes 2B6, 3A4 and 2D6. Firstly, methadone is N-demethylated and cyclize to form its major 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) metabolites. Several alternate minor pathways have been described namely various methadol metabolites, which proved to be active. It is expected that knowing the metabolomics of methadone may provide further insights, attempting a personalized therapy aiming to attain effective blood concentrations. The historical record is therefore especially important when investigating clinical and forensic cases related to methadone administration, since interindividual responses are known to vary considerably.
Topics: Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Humans; Liver; Metabolomics; Methadone
PubMed: 27320437
DOI: 10.1080/03602532.2016.1192642 -
Paediatric Drugs Oct 2018Methadone is a synthetic opioid with unique pharmacodynamic and pharmacokinetic properties. It is effective in treating both nociceptive and neuropathic pain, which... (Review)
Review
Methadone is a synthetic opioid with unique pharmacodynamic and pharmacokinetic properties. It is effective in treating both nociceptive and neuropathic pain, which commonly co-exist in children with cancer. Upon reviewing the literature describing the use of methadone in pediatric oncology patients, publications are limited in number and low in quality of evidence; nevertheless, there is support for the safety and efficacy of methadone in treating pain in children with cancer, particularly when pain is refractory to conventional treatment. Although the risk of life-threatening arrhythmia is commonly cited as an argument against the use of methadone, our review of the literature did not support this finding in children. Further evaluation with prospective studies is warranted to develop evidence-based recommendations for the use of methadone in pediatric oncology.
Topics: Analgesics, Opioid; Cancer Pain; Child; Humans; Methadone; Neoplasms; Pain Management; Pain Measurement
PubMed: 30047027
DOI: 10.1007/s40272-018-0304-2 -
Clinical Pharmacology and Therapeutics Oct 2021Methadone, a widely prescribed medication for chronic pain and opioid addiction, is associated with respiratory depression and increased predisposition for torsades de...
Methadone, a widely prescribed medication for chronic pain and opioid addiction, is associated with respiratory depression and increased predisposition for torsades de pointes, a potentially fatal arrhythmia. Most methadone-related deaths occur during sleep. The objective of this study was to determine whether methadone's arrhythmogenic effects increase during sleep, with a focus on cardiac repolarization instability using QT variability index (QTVI), a measure shown to predict arrhythmias and mortality. Sleep study data of 24 patients on chronic methadone therapy referred to a tertiary clinic for overnight polysomnography were compared with two matched groups not on methadone: 24 patients referred for overnight polysomnography to the same clinic (clinic group), and 24 volunteers who had overnight polysomnography at home (community group). Despite similar values for heart rate, heart rate variability, corrected QT interval, QTVI, and oxygen saturation (SpO ) when awake, patients on methadone had larger QTVI (P = 0.015 vs. clinic, P < 0.001 vs. community) and lower SpO (P = 0.008 vs. clinic, P = 0.013 vs. community) during sleep, and the increase in their QTVI during sleep vs. wakefulness correlated with the decrease in SpO (r = -0.54, P = 0.013). QTVI positively correlated with methadone dose during sleep (r = 0.51, P = 0.012) and wakefulness (r = 0.73, P < 0.001). High-density ectopy (> 1,000 premature beats per median sleep period), a precursor for torsades de pointes, was uncommon but more frequent in patients on methadone (P = 0.039). This study demonstrates that chronic methadone use is associated with increased cardiac repolarization instability. Methadone's pro-arrhythmic impact may be mediated by sleep-related hypoxemia, which could explain the increased nocturnal mortality associated with this opioid.
Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Arrhythmias, Cardiac; Electrocardiography; Female; Heart Conduction System; Humans; Male; Methadone; Middle Aged; Polysomnography; Sleep
PubMed: 34287835
DOI: 10.1002/cpt.2368 -
The Annals of Pharmacotherapy Aug 2016To evaluate maternal and neonatal safety outcomes for methadone and buprenorphine in the obstetric population. (Review)
Review
OBJECTIVE
To evaluate maternal and neonatal safety outcomes for methadone and buprenorphine in the obstetric population.
DATA SOURCES
A literature search of PubMed (1966 to March 2016) and EMBASE (1973 to March 2016) was completed using the search terms buprenorphine, methadone, pregnancy, opioid, and neonatal abstinence syndrome Priority was given to randomized controlled trials and trials directly comparing buprenorphine and methadone during pregnancy. The bibliographies were reviewed for other relevant articles.
STUDY SELECTION AND DATA EXTRACTION
All human studies published in English, that compared methadone and buprenorphine use in pregnancy were evaluated. Because of the limited number of obstetric studies, only 5 critical studies were found.
DATA SYNTHESIS
Buprenorphine significantly improved or had similar outcomes to methadone for development of neonatal abstinence syndrome (NAS), percentage of infants requiring treatment for NAS (20%-47% vs 45.5%-57%, respectively), total amount of morphine used to treat NAS (0.472-3.4 vs 1.862-10.4 mg, respectively), duration of NAS (4.1-5.6 vs 5.3-9.9 days, respectively), peak NAS (3.9-11 vs 4.9-12.8 score, respectively), infant hospital stay (6.8-10.6 vs 8.1-17.5 days, respectively), and gestational age at delivery (38.8-39.7 vs 37.9-38.8 weeks, respectively). No difference was found with other neonatal or maternal outcomes.
CONCLUSIONS
Both methadone and buprenorphine are effective agents, with improved safety compared with continued nonmedical opioid use during pregnancy. There is evidence to suggest that buprenorphine should be considered as an equivalent option to methadone for use in pregnancy; however, larger studies are still needed to fully evaluate buprenorphine safety and advantages over methadone in the obstetric population.
Topics: Buprenorphine; Female; Humans; Infant; Infant, Newborn; Length of Stay; Methadone; Neonatal Abstinence Syndrome; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Pregnancy Complications; Randomized Controlled Trials as Topic
PubMed: 27199497
DOI: 10.1177/1060028016648367 -
Pain Medicine (Malden, Mass.) Oct 2015The use of opioids to treat chronic pain has come under increased scrutiny, as such use has been associated with significant risk of death, with limited data regarding... (Review)
Review
OBJECTIVE
The use of opioids to treat chronic pain has come under increased scrutiny, as such use has been associated with significant risk of death, with limited data regarding the long-term effectiveness, especially when used to treat noncancer pain. The purpose of this manuscript is to discuss the cardiac effects associated with long-term opioid therapy.
DESIGN
A literature search was performed using OVID.
RESULTS
Most opioids have little direct negative effect on cardiac contractility. However, opioid administration can be associated with decreased cardiac function when administered in combination with other medications, including benzodiazepines. Opioids can lead to bradycardia and vasodilation, and as a result can rarely lead to edema, hypotension, orthostatic hypotension, and syncope when used at analgesic doses. While most opioids have no effect on cardiac conductivity, methadone, and buprenorphine can prolong QTc, especially when used in patients at increased risk for QTc prolongation. Electrocardiogram (ECG) monitoring of QTc at baseline and following dose increases is appropriate in patients receiving these medications.
CONCLUSIONS
There are limited data to suggest that chronic opioid administration may be associated with an increased risk for cardiac-related adverse effects. However, this observation has not yet been confirmed. Regardless, while opioids are an important medication for the treatment of a multitude of chronic pain conditions, careful patient selection, and diligent monitoring is likely to decrease the risk of harm and improve patient outcomes.
Topics: Analgesics, Opioid; Chronic Pain; Heart; Humans; Methadone; Risk
PubMed: 26461073
DOI: 10.1111/pme.12915 -
The New York State Dental Journal 2015Methadone is a Schedule II drug best known for its use in the treatment of opioid dependence. Dental providers should be aware of the oral and systemic effects of... (Review)
Review
Methadone is a Schedule II drug best known for its use in the treatment of opioid dependence. Dental providers should be aware of the oral and systemic effects of methadone. In patients undergoing methadone maintenance therapy, there is a higher incidence of rampant caries, xerostomia, bruxism and poor oral hygiene. A review of the pharmacology, systemic effects, drug interactions and oral manifestations is presented, as well as possible modifications to treatment and specific considerations in dental therapies.
Topics: Dental Care for Chronically Ill; Heroin Dependence; Humans; Methadone; Mouth Diseases; Opiate Substitution Treatment; Oral Hygiene; Tooth Diseases
PubMed: 26521328
DOI: No ID Found -
Veterinary Anaesthesia and Analgesia Mar 2021To evaluate the pharmacokinetics and selected pharmacodynamic effects of a commercially available l-methadone/fenpipramide combination administered to isoflurane...
OBJECTIVE
To evaluate the pharmacokinetics and selected pharmacodynamic effects of a commercially available l-methadone/fenpipramide combination administered to isoflurane anaesthetized ponies.
STUDY DESIGN
Prospective single-group interventional study.
ANIMALS
A group of six healthy adult research ponies (four mares, two geldings).
METHODS
Ponies were sedated with intravenous (IV) detomidine (0.02 mg kg) and butorphanol (0.01 mg kg) for an unrelated study. Additional IV detomidine (0.004 mg kg) was administered 85 minutes later, followed by induction of anaesthesia using IV diazepam (0.05 mg kg) and ketamine (2.2 mg kg). Anaesthesia was maintained with isoflurane in oxygen. Baseline readings were taken after 15 minutes of stable isoflurane anaesthesia. l-Methadone (0.25 mg kg) with fenpipramide (0.0125 mg kg) was then administered IV. Selected cardiorespiratory variables were recorded every 10 minutes and compared to baseline using the Wilcoxon signed-rank test. Adverse events were recorded. Arterial plasma samples for analysis of plasma concentrations and pharmacokinetics of l-methadone were collected throughout anaesthesia at predetermined time points. Data are shown as mean ± standard deviation or median and interquartile range (p < 0.05).
RESULTS
Plasma concentrations of l-methadone showed a rapid initial distribution phase followed by a slower elimination phase which is best described with a two-compartment model. The terminal half-life was 44.3 ± 18.0 minutes, volume of distribution 0.43 ± 0.12 L kg and plasma clearance 7.77 ± 1.98 mL minute kg. Mean arterial blood pressure increased from 85 (±16) at baseline to 100 (±26) 10 minutes after l-methadone/fenpipramide administration (p = 0.031). Heart rate remained constant. In two ponies fasciculations occurred at different time points after l-methadone administration.
CONCLUSIONS AND CLINICAL RELEVANCE
Administration of a l-methadone/fenpipramide combination to isoflurane anaesthetized ponies led to a transient increase in blood pressure without concurrent increases in heart rate. Pharmacokinetics of l-methadone were similar to those reported for conscious horses administered racemic methadone.
Topics: Animals; Female; Heart Rate; Horses; Isoflurane; Ketamine; Male; Methadone; Prospective Studies; Respiration, Artificial
PubMed: 33423953
DOI: 10.1016/j.vaa.2020.04.018 -
Pain Medicine (Malden, Mass.) Sep 2015Methadone has been a stalwart pharmacologic option for the management of opioid drug dependence for many years. It substitutes for opioid agonists and possesses certain... (Review)
Review
BACKGROUND
Methadone has been a stalwart pharmacologic option for the management of opioid drug dependence for many years. It substitutes for opioid agonists and possesses certain pharmacokinetic properties that confer characteristics preferable to those of other opioids for this application. Methadone is likewise used as an option for the treatment of pain, particularly chronic pain. It has a spectrum of pharmacodynamic activity, including contributions from non-opioid components, that translates to its specific clinical attributes as an analgesic. Unfortunately, basic science studies and accumulated clinical experience with methadone have revealed some undesirable, and even worrisome, features, including issues of safety. The benefit/risk ratio of methadone might be acceptable if there was no better alternative, but neither its pharmacokinetic nor pharmacodynamic properties are unique to methadone.
OBJECTIVE
We review the basic and clinical pharmacology of methadone and suggest that levorphanol should receive attention as a possible alternative.
CONCLUSION
Unlike methadone, levorphanol is a more potent NMDA antagonist, possesses a higher affinity for DOR and KOR, has a shorter plasma half-life yet longer duration of action, has no CYP450 interactions or QTc prolongation risk, can be a viable option in the elderly, palliative care, and SCI patients, requires little to no need for co-administration of adjuvant analgesics, and has potentially a lower risk of drug-related Emergency Department visits compared to other opioids.
Topics: Analgesics, Opioid; Humans; Levorphanol; Methadone; Pain Management
PubMed: 26307179
DOI: 10.1111/pme.12795 -
Current Treatment Options in Oncology Mar 2020The opioid epidemic is one of the most important public health crises as opioid-related deaths have become a leading cause of accidental death in the USA. Various... (Review)
Review
The opioid epidemic is one of the most important public health crises as opioid-related deaths have become a leading cause of accidental death in the USA. Various efforts have been made to understand how to safely and appropriately prescribe opioids for patients with chronic pain, including those with cancer-related pain. We find the guidelines proposed by the Expert Consensus White Paper on the use of methadone to be current, comprehensive, and practical. While methadone is a complex medication with unique pharmacokinetics and pharmacodynamics, it remains a superior choice for many patients with cancer pain given its cost and applicability in a variety of situations. Methadone should be prescribed in the context of experienced clinicians as well as an interdisciplinary team. At a critical time when preventing opioid-related deaths is a priority, we recommend implementing additional precautions for monitoring including universal screening for risk of non-medical opioid use, education on proper storage and disposal, as well as discussing a plan with patients and caregivers in the case of serious complications such as opioid overdose.
Topics: Analgesics, Opioid; Cancer Pain; Clinical Decision-Making; Disease Management; Humans; Methadone; Opiate Substitution Treatment; Opioid Epidemic
PubMed: 32193644
DOI: 10.1007/s11864-020-0724-4