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Annals of Internal Medicine Jan 1973
Topics: Accidents, Home; Beverages; Fruit; Humans; Male; Methadone; Middle Aged; Substance-Related Disorders
PubMed: 4682304
DOI: 10.7326/0003-4819-78-1-154_2 -
Acta Anaesthesiologica Scandinavica.... 1982Studies with single doses of methadone have shown that the oral biological availability is 79 +/- 21%, range 41-99%. The rate of elimination is mostly due to metabolic...
Studies with single doses of methadone have shown that the oral biological availability is 79 +/- 21%, range 41-99%. The rate of elimination is mostly due to metabolic clearance. Below a urinary pH of 6, renal clearance becomes of quantitative importance. In five subjects treated with ammonium chloride (acidic urine), the plasma half-life of methadone was found to be 19.5 +/- 3.6 h. When treated with sodium bicarbonate the same subjects had plasma half-lives of 42.1 +/- 8.8 h. During continuous treatment with methadone, cellular tolerance may occur and in some subjects also metabolic tolerance. In treatment of severe cancer pain such adaptive changes in methadone pharmacodynamics and pharmacokinetics are best managed by a regimen involving a fixed dose but a flexible and patient-controlled dosage interval.
Topics: Administration, Oral; Biological Availability; Half-Life; Humans; Hydrogen-Ion Concentration; Kinetics; Methadone
PubMed: 6953740
DOI: 10.1111/j.1399-6576.1982.tb01850.x -
American Journal of Hospital Pharmacy Jul 1975A colorimetric method for direct quantitative assay of methadone hydrochloride in liquid oral dosage forms is presented. The procedure involves the formation of a dye...
A colorimetric method for direct quantitative assay of methadone hydrochloride in liquid oral dosage forms is presented. The procedure involves the formation of a dye complex with bromothymol blue buffer solution. The resultant complex is extracted with benzene and measured spectrophotometrically. Duplicate tests on the formulation showed 99.2% of the labeled amount of methadone.
Topics: Administration, Oral; Benzene; Colorimetry; Methadone; Solutions; Spectrophotometry
PubMed: 1146832
DOI: No ID Found -
Anesthesiology Dec 2011Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized,...
BACKGROUND
Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized, including the perioperative period. Methadone is also used in children. There is, however, no information on methadone pharmacokinetics in children of any age. The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed.
METHODS
Eligible subjects were children 5-18 yr undergoing general anesthesia and surgery, with an anticipated postoperative inpatient stay exceeding 3 days. Three groups of 10 to 11 patients each received intravenous methadone hydrochloride after anesthetic induction in ascending dose groups of 0.1, 0.2, and 0.3 mg/kg (up to 20 mg). Anesthetic care was not otherwise changed. Venous blood was obtained for 4 days, for stereoselective determination of methadone and metabolites. Pain assessments were made each morning. Daily and total opioid consumption was determined. Perioperative opioid consumption and pain was determined in a second cohort, which was matched to age, sex, race, ethnicity, surgical procedure, and length of stay, but not receiving methadone.
RESULTS
The final methadone study cohort was 31 adolescents (14 ± 2 yr, range 10-18) undergoing major spine surgery for a diagnosis of scoliosis. Methadone pharmacokinetics were linear over the dose range 0.1-0.3 mg/kg. Disposition was stereoselective. Methadone administration did not dose-dependently affect postoperative pain scores, and did not dose-dependently decrease daily or total postoperative opioid consumption in spinal fusion patients.
CONCLUSIONS
Methadone enantiomer disposition in adolescents undergoing surgery was similar to that in healthy adults.
Topics: Adolescent; Analgesics, Opioid; Analysis of Variance; Anesthesia, General; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Methadone; Pain Measurement; Pain, Postoperative; Perioperative Period; Scoliosis
PubMed: 22037641
DOI: 10.1097/ALN.0b013e318238fec5 -
Canadian Journal of Anaesthesia =... May 2005Methadone, an opioid traditionally associated with the management of opioid addictive disorders, has been prescribed increasingly as an analgesic for the management of... (Review)
Review
PURPOSE
Methadone, an opioid traditionally associated with the management of opioid addictive disorders, has been prescribed increasingly as an analgesic for the management of various chronic pain conditions. Despite the increasing popularity of methadone, most anesthesiologists are not familiar with its complex pharmacology. The purpose of this article is to review the pharmacology of methadone and to suggest a management algorithm for the perioperative care of methadone patients.
SOURCE
A Medline search was performed to obtain the published literature on the pharmacology of methadone and its use perioperatively.
PRINCIPAL FINDINGS
The complexity of methadone's pharmacology is characterized by a high inter-individual variability, a potential for interaction with other medications, and a long elimination half-life. The postoperative management of methadone patients may be difficult as they are often 'opioid-tolerant' but may be 'pain-intolerant'. For those patients who are taking part in methadone-maintenance programs, there is a potential for the problematic use of opioids or other substances. The management plan for patients taking methadone may differ depending on the type of surgery and the associated perioperative differences in fasting status and gastrointestinal function. In consideration of all the factors listed above, a management algorithm is outlined for the perioperative care of methadone patients.
CONCLUSION
Methadone is an opioid with complex properties, and a patient that is taking methadone can represent a unique challenge to the anesthesiologist. A good understanding of the pharmacology of methadone and of the type of patients on this medication will help to improve their perioperative care.
Topics: Drug Interactions; Drug Overdose; Humans; Methadone; Opioid-Related Disorders; Pain, Postoperative
PubMed: 15872131
DOI: 10.1007/BF03016532 -
Veterinary Anaesthesia and Analgesia Jan 2010To investigate the pharmacokinetics and effects of methadone on behaviour and plasma concentrations of cortisol and vasopressin in healthy dogs. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the pharmacokinetics and effects of methadone on behaviour and plasma concentrations of cortisol and vasopressin in healthy dogs.
STUDY DESIGN
Randomized, cross-over, experimental trial.
ANIMALS
Nine adult dogs (beagle and beagle cross breeds), four males and five females.
METHODS
Methadone hydrochloride, 0.4 mg kg(-1), was administered intravenously (IV) and subcutaneously (SC) with a crossover design. Drug and hormone analyses in plasma were performed using Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry and radioimmunoassay respectively. Behavioural data were collected using a standardized protocol.
RESULTS
After IV administration, the plasma concentration of methadone at 10 minutes was 82.1 +/- 9.2 ng mL(-1) (mean +/- SD), the terminal half-life was 3.9 +/- 1.0 hours, the volume of distribution 9.2 +/- 3.3 L kg(-1) and plasma clearance 27.9 +/- 7.6 mL minute(-1) kg(-1). After SC administration, time to maximal plasma concentration was 1.26 +/- 1.04 hours and maximal plasma concentration of methadone was 23.9 +/- 14.4 ng mL(-1), the terminal half-life was 10.7 +/- 4.3 hours and bioavailability was 79 +/- 22%. Concentrations of both cortisol and vasopressin were increased for an hour following IV methadone. The observed behavioural effects of methadone were decreased licking and swallowing and an increase in whining after SC administration. The latter finding is notable as it can be misinterpreted as pain when methadone is used as an analgesic.
CONCLUSION AND CLINICAL RELEVANCE
When methadone was administered by the SC route, the half-life was longer, but the individual variation in plasma concentrations was greater compared with IV administration. Increased frequency of whining occurred after administration of methadone and may be a drug effect and not a sign of pain. Cortisol and vasopressin concentrations in plasma may not be suitable for evaluating analgesia after methadone treatment.
Topics: Analgesics, Opioid; Animals; Cross-Over Studies; Dogs; Female; Half-Life; Hydrocortisone; Hypodermoclysis; Injections, Intravenous; Male; Metabolic Clearance Rate; Methadone; Vasopressins
PubMed: 20017819
DOI: 10.1111/j.1467-2995.2009.00476.x -
Journal of Veterinary Pharmacology and... Aug 2017We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and...
We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC-MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vd /F) and increased mean residence time (MRT) for NANO. One-compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone.
Topics: Administration, Oral; Analgesics, Opioid; Animals; Cross-Over Studies; Drug Carriers; Female; Horses; Lipids; Methadone; Prospective Studies; Tandem Mass Spectrometry
PubMed: 28092108
DOI: 10.1111/jvp.12393 -
The Medical Letter on Drugs and... Apr 1978
Topics: Heroin Dependence; Humans; Methadone; Methadyl Acetate
PubMed: 634227
DOI: No ID Found -
Neuro Endocrinology Letters Dec 2006A stereoselective HPLC method was developed to separate and quantify both enantiomers of methadone and its main metabolite EDDP in serum and urine. The method was used...
OBJECTIVES
A stereoselective HPLC method was developed to separate and quantify both enantiomers of methadone and its main metabolite EDDP in serum and urine. The method was used to establish that there is a relationship between the dose of methadone prescribed and its serum concentration as well as urine excretion of methadone and its metabolite enantiomers.
METHODS
The chiral alpha1-glycoprotein stationary phase was used for enantioseparation of (R)-methadone, (S)-methadone and (R)-EDDP (S)-EDDP. The enantiomers of methadone and EDDP were extracted from urine and serum by a simple solidphase procedure.
RESULTS
The validated method was applied to the analysis of 31 serum and urine samples obtained from methadone-maintained outpatients (65% male, age 28.8+/-4; methadone dose 146+/-47 mg). A significant correlation (Pearson) r=0.67 (p<0.001) between methadone dose and serum concentration of (R)-methadone was found. Due to the large variation in results obtained from analysis of the subjects' urine specimens, no statistically significant relationship between methadone dose and urine excretion of methadone and EDDP enantiomers was established. The rate of R/S methadone (1.38 in serum, 2.43 in urine) and R/S EDDP (0.83 in urine) confirmed stereoselectivity in methadone metabolism with high individual variability.
CONCLUSIONS
The enantioselective evaluation of serum methadone concentration might be an interesting tool in methadone maintenance programme. On the other hand, the urinary excretion of methadone and EDDP enantiomers is not reliable as marker of methadone compliance but could be useful for monitoring individual metabolism or for studying the stereoselectivity in pharmacokinetics and metabolism of methadone.
Topics: Adult; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Humans; Male; Methadone; Molecular Conformation; Opioid-Related Disorders; Sensitivity and Specificity
PubMed: 17159797
DOI: No ID Found -
Pharmacological Research Apr 2011Methadone (d,l-methadone hydrochloride) is a full-opioid agonist, originally developed as a substitution for heroin or other opiates abusers. Nowadays methadone is also...
Methadone (d,l-methadone hydrochloride) is a full-opioid agonist, originally developed as a substitution for heroin or other opiates abusers. Nowadays methadone is also being applied as long-lasting analgesics in cancer, and it is proposed as a promising agent for leukemia therapy. Previously, we have demonstrated that high concentrations of methadone (0.5mM) induced necrotic-like cell death in SH-SY5Y cells. The pathway involved is caspase-independent but involves impairment of mitochondrial ATP synthesis and mitochondrial cytochrome c release. However, the downstream mitochondrial pathways remained unclear. Here, we studied the participation of apoptosis inducing factor (AIF) in methadone-induced cell death. Methadone resulted in a translocation of AIF from mitochondria to the nucleus. Translocation was inhibited by cyclosporine A, but not by lack of Bax protein. Therefore the effect seems mediated by the formation of the mitochondrial transition pore, but is apparently independent of Bax. Furthermore, methadone-treated SH-SY5Y nuclei show characteristics that are typical for stage I nuclear condensation. Methadone did not induce degradation of DNA into oligonucleosomal fragments or into high molecular weight DNA fragments. Absence of DNA fragmentation coincided with a considerable decrease in the levels of the caspase-actived endonuclase DNase and its chaperone-inhibitor ICAD. In conclusion, our results provide mechanistic insights into the molecular mechanisms that underlie methadone-induced cell death. This knowledge may prove useful to develop novel strategies to prevent toxic side-effects of methadone thereby sustaining its use as therapeutical agent against tumors.
Topics: Analgesics, Opioid; Animals; Apoptosis Inducing Factor; Cell Line, Tumor; Histones; Humans; Methadone; Mice; Mitochondria; Necrosis; Neuroblastoma; Protein Transport; bcl-2-Associated X Protein
PubMed: 21145398
DOI: 10.1016/j.phrs.2010.12.001