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PubMedDate not supplied

Effect of methadone dose on the biliary excretion of methadone metabolites in the rat.

The effect of three different doses of 14C-methadone (0.08, 1.0 and 2.5 mg/kg) on the biliary excretion of methadone metabolites was studied in the rat. After administration of the 0.08- and 1.0-mg/kg doses of 14C-methadone there was no difference in the percentage of administered 14C excreted into bile with time. However, after the 2.5-mg/kg dose a significant increase was observed in the percentage of administered 14C excreted into bile. Analysis of bile samples showed that this increase was due to increases in the biliary excretion of two of the major metabolites of methadone. Several mechanisms could be responsible for this disproportionate increase in biliary excretion of methadone metabolites after high doses of methadone. It was found that the effect of high methadone dose on the biliary excretion of its metabolites was nearly eliminated when studied in phenobarbital (PB)-pretreated rats. Pretreatment of rats with PB increases the biliary excretion of methadone metabolites, primarily by increasing rates of methadone metabolism. The lack of additivity of the effect of the high dose of methadone and PB pretreatment on the biliary excretion of methadone metabolites suggests that a high dose of methadone also stimulates methadone metabolism, which results in the observed increased percentage of the administered dose excreted into bile.

Animals↗
PubMed1978

The placental transfer and materno-fetal disposition of methadone in monkeys.

A method is described for the quantitation of levo-methadone[3H] in biological samples which involves sample extraction and thin-layer chromatographic separation. Four pregnant Macaca mulata monkeys, two in early gestation and two in late gestation, were given single i.m. injections of levo-methadone[3H]. Twenty-nine fetal and maternal tissues and fluids were assayed to provide quantities of unchanged methadone and methadone plus metabolites. Little placental transfer of methadone or its metabolites occurred during early gestation, but equivalent concentrations of unchanged methadone were found in maternal and fetal tissues during late gestation (maternal brain, 172 ng/g; fetal brain, 123 ng/g). With few exceptions, tissues or fluids from the late gestation mothers showed higher levels of unchanged methadone than those from early gestation mothers at both 1 hour (P less than .001) and 6 hours (P less than .010) after administration. The late gestation mother had a 40.2% greater concentration of unchanged methadone at 6 hours and a 50.1% greater concentration at 1 hour than the early gestation mothers. These data suggest a slowing of metabolism during advanced pregnancy. At 6 hours after administration the eyes of both early and late gestation mothers and late gestation fetuses showed the highest concentrations of unchanged methadone of any maternal or fetal tissue. This localization of methadone appears to be associated with pigmented epithelium.

Animals↗
PubMed1977

Characterization of (+/-)-methadone uptake by rat lung.

1. By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (+/-)-methadone was concentrated in the lung. Lung to serum ratios ranging from 25 to 60 were obtained indicating that the rat lung tissue was capable of extracting (+/-)-methadone against a concentration gradient. 2. This phenomenon was investigated in vitro with rat lung slices incubated in Krebs-Ringer phosphate buffer (pH 7.4). The uptake was expressed in terms of tissue to medium concentration ratios (T/M ratio). 3. The principal observations were: (i) Studies on the time-course of the uptake showed that the T/M ratios of (+/-)-methadone increased rapidly during the first 60 min of incubation and then more slowly, with a plateau occurring at 180 min; (ii) The T/M ratio of (+/-)-methadone progressively increased from 9.5 to 17 as the pH of the incubation medium was varied from 6.2 to 7.5; (iii) When the concentration of (+/-)-methadone in the incubation medium was varied from 0.005 to 0.5 mM, the T/M ratio decreased rapidly suggesting self-saturation of the transport process. Beyond the medium concentration of 0.5 mM, the T/M ratio declined very slowly. 4. These results suggested that at low concentrations, (+/-)-methadone was transported predominantly by a self-saturable process while at higher concentrations it was transported by a process of simple diffusion. 5. At low concentrations (0.01 mM) the uptake of (+)-methadone was higher than that of (-)-isomer indicating stereo-specificity of the uptake process. The uptake of (+/-)-methadone at low concentration (0.01 mM) was significantly inhibited by low temperature, lack of O2, lack of glucose, lack of Na+ in the incubation medium, and by exposure of the tissue to high temperature (approximately 100 degrees C). The uptake was also inhibited by relatively high concentration of iodoacetate (1.0 mM) and of naloxone (1.0 mM). 6. Kinetic analysis of data showed that the diffusion constant for (+/-)-methadone was 5.0 (h-1) and the Vmax of the active transport process was 6.5 micronmol g-1h-1.

Animals↗
PubMed1976

The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone.

This review illustrates current approaches to the study of the disposition in man of the strong analagesics morphine and methadone and the narcotic antagonist naloxone. Morphine administered orally is rapidly absorbed but equally rapidly metabolised to morphine glucuronide. This contributes to the diminished oral efficacy of morphine. Following intramuscular administration morphine is very rapidly absorbed. After intravenous injection, the serum levels of morphine during the first 10 minutes are higher and more variable in older patients. The half-life of morphine between 20 minutes and 6 hours is 2 to 3 hours and this value does not appear to be influenced by the age of the patient. Similar half-lives for morphine have been reported to normal volunteers and in anaethetised patients who received morphine. Thus, surgical anaesthesia may not markedly influence morphine half-life and disposition. Based on urinary excretion data in man, accelerated morphine metabolism and excretion do not contribute to morphine tolerance. Methadone is now widely used in the treatment of narcotic abuse. The half-life of methadone averages 25 hours. The prolonged retention of methadone in the plasma may be related to its extensive binding to plasma proteins. With chronic dosing, studies in both animals and man indicate an increase in the metabolism of methadone. Unlike morphine, the urinary excretion of methadone increases with acidification of the urine. Women may metabolise methadone to a greater extent than do men. With the exception of pupillary effects, the plasma levels of methadone correlate poorly with its pharmacological activity. There is a marked variation in methadone plasma levels between patients and within the same patient. Naloxone rapidly disappears from the serum in man and the initial distribution phase has a half-life of 4 minutes. The half-life of naloxone in serum following distribution is 64 minutes. Based on animal studies, the rapid onset of the narcotic antagonist action of naloxone can be related to its rapid entry into the brain, whereas its potency stems in part from its high lipid solubility which allows a high brain concentration to be achieved. The short duration of action of naloxone may result from its rapid egress from the brain.

Absorption↗
PubMed1976

The binding of the optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives to the opiate receptors of rat brain.

The optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives have been systematically studied for their effects on the binding of 3H-dihydromorphine (3H-DHM) and 3H-naloxone (3H-NLX) to opiate receptors in rat brain homogenate. The relative affinities of these agents in competing for both 3H-DHM and 3H-NLX binding parallel their analgesic effects. 1-Methadone is about 30 times as effective as d-methadone in competing for both 3H-DHM and 3H-NLX binding sites. The reduction of 1-methadone to alpha-d-methadol and subsequent N-demethylation to alpha-d-normethadol reduce its effectiveness as indicated by the increase in the IC50 values for both 3H-DHM and 3H-NLX binding. The reduction of d-methadone followed by N-demethylation produces a potent derivative, alpha-1-normethadol, which has IC50 values on 3H-DHM and 3H-NLX binding similar to those of 1-methadone. The affinity of alpha-1-acetyl-methadol on the binding of both 3H-ligands falls between those of 1-methadone and d-methadone, and increases as it is N-demethylated. alpha-d-Acetyl-methadol is more effective than alpha-1-acetylmethadol in competing for both 3H-ligands from the opiate receptors, and its affinity, unlike that of alpha-1-acetylmethadol, decreases when it is N-demethylated. The affinities of the methadone isomers and related compounds on the binding of 3H-NLX fall in the presence of Na+. The latter property indicates the agonistic nature of this series of druges.

Animals↗
PubMedDate not supplied

Microsomal spectral properties and narcotic N-demethylase activity in methadone-dependent rats.

Rats were given access ad lib. to various concentrations (0.3 to 1.0 mg/ml) of methadone hydrochloride dissolved in sucrose solution. The N-demethylation of various narcotics was studied in hepatic preparations from methadone-consuming rats in order to determine if there was substrate specificity for the microsomal demethylase system. The Vmax for the N-demethylation of methadone, ethylmorphine, and meperidine was increased by 40-65%, whereas that for morphine N-demethylation was reduced to 55% of the control value. Additive or synergistic effects on microsomal cytochrome P-450 content were seen when methadone consumption was supplemented by administration of maximally inducing doses of either 3-methylcholanthrene (3-MC) or phenobarbital (PB). This suggested that there was an increase in a type of cytochrome P-450 which was independent of that induced by PB or 3-MC. The qualitative change in cytochrome P-450 reflected in the ethylisocyanide binding spectrum was also apparent after treatment with methadone, PB, or 3-MC, and the combination of methadone and PB exhibited effects that differed from PB alone. Two-substrate kinetic analysis with methadone and morphine as substrates indicated that more than one enzymic system may be involved in the N-demethylation reaction and that a common component of this N-demethylase system could not be induced with phenobarbital. However, methadone and meperidine seem to be demethylated by the same enzymic system.

Animals↗
PubMed1977

1-alpha-acetylmethadol (LAAM), methadone and morphine abstinence in dependent rats: EEG and behavioral correlates.

Adult female Sprague-Dawley rats were prepared with chronic intravenous cannulas and cortical and muscle electrodes for recording electroencephalograms and electromyograms, respectively. They were made physically dependent on morphine by automatic intravenous injections and then trained to lever press in order to self-administer morphine on a FR-20 schedule of reinforcement. Upon stabilization of morphine self-administration, one group continued to self-administer morphine, while two other groups were switched to methadone or 1-alpha-acetylmethadol (LAAM) self-administration for an additional five to ten days. Continuous EEG and EMG recordings were collected. Initially, automatic injections of morphine suppressed rapid eye movement (REM) sleep time, then tolerance developed to this effect. REM sleep time in rats self-administering LAAM, methadone or morphine was within the lower limit of the normal range. Following withdrawal, REM sleep was severely suppressed during the first 24 h with morphine and methadone, but only moderately suppressed with LAAM. Increases in lever pressing during withdrawal from morphine and methadone occurred earlier and were more intense and prolonged than for LAAM. The incidence of head shakes peaked earlier and was higher for morphine and methadone during withdrawal than for LAAM. Irritability scores increased for morphine and methadone during the first day of withdrawal, but did not show any increase until the third day for LAAM. These findings suggest that in dependent rats withdrawal from LAAM is less severe than withdrawal from morphine or methadone.

Animals↗
PubMedDate not supplied

The secretion of methadone and its major metabolite in the gastric juice of humans: comparison with blood and salivary concentrations.

Four healthy subjects and four addicts on high daily maintenance doses of methadone each received a parenteral dose of methadone hydrochloride following an overnight fast. The concentration of methadone in blood was compared with that in the gastric juice obtained over 8 hr by continuous low-pressure suction via a nasogastric tube. The concentration in the gastric juice was 25-200 times that measured at the same time in the blood. Thus, 8 hr after the injection mean blood concentrations of 28 and 210 ng of methadone per ml were recorded in the normal subjects and the addicts, respectively. The corresponding concentrations in gastric juice were 2,200 ng/ml and 18,000 ng/ml, respectively. In the normal subjects about 2% of the administered dose was recovered in the gastric juice in 8 hr, whereas in addicts about 7% was recovered. The greater recovery of methadone from the addicts appears to be the result of the larger volume of gastric juice recovered from the latter subjects. Methadone was also excreted in the saliva of both groups of subjects. In addicts, salivary concentrations were often 10 times those recorded in the blood. The N-monodemethylated metabolite of methadone was identified in the gastric juice of addicts by gas chromatography and mass spectrometry.

Adult↗
PubMed1979

Acute and chronic methadone exposure in adult rats: studies on arterial blood gas concentrations and pH.

The effects of different dosages of methadone on respiration were determined by evaluating arterial blood pCO2, pO2 and pH in naive and opioid-addicted animals. Male Sprague-Dawley rats were treated (i.p.), acutely or chronically, with either 2.5, 5.0 or 7.5 mg/kg of dl-methadone hydrochloride; appropriate saline controls were utilized. Blood was sampled from the tail artery before injection and 15, 30, 60, 120, 180 and 240 min postinjection. Animals exposed to methadone in acute experiments exhibited a respiratory depression that involved hypoxemia, hypercapnia and/or acidosis. In addition, the magnitude of this respiratory depressant action was dose-dependent and reached a maximal point 15 to 30 min after drug administration. Rats receiving chronic methadone exposure showed few alterations from control blood gas concentrations and pH. This study demonstrates that acute methadone administration is associated with respiratory depression, with the extent of reductions in pCO2, pO2 and pH related to drug dosage. In addition, chronic methadone treatment confers a substantial tolerance to the respiratory depressant action of methadone.

Animals↗
PubMed1979

Methadone-induced changes in the visual evoked response recorded from multiple sites in the cat brain.

Visual evoked responses (VERs) and EEG were recorded following the i.p. administration of five doses of methadone (0.5--4 mg/kg) to 12 adult cats, which were implanted with cortical and subcortical electrodes. Additional cats, subjected to the same drug regimen, were used to evaluate plasma methadone concentrations. Doses of methadone that produced plasma concentrations between 80 and 190 ng/ml differentially affected VERs recorded from cortical and subcortical sites. Of the subcortical structures evaluated, the limbic system, specifically the hippocampus, was the most sensitive to the effects of the drug. These effects appeared to be primarily depressant. Responses recorded from the reticular formation and centromedian were affected only by the highest dose of methadone, while VERs recorded from cortical sites were reliably altered following the two highest doses and appeared to reflect both excitation and depression. Behavioral changes, however, were clearly evidenced in some cats at lower doses of methadone. Therefore, the data suggest (1) that those structures evaluated electrophysiologically did not reflect the full force of the drug's action as evidenced by its effect on behavior, (2) that cortical and subcortical recording sites have differential sensitivities, and (3) that one clearly defined, principal size of action of methadone is absent in the cat.

Animals↗
PubMed1976

Management of surgical problems in patients on methadone maintenance.

One hundred patients on methadone maintenance admitted to our surgical service were analyzed. The average duration of prior narcotics abuse was ten years and was followed by an average of 2.2 years of methadone maintenance treatment. Sixty-three patients were admitted on an emergency basis, half of these for trauma. Sixty-two patients underwent operative procedures. There were four deaths, none directly related to methadone use. Five patients were admitted for intestinal obstruction secondary to methadone ingestion. This disease entity results from fecal impaction which is induced by methadone's spastic effect on the gastrointestinal tract. Evidence of chronic liver disease was present in half the patients. The associated medical illnesses presented no problems with anesthesia. WHILE METHADONE MAINTENANCE WAS CONTINUED IN THE ACCUSTOMED DOSAGE, POSTOPERATIVE ANALGESIA WAS ACCOMPLISHED SATISFACTORILY WITH 5O TO 100 MG DOSES OF MEPERIDINE AT 3 HOUR INTERVALS, AS REQUIRED.

Adolescent↗
PubMed1979

Double-blind comparison of methadone and placebo maintenance treatments of narcotic addicts in Hong Kong.

In a double-blind study carried out between 1972 and 1975 in Hong Kong 100 heroin addict volunteers were initially admitted to hospital for two weeks for stabilisation on 60 mg of methadone before being assigned at random to two groups: one group received methadone (range 30--130 mg, average 97 mg/day); those in the other group had their dose of methadone reduced at the rate of 1 mg/day and were then maintained on placebo. All subjects were provided with a broad range of supportive services. After thirty-two weeks 10% of the controls were still on treatment, compared with 76% of those receiving methadone. At the end of the three-year project, only 1 of the original 50 placebo subjects still turned up for treatment (2%), whereas the retention-rate (proportion still on treatment) for methadone subjects was 56%. Subjects who had dropped out of the study and were readmitted for methadone treatment under known conditions had the same retention-rate as the original treatment group.

Adult↗
PubMed1978

Methadone blockade of 2-deoxyglucose-induced pancreatic secretion in the rat.

The effects of methadone on pancreatic exocrine secretions in the rat were tested under basal conditions and after hormonal stimulation by secretin and caerulein or after stimulation of the differentially acting cholinergic agents acetylcholine, 2-deoxyglucose, and electrical stimulation of the vagus. Methadone had no effect on basal hydroelectrolytic secretion. It decreased basal enzyme secretion very slightly under our experimental conditions. The stimulatory effects of 75 mg of 2-deoxyglucose per kg were completely blocked by methadone at 5 mg per kg and this blockade was reversed by nalorphine at 6 to 9 mg per kg. It was found that there are doses of methadone (100 microgram) which block 2-deoxyglucose effects when injected into brain ventricles but are ineffective when systemically introduced. The effects of secretin, caerulein, acetylcholine, and electrical stimulation of the vagus were not depressed by methadone. These results strongly suggest that the methadone blockade of 2-deoxyglucose effects occurs at a central level and is mediated by narcotic drug receptors.

Acetylcholine↗
PubMed1978

New approach to the rehabilitation of the hard core drug addict (heroin methadone addicts) a pilot community study.

The limitation of the methadone maintenance program has pressed for a re-evaluation of our understanding of the underlying causes of addiction. Apparently, one of theunderlying causes or end result produced by the drug itself is that of depression. It explains why the addicts try to maintain to the maximum, the euphoric state and are unwilling to rehabilitate. A pilot study was conducted for the treatment of ex-methadone addicts with large dosages of antidepressants and anxiolytics. Out of 117 ex-methadone and soft drug addicts treated with antidepressants and anxiolytics, 46% ex-methadone and 46.3% soft drug abusers failed to become abstinent. The failures were basically related to the management of treatment. The study suggests a possibility for detoxification from methadone and control of relapse by antidepressants and anxiolytics.

Anti-Anxiety Agents↗
PubMed1977

Methadone maintenance: effect of urinary pH on renal clearance in chronic high and low doses.

The subjects were 12 male patients stabilized on methadone for many months or years. A comparison was made of the plasma levels and renal clearance of methadone between patients on "high" doses (80 to 110 mg/day) and those on "low" doses (15 to 40 mg/day). A general trend to higher renal clearance was seen in the "high" -dose group, but on more detailed examination there was a direct correlation only when the patients were categorized by urinary pH. At low pHs, there was nearly a 3-fold increase in renal clearance which was associated with a decreased major metabolite to methadone ratio. No evidence for a difference in rate of metabolism between the two groups was found nor were there differences in hepatic function. It was concluded that urinary pH was a major factor in renal clearance of methadone.

Adult↗
PubMed1979

Sensitive fluorescence assay for d,l-methadone.

d,l-Methadone forms a fluorophore when reacted with paraformaldehyde in concentrated sulfuric acid. Based on this reaction, a fluorescence assay suitable for quantitative d,l-methadone analysis from plasma and other tissues was developed. d,l-Methadone was extracted at pH 9.2 from the deproteinized filtrate of plasma or of aqueous tissue homogenate into an organic phase of 25% isobutanol in ethylene dichloride. After an aliquot of the organic phase was evaporated to dryness at 50--55 degrees with an air jet, paraformaldehyde (0.1%, in concentrated sulfuric acid) was added, and fluorescence was read at 450 nm with excitation at 275 nm. By this method, d,l-methadone can be assayed in the presence of its metabolites, morphine, diacetylmorphine (heroin), codeine, and cocaine; however, amphetamine, meperidine, and quinine interfere.

Animals↗
PubMed1975

Drug-seeking behavior during methadone maintenance.

Six subjects were given the opportunity to work for saline placebo and hydromorphone (4 mg i.v.) several times weekly before and during a period of maintenance on methadone (100 mg p.o. daily). Measures of pupillary change and reports of "liking" in response to hydromorphone dropped to saline control levels when the daily dose of methadone was approximately 60 mg. Half of the subjects continued to work intermittently for hydromorphone for four weeks while they were receiving 100 mg of methadone daily. These data support the assumption that methadone maintenance reduces the reinforcement value of other opiates and behaviors associated with obtaining them.

Adult↗