Plasma Methadone Concentrations Research Articles

The effect of changes in gastric pH induced by omeprazole on the absorption and respiratory depression of methadone.

The effect of omeprazole (2 mg kg-1 i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg-1) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial Pco2,Po2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration-time curve (AUC0-180), was also evaluated. The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p < 0.01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (Cmax = 156 +/- 6.5 ng mL-1 against 51 +/- 5.8 ng mL-1 in control; p < 0.05). AUC0-180 was higher (p < 0.05) after omeprazole treatment (18.6 +/- 1.4 micrograms mL-1 min) than in control (6.8 +/- 0.6 microgram mL-1 min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4.7 +/- 0.1 against 2.2 +/- 0.04) and continued increasing, being 6.4 +/- 0.1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect- (respiratory depression-) time curve (r = 0.74; p < 0.001). A relationship between plasma methadone levels at 120 min and gastric pH (r = 0.92; p < 0.001) was detected. A significant correlation between the area under the effect-time curve (0-120 min) and AUC0-180 has been also observed (r = 0.90; p < 0.01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH2 solution.

THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

The effect of omeprazole (2 mg kg−1 i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg−1) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial pCO2, pO2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration–time curve (AUC0–180 ), was also evaluated. The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p<0·01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (Cmax=156± 6·5 ng mL−1 against 51±5·8 ng mL−1 in control; p<0·05). AUC0–180 was higher (p<0·05) after omeprazole treatment (18·6±1·4 μg mL−1 min) than in control (6·8± 0·6 μg mL−1 min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4·7±0·1 against 2·2±0·04) and continued increasing, being 6·4±0·1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect– (respiratory depression–) time curve (r=0·74; p<0·001). A relationship between plasma methadone levels at 120 min and gastric pH (r=0·92; p<0·001) was detected. A significant correlation between the area under the effect–time curve (0–120 min) and AUC0–180 has been also observed (r=0·90; p<0·01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH 2 solution.

The effect of hair color on the incorporation of methadone into hair in the rat.

Six groups of six male, hooded, Lister rats were administered methadone in their drinking water over the concentration range 0-0.25 mg/mL for 6 weeks. Black pigmented and white nonpigmented hair and trunk blood samples were collected. Plasma and alkali digests of hair were analyzed for methadone by radioimmunoassay. Hair melanin content was estimated in digests by turbidimetry. Oral methadone intake rose in a linear fashion over the six dose groups, and plasma methadone concentration followed a similar trend. The methadone content of both white and black hair increased over the six dose groups, but concentrations were significantly higher in black compared with white hair. The mean ratio of methadone concentration between black and white hair was 21.3:1, and the mean ratio in hair melanin content was 3.5:1. The results demonstrate that pigmented hair incorporates larger quantities of methadone than nonpigmented hair and that methadone binds with higher affinity to the pigmented components as compared with other components of hair.

Patterns of Craving and Pharmacokinetics in Long-Term Opiate Addicts in Methadone Maintenance Therapy

Results are presented and discussed of a clinical study of 20 long-term opiate addicts currently enrolled in Methadone Maintenance Therapy (MMT) and hospitalized in the Jellinek Clinic in Amsterdam. The purpose of this study was to better understand the craving and pharmacokinetics associated with difficulties in determining an optimal dosage schedule in MMT. Plasma methadone concentrations were determined using a newly developed HPLC (high pressure liquid chromatography) procedure. Drug craving was measured using the Experience Sampling Method (ESM), a new technique for measuring craving in MMT which provides data not previously reported in methadone literature. Within the subjects medicated in the normal therapeutic dosage range of MMT (10-90 mg/day), a significant relationship was found between higher methadone dose and higher craving levels, a finding that counters much of the accepted knowledge on MMT. Supporting this finding, some subjects showed high plasma methadone trough levels and high craving ...

Utilization of plasma and urine methadone concentration measurements to limit narcotics use in methadone maintenance patients: II. Generation of plasma concentration response curves.

Controversy exists still concerning the proper daily dose of methadone required to eliminate illicit narcotics use. To address this, urine methadone and opioid concentrations were measured prospectively (150 maintenance patients, 18 month period, 9250 urine samples) using fluorescence polarization immunoassay. Results demonstrate that current thresholds (EMIT uses 300 micrograms/L) defining opiate positive urines are overly high (FPIA can go as low as 25 micrograms/L), causing severe underestimation of opioid use in the typical clinic. Using this data, plasma methadone concentration and dose response probability curves were generated for illicit opiate use. Results demonstrate a S-shaped, 24 hr trough plasma methadone concentration response curve with effective concentrations, EC90 = 80 micrograms/L, EC98 = 600 micrograms/L. Plotting mean plasma methadone concentration versus dose gives a monotonically increasing function: Conc = 5.367*dose0.858, raw R-squared = 0.967, corrected R-squared = 0.802. Unfortunately, coefficients of variation for plasma concentrations at each prescribed dose are unacceptably large, explaining poor dose response relationships for some patients.

Subjective and objective symptoms in relation to plasma methadone concentration in methadone patients

Two rating scales, which were originally developed for measurements of objective and subjective signs of opiate withdrawal, were used to evaluate potential estimates (correlates) of methadone effects in relation to plasma methadone concentrations. Patients participating in our regular methadone maintenance treatment project were studied during 24 h after the intake of the daily methadone dose. Methadone concentrations in plasma were compared to the subjective (estimated by the patients) and objective (estimated by the investigator) signs of the drug effects before, and 2.5, 5, 9 and 24 h after intake of methadone. Some new items possibly related to rising methadone concentrations were added to the subjective scale. Results indicated that, for subjective ratings, the majority of the items investigated corresponded well with the plasma methadone concentrations. The most significant associations were found for the following items: low psychomotor speed, alertness, running nose, yawning and anxiety. For objective ratings, only the items rhinorrhea, piloerection and signs of anxiety were significantly associated with the methadone concentrations. These rating scales may, together with plasma methadone determinations, be of considerable value when making dose adjustments for methadone maintenance patients. Further work is, however, needed to establish concentration-effect relationships.

Demonstration of physical dependence following chronic continuous methadone delivery via osmotic minipumps in pregnant rats

The effects of a 14-day (gestation days 7–20) chronic methadone (6.3–9.0 mg/kg/day) infusion via osmotic minipumps were studied on the induction of physical dependence in both pregnant and nonpregnant female rats. Following continued methadone exposure, an acute injection of naloxone (2.0 mg/kg, SC) produced the following symptoms of withdrawal in both pregnant and nonpregnant methadone-exposed rats: increased frequency of head shakes, teeth-chattering and face-rubbing episodes, as well as the induction of burrowing, diarrhea, facial tremor, squeaking and vaginal sniffing. Increased fetal movement in the maternal abdomen was also observed in the pregnant rats. In the saline-exposed pregnant controls, naloxone failed to induce a significant effect. In addition, brain and plasma methadone levels during the various stages of pregnancy (gestation days 8–20) were determined. The methadone levels in plasma were initially variable (gestation days 8–12) but became more constant (approximately 50 ng/ml) from gestation day 14 to 20. Methadone brain levels also followed a similar pattern, except that the brain methadone content was at least 20-fold greater than plasma concentrations at any given time. Thus, relative to the high brain levels, the present data suggest that acute changes in methadone plasma concentration may not be a good index of pharmacological effect.

Measuring compliance in methadone maintenance patients: Use of a pharmacologic indicator to “estimate” methadone plasma levels

A quantitative indicator of compliance is not available for methadone--the drug of choice for the treatment of opioid addiction. We successfully used low-dose phenobarbital (a valid pharmacologic indicator) to measure compliance by incorporating the drug into the methadone medication of patients attending an addiction unit. Plasma phenobarbital and methadone concentrations were measured in 20 (11 clinic-based and 9 community-based) patients receiving long-term treatment with the phenobarbital level-to-dose ratio, together with interviews, to validate methadone measurements and to monitor compliance. Patients attending the unit on a daily basis and who consumed their medication in the clinic were substantially more compliant than community-based patients. Laboratory measurements of phenobarbital and methadone helped to identify the use of illicit methadone, as well as incorrect self-administration, such as the consumption of several days' dosage at one time.

Psychophysiological reactions in methadone maintenance patients do not correlate with methadone plasma levels

In methadone maintenance therapy methadone plasma concentrations of 400 ng/ml are necessary to suppress any further opiate action and to provide stabilized maintenance. In a controlled study we have searched for a differentiation in autonomous activation between patients having low and high methadone plasma levels, using static and dynamic pupillometry and habituation of skin conductance response. Results show that there is no difference in psychophysiological response between patients with high (greater than 400 ng/ml) or low (less than 400 ng/ml) plasma levels of methadone. This indicates that there is no reduction in behavioral arousal in patients with high plasma methadone levels. On the basis of these findings, there is no rationale to maintain patients on plasma levels below 400 ng/ml.

Methadone concentrations in plasma and their relationship to drug dosage

Abstract We have developed a sensitive HPLC method for measuring methadone in plasma and have used it to establish that there is a linear relationship between plasma concentration and methadone dose over the range of 3-100 mg of methadone per day in a group of 31 addicts. We found a good correlation between dose and plasma concentration (r = 0.89), with the plasma methadone concentration increasing by 0.263 mg/L for every milligram of methadone consumed per kilogram of body weight. Five patients had unexpected high or low concentrations; this finding is discussed.

PLASMA CONCENTRATIONS OF METHADONE DURING POSTOPERATIVE PATIENT-CONTROLLED EXTRADURAL ANALGESIA

Plasma concentrations of methadone were measured by gas chromatography in 16 patients receiving extradural methadone by continuous infusion for relief of postoperative pain. Venous blood samples were taken after a loading dose of extradural methadone 2 mg and during infusion of 0.46 mg h-1 plus patient-controlled increments of 0.2-1 mg. Mean (SD) plasma concentration of methadone was 9.8 (2.1) ng ml-1 at 15 min; this did not change significantly during the first 2 h, after which it increased gradually to 32.2 (4.6) ng ml-1 (P less than 0.001) at the end of 24 h. The mean quantity of extradural methadone required to produce effective analgesia was 10.3 (1.8) mg during the first 12 h after operation and 6 (1.0) mg for the subsequent 12 h. The mean amount of methadone for effective analgesia on the second day was 7.6 (1.1) mg. No adverse effects were detected during the 2-3 days of methadone therapy. Plasma concentration of methadone increased significantly during patient-controlled infusion of extradural methadone in the first 24 h after operation, suggesting rapid vascular uptake. Systemic activity of the drug contributes to the analgesic effect of extradural methadone.

Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain

To determine the relationship between changes in plasma methadone concentration and pharmacodynamic effects, plasma methadone profiles and pharmacodynamics (analgesia and sedation) were measured during and after the continuous infusion of methadone for 180 to 270 minutes in 15 patients with pain caused by cancer. An increase in plasma methadone concentration resulted in a rapid increase in pain relief or sedation. The estimates of values of 50% of maximum effect (Css50) for pain relief and sedation obtained with a pharmacokinetic-pharmacodynamic model varied tenfold to twentyfold among patients; the mean Css50 value for pain relief (0.359 +/- 0.158 [SD] micrograms/ml) was virtually the same as the mean Css50 value for sedation (0.336 +/- 0.205 [SD] micrograms/ml). Similarly, the mean gamma (slope function) for pain relief (4.4 +/- 3.8 [SD]) and sedation (5.8 +/- 5.4 [SD]) did not differ. Examination of hysteresis plots of data obtained during the infusion and for 4 to 5 hours after cessation of the infusion revealed a very rapid equilibration between plasma methadone values and the sites mediating pain relief. There was no indication of the development of tolerance to the pharmacodynamic effects of methadone during the study. This report describes a method for quantitating the pharmacokinetic-pharmacodynamic relationships of the desirable and undesirable effects of opioid analgesics.

Methadone and Theories of Addiction

To the Editor. — In the article by Dr Dole 1 in the November 25 issue of JAMA , it was stated that clinical success in the rehabilitation of heroin addicts requires stabilization of the blood level of methadone in a pharmacologically effective range (150 to 600 ng/mL). Other investigators have studied plasma concentrations of methadone and have attempted to establish whether a threshold serum concentration or therapeutic window exists for methadone in the treatment of opiate dependency. 2-7 All these studies measured the total serum concentration of methadone (protein-bound fraction and free fraction). Olsen 8 studied the binding of tritiated l -methadone with solutions of purified human γ-globulin and human plasma. γ-Globulin bound 13% to 17.5% of the methadone and human plasma bound 83.7% to 87.3%. Since the maximum albumin binding was 43.8%, the author thought that other proteins probably bound methadone as well. Romach et al 9 reported the

Altered Methadone Pharmacokinetics in Pregnancy: Implications For Dosing

Lower plasma methadone levels have been reported in pregnant women receiving methadone maintenance for heroin addiction. Methadone pharmacokinetics was examined in a 24-year-old woman 8 months pregnant with twins, who experienced severe withdrawal symptoms beginning 10-12 hours after her daily 30 mg methadone dose. Methadone plasma concentration-time data were fit to a one-compartment pharmacokinetic model by extended least-squares regression. Estimated half-life for methadone was 8.1 hours, which is much shorter than the usual methadone half-life (greater than 24 hours). Plasma methadone concentrations were estimated for the cases of a) increasing the 30 mg methadone dose by 50% and administering it once daily and b) continuing the 30 mg methadone dose but administering it at 12-hour intervals. Although the model is derived from a single subject, the simulations performed clearly suggest a need for altered methadone dosing in pregnancy. More sustained plasma methadone levels are achieved with twice-daily dosing of methadone than are achieved by administering an increased methadone dose once daily. Twice-daily dosing would be expected to produce fewer withdrawal symptoms and, ultimately, improved compliance with treatment.

Application of a New Method for Measurement of Plasma Methadone Levels to the Use of Epidural Methadone for Relief of Postoperative Pain

A method is described for measurement of plasma methadone concentrations using a gas chromatic technique that is rapid and specific and enables the detection of concentrations of less than 1 ng/ml in plasma samples of only 1 ml. The method, when used to determine the plasma methadone levels in patients given continuous epidural infusions of methadone plus on-demand supplementation for relief of postoperative pain, showed plasma methadone plateaus of around 10 ng/ml (starting at 15 min and lasting over 2 hr) and 20 ng/ml (starting at 3 hr and lasting over the period of treatment) (P less than 0.001) after an initial 2-mg methadone epidural bolus and with continuous epidural methadone. Mean plasma methadone levels of around 10 ng/ml were associated with pain relief. Analgesia could be safely maintained for 24 hr.

Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain.

Concentrations of methadone in plasma, estimates of pain relief, and pupillary size were determined after a single intravenous dose (10 to 30 mg) of methadone hydrochloride to eight patients with chronic pain, five of whom had cancer. The pharmacokinetic parameter estimates reveal rapid and extensive distribution (Varea) and a slow apparent elimination half-life (t1/2) (mean Varea = 3.59 L/kg and harmonic mean t1/2 = 23 hours). The harmonic mean blood clearance is 106 ml/min, the harmonic mean renal clearance is 3.9 ml/min, the mean hepatic extraction ratio is 0.089, and plasma protein binding is 86% to 89%. These results suggest that only the free (unbound) fraction of methadone present in blood is extracted by the liver and that methadone can be classified as a low (hepatic)-extraction drug. The data were fit to a pharmacokinetic-pharmacodynamic model to obtain estimates of the steady-state plasma methadone concentration required to produce 50% of the maximum pain relief. This value varied from 0.04 to 1.13 micrograms/ml (mean = 0.29 micrograms/ml). These results indicate substantial interindividual variation in the relationship between changes in plasma methadone concentration and analgesia in patients with chronic pain receiving opioids. A pharmacokinetic-pharmacodynamic model may be useful for the individualization of analgesic dosage and therefore the optimization of pain management in patients with chronic pain.

Methadone plasma concentrations after, pattient-controlled epidural analgesia

Methadone plasma concentrations after, pattient-controlled epidural analgesia

Sensitive assay of methadone in plasma by using capillary gas chromatography with photoionization detection

A new gas chromatographic assay for methadone, utilizing a fused-silica capillary column, is presented. Extreme sensitivity was reached, compared to nitrogen—phosphorus and mass spectrometry detection, by employing a photoionization detector. Plasma concentrations of methadone as low as 1 ng/ml can easily be detected and, by further optimization, 0.1 ng/ml was reached. The minimum detectable amount of methadone reaching the detector was 70 fg. The results indicate that the photoionization detector has potential as a tool in drug monitoring.

Preliminary study on the absorption profile after rectal and oral administration of methadone in human volunteers.

Methadone is a potent, long acting narcotic analgesic which can be orally administered due to its almost complete bioavailability. There is a growing interest in the rectal route of administration in the case of acute post-operative or chronic malignant pain. Since virtually no data were available on the rectal absorption profile of methadone in man, plasma concentrations of methadone were determined by means of HPLC analysis after a single dose of 10 mg methadone HCl in a cross-over pilot study in five volunteers. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. Compared with oral dosing, the extent of rectal absorption from an aqueous solution was almost 80% up to 8 h after dosing. Although the mean peak concentration and the AUC0-8h was significantly lower (p less than 0.01), no marked difference in tmax was observed: 2.8 and 3.1 h respectively. Rectal absorption conditions of methadone from fatty suppositories (3 ml) were found to be less favourable. The peak plasma concentration was only reached 3-4 h after administration, whereas the relative bioavailability up to 8 h after dosing ranged from 35-58%. This rate-limiting absorption pattern may be due to the critical solubility properties of methadone HCl at physiological pH.

COMPARISON OF EFFECTS OF INTRAOPERATIVE AND POSTOPERATIVE METHADONE: ACUTE TOLERANCE TO THE POSTOPERATIVE DOSE?

The effects of methadone 10 mg administered in two different clinical contexts, at induction of anaesthesia and following operation, were studied in two groups of patients undergoing elective total hip replacement. The intraoperative group received methadone 10 mg i.v. at induction of anaesthesia as part of a balanced anaesthetic technique. The postoperative group received methadone 10 mg i.v. following operation, extradural bupivacaine being used for the operative period. A demand analgesia system delivering methadone i.v. was used after operation in both groups. Arterial blood-gas tensions, cortisol and glucose concentrations, analgesic effects and plasma methadone concentrations were compared in the two groups. The only major difference between the two groups was in analgesic requirement. At the time of connection to the demand system the two groups had the same plasma methadone concentrations. Subsequently, the postoperative group had a significantly greater analgesic requirement which resulted in significantly greater plasma methadone concentrations the following morning. Thus, the administration of methadone following operation appeared to exert less analgesic effect than the same dose given during operation. The reasons for this are discussed.