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1.--The delayed onset and long duration of action of the opioid agonist levo-alpha-acetyl-methadol (LAAM) has been attributed to the formation of active metabolites. However, at present, little is known about the time course of blood-brain equilibration of LAAM itself. 2.--The cerebral kinetics of LAAM were quantified using physiologically based kinetic models and a conscious chronically instrumented sheep preparation. Seven sheep were administered 4 min intravenous infusions of 30 mg LAAM. Concentrations of LAAM and N-demethylated metabolites (nor-LAAM and di-nor-LAAM) in whole blood (0-75 min) were measured using a validated HPLC assay. 3.--LAAM did not alter cerebral blood flow, mean arterial pressure or cause significant respiratory depression. Cardiac output was similar to baseline at 4 min, but decreased by 30% at 10 min and remained at this level for the duration of the 75 min study period. 4.--Cerebral kinetics were best described by a membrane-limited model, with a relatively slow blood-brain tissue equilibration half-life of 22 min due to intermediate permeability (56 ml min(-1)) and a large cerebral distribution volume (724 ml). 5.--In conclusion, pharmacokinetic-pharmacodynamic modelling of LAAM should account for the large equilibration delay between brain and blood caused by slow equilibration kinetics. This may account for some of the delay in onset of effect previously attributed to the delayed appearance of active metabolites in blood.

Pharmaceutical smokable heroin was developed for a clinical trial on medical co-prescription of heroin and methadone. This product, consisting of 75% w/w diacetylmorphine base and 25% w/w caffeine anhydrate, was intended for use via "chasing the dragon", that is, inhalation after volatilization. This procedure involves heating the powder mixture, which may lead to formation of degradation products that could subsequently be inhaled. We developed a method that used a high-performance liquid chromatography system that was compatible with photodiode-array detection and mass spectrometric detection to separate diacetylmorphine- and caffeine-related compounds in a wide polarity range for analysis of the vapor. This method was used to analyze the contents of the plastic drinking straws that were used by patients to inhale the vapors from pharmaceutical heroin used via chasing the dragon, which were considered to be representative of the vapors the patients inhaled. They contained primarily unchanged diacetylmorphine, its main metabolite 6-acetylmorphine, caffeine, and some morphine. Several unidentified peaks were observed in the straw chromatograms. Chemical structures were proposed for nine degradation products: morphine derivatives with different substitution patterns of the C(3), C(6), and/or N(17) positions, which comprised 0.4-9.7% of the straw sample residue weight. Activity and toxicity of most of these compounds are unknown and require further investigation.

Aim: Our aim was to judge the importance of candidate pharmacogenetic modulators of the central nervous effects of levomethadone by both magnitude of the modulatory effect and frequency of the mutation to assess the utility of genotyping for clinical levomethadone therapy in a random sample of subjects that, by distribution of genotypes, resembled the clinical setting., Methods: Candidate pharmacogenetic modulators were polymorphisms reported to be of functional consequence and therefore potentially important for metabolism, distribution, or pharmacodynamic action of levomethadone, consisting of genes coding for cytochrome P450 (CYP) 2B6 and 3A, as well as 1A2, 2C8, 2C9, 2C19, and 2D6, for P-glycoprotein (ABCB1), and for mu-opioid receptors (OPRM1). The central nervous effects of levomethadone were investigated by means of measuring pupil size in a random sample of 51 healthy volunteers for 9 hours after oral administration of 0.075 mg/kg levomethadone. Plasma concentrations of levomethadone and its metabolites were assessed concomitantly, and to judge the role of metabolites, the affinities of levomethadone and its metabolites at mu-opioid receptors were estimated by use of displacement of the selective mu-opioid receptor agonist [(3)H]-DAMGO ((3)H-[D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin)., Results: Pupil size decreased to -41.8% +/- 9.6% from baseline at 3.5 +/- 1.1 hours after levomethadone administration. Miosis was still manifest to a lower degree (-25.1% +/- 12.3%) at the end of the observation period. In carriers of the variant 118G allele (118A>G single-nucleotide polymorphism) of the mu-opioid receptor gene (OPRM1), levomethadone had a 1.74 times (95% confidence interval, 1.4-2.2 times) lower miotic potency (P < .001) as compared with noncarriers (concentration at half-maximum effects, 52.3 nmol/L; 95% confidence interval, 36.7-66.2 nmol/L). The maximum percent decrease in pupil diameter from baseline was 44.9% +/- 7.6%, 33% +/- 6.5%, and 24% +/- 6.9% for carriers of the OPRM1 118AA, AG, and GG genotypes, respectively (P < .001 for AG and GG versus wild type, without significant differences between AG and GG). Other candidate polymorphisms in the ABCB1 or in CYP genes had no significant influence on the effects of levomethadone, either because of lack of functional consequences or because of their low allelic frequency. The metabolites of levomethadone did not contribute to the effects as indicated by low metabolite plasma concentrations and their 120- to 1300-fold lower affinities at mu-opioid receptors as compared with levomethadone., Conclusions: Among polymorphisms in OPRM1, ABCB1, and CYP genes previously associated with functional consequences in a different context, the most important pharmacogenetic factor modulating the short-term effects of levomethadone is a polymorphism (OPRM1 118A>G) affecting mu-opioid receptors.

An intranasal (IN) diamorphine spray was investigated as a possible alternative to injectable diamorphine for maintenance treatment. Plasma morphine and 6-monoacetylmorphine (6MAM) concentrations and pharmacodynamic responses were measured for 4 h following intravenous (IV) and IN administration of 40 mg diamorphine in 4 patients prescribed injectable diamorphine. The two routes were primarily differentiated by the significantly greater speed and magnitude of peak plasma morphine and 6MAM concentrations for IV versus IN diamorphine. Beyond this initial peak, mean ratings suggested that withdrawal suppression and positive effects were at least as strong for IN compared to IV administration. All subjects gave favourable appraisals of the IN diamorphine spray, citing advantages including ease of use, the avoidance of needle hazards, and reduced stigma. IN administration may be an alternative or supplementary form of diamorphine maintenance and deserves serious further investigation., (Copyright 2006 S. Karger AG, Basel.)

Background: In several European countries and in Canada, clinical trials are being conducted in which heroin-addicted patients are treated with pharmaceutically prepared heroin in order to reduce the destructive behaviour that is so often associated with this drug., Objective: To develop an integrated population pharmacokinetic model for heroin (diamorphine) and its pharmacodynamically active metabolites 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide. Additionally, the influence on heroin pharmacokinetics of several covariates that are typical for this population was determined., Method: Plasma concentration data from 106 heroin-dependent patients in The Netherlands (74 heroin inhalers and 32 injectors) were obtained. The 'chasing the dragon' technique was used for inhalation, in which the fumes of heroin base, heated on aluminum foil, were inhaled. Heroin doses varied between 66 and 450 mg. Heroin, 6-acetylmorphine and morphine data were fitted simultaneously using sequential two-compartment models. Morphine-3-glucuronide and morphine-6-glucuronide data were fitted separately to one-compartment models. All data analysis was performed using nonlinear mixed-effect modelling., Results: The bioavailability of inhaled heroin was estimated to be 53% (95% CI 43.7, 62.3). The terminal half-lives of heroin and 6-acetylmorphine were estimated to be 7.6 and 21.8 minutes, respectively. The clearances of morphine and the morphine-glucuronides were estimated to be 73.6 L/h (95% CI 62.8, 84.4) and between 6 and 10 L/h, respectively. The terminal half-life of 6-acetylmorphine was 13% lower in cocaine users (p < 0.05). No other significant relationships between covariates and pharmacokinetic parameters were discovered., Conclusions: Pharmacokinetic parameters of heroin and its five major metabolites were assessed simultaneously in one integrated model. Covariate analyses revealed that sex, bodyweight, benzodiazepine use and creatinine clearance (>60 mL/min) do not need to be taken into account in the medical prescription of pharmaceutically prepared heroin for the treatment of heroin dependency.

Salvinorin A, a potent hallucinogen isolated from the leaves of Salvia divinorum, has gained popularity among adolescents in the USA. No detailed study of the pharmacokinetics has been conducted in vivo. The present study investigates the in vivo pharmacokinetics of salvinorin A (0.032 mg/kg, i.v. bolus) in rhesus monkeys (n=4, 2 male, 2 female). The elimination t(1/2) was rapid (56.6+/-24.8 min) for all subjects. Pharmacokinetic differences (distribution t(1/2), elimination t(1/2), and AUC) were observed between males and females, suggesting potential sex differences in its pharmacologic effects. Salvinorin B, the presumed major metabolite, is observed to accumulate ex vivo; however, in this study it never reached the limit of detection., (Synapse 58:208-210, 2005. (c) 2005 Wiley-Liss, Inc.)

Objective: Measurement of plasma methadone concentration to investigate the rate of clearance of methadone prescribed for heroin dependence in the first, second and third trimesters of pregnancy. A secondary objective was to evaluate the outcome of pregnancy., Methods: Longitudinal within subject study of nine pregnant opioid dependent subjects prescribed methadone at the Leeds Addiction Unit, an outpatient community based treatment centre. Plasma concentration versus time data for methadone was collected during each trimester and post-partum for our subjects. Data was available for the first and second trimesters for 4/9 cases. All but one of the subjects provided data during the third trimester and data post-partum was collected from three respondents. Measurements of methadone levels in plasma were carried out using high performance liquid chromatography (HPLC)., Results: Trough mean plasma methadone concentrations reduced as the pregnancies progressed from 0.12 mg/L (first trimester) to 0.07 mg/L (third trimester). The weight-adjusted clearance rates gradually increased from a mean of 0.17 to 0.21 L/hr/kg during pregnancy, although patterns differed substantially between the nine women. An assessment of relative clearance of methadone using two patients for whom we have had all three CL values (trimester 1-3) demonstrated notable change of CL (P = 0.056) over time. Eight of our subjects delivered (3 males), within two weeks of their due date the ninth (male) was premature (21 days). The mean length of gestation was 39.7 weeks (SD = 10 days) and none of the neonates met criterion for 'low birth weight' mean = 3094, SD = 368 g). Five neonates spent time (0.5-28 days) in a special care baby unit (SCUBU) and 4 of these displayed signs of methadone withdrawal., Conclusions: General Practitioners and hospital doctors should recognise the significant benefits of prescribing methadone for heroin-dependent women during pregnancy. We recommend that if a pregnant opioid user complains of methadone withdrawal symptoms (i.e. that the methadone dose does not "hold" them) the prescribing clinician takes this observation seriously and considers a more detailed assessment. Further work on key factors undergoing changes during pregnancy accounting for differences in methadone metabolism in the mother, fetus and neonate are required.

Aims: To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state., Methods: Six non-holder subjects were studied on three occasions at 7-16 day intervals; doses (20-170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10-12 times over a 24-h inter-dosing interval. All pharmacodynamic data were expressed as the area under the end-point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between- to within-subject variation, with corresponding 95% confidence intervals (CI) for within-subject variation at the average value., Results: Subjects were relatively consistent between occasions, whereas there was much greater between-subject variability (P < 0.02) for all measures. Estimates of the ratio of between- to within-subject variation ranged from 2.2-12.8 for pharmacodynamic measures, and 1.3-7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within-subject measures ranged < or = 2-fold, while this was greater for subjective direct opioid effects (4.2-fold). For CL/F of the active (R)-methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within-subject measures ranging < or = 2-fold. (S)-methadone CL/F demonstrated greater within-subject variability (3.4-fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between- to within-subject variance., Conclusions: Non-holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1-2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population.

For a pharmacokinetic-pharmacodynamic study in opioid tolerant patients, who were treated with heroin in combination with methadone, a liquid chromatographic assay with tandem mass spectrometry detection (LC-MS/MS) was developed for the simultaneous determination of heroin, methadone, heroin metabolites 6-monoacetylmorphine, morphine, and morphine-6 and 3-glucuronide and methadone metabolite EMDP. To detect any abuse of substances besides the prescribed opioids the assay was extended with the detection of cocaine, its metabolites benzoylecgonine and norcocaine and illicit heroin adulterants acetylcodeine and codeine. Heroin-d6, morphine-d3, morphine-3-glucuronide-d3 and methadone-d9 were used as internal standards. The sample pre-treatment consisted of solid phase extraction using mixed mode sorbent columns (MCX Oasis). Chromatographic separation was performed at 25 degrees C on a reversed phase Zorbax column with a gradient mobile phase consisting of ammonium formate (pH 4.0) and acetonitrile. The run time was 15 min. MS with relatively mild electrospray ionisation under atmospheric pressure was applied. The triple quadrupole MS was operating in the positive ion mode and multiple reaction monitoring (MRM) was used for drug quantification. The method was validated over a concentration range of 5-500 ng/mL for all analytes. The total recovery of heroin varied between 86 and 96% and of the heroin metabolites between 76 and 101%. Intra-assay and inter-assay accuracy and precision of all analytes were always within the designated limits (< or =20% at lower limit of quantification (LLQ) and < or =15% for other samples). This specific and sensitive assay was successfully applied in pharmacokinetic studies with medically prescribed heroin and toxicological cases.

A rapid and sensitive assay for quantification of nalbuphine, butorphanol and morphine in blood (50 microL) and brain microdialysate ( approximately 40 microL) samples was developed. Blood samples were extracted with ethyl acetate. Analysis was performed with high-performance liquid chromatography (HPLC) coupled to an electrochemical detector. The mobile phase was a mixture of 0.1 M sodium phosphate buffer, methanol and octane-sulfonic acid with ratio and pH depending on compound and matrix. The limits of quantification in blood samples were 25, 50 and 25 ng/mL for nalbuphine, butorphanol and morphine, respectively and 0.5 ng/mL for morphine in microdialysate samples. Based on sample volume, sensitivity and reproducibility, these assays are particularly suitable for pharmacokinetic/pharmacodynamic studies in rodents.

The occurrence of human immunodeficiency virus (HIV) disease and hepatitis C is common in injection drug users, most of whom are opioid dependent. Methadone pharmacotherapy has been the most widely used treatment for opioid addiction in this population. Methadone has significant, adverse drug-drug interactions with many antiretroviral therapeutic agents that can contribute to nonadherence and poor clinical outcomes in this high-risk population. The present article summarizes current knowledge about interactions between methadone and antiretroviral medications. Buprenorphine is the newest agent available for the treatment of opioid dependence and may have fewer adverse interactions with antiretroviral agents. Buprenorphine has a significant pharmacokinetic interaction with efavirenz but no pharmacodynamic interaction; therefore, simultaneous administration of these drugs is not associated with opioid withdrawal, as has been observed with methadone. This promising finding may simplify the treatment of opioid-dependent patients with HIV disease and should also improve clinical outcomes for persons coinfected with HIV and hepatitis C virus.

Regardless of the clinical scenario in which they are administered, opioids can have adverse effects in infants and children. These adverse effects may be particularly problematic when opioids are inadvertently administered since the clinical signs and symptoms may not be readily attributed to opioids without an appropriate history. The authors present 3 clinical scenarios in which adverse effects occurred related to the inadvertent administration of opioids when: (1) acetaminophen with codeine were administered instead of acetaminophen, (2) a mother was breastfeeding while taking opioids, and (3) a fentanyl patch was placed on a superficial injury. A thorough history and physical examination combined with urine/plasma drug screening resulted in the identification of the problem and its effective therapy.

The immunosuppressive as well as modulatory effects of morphine have been known in clinical medicine for > 100 years. Recent developments in molecular immunology, including experiments in mu (mu) opioid receptor knockout mice has led to a better understanding of central and peripheral mechanisms involved in this process. Though there is a large volume of literature documenting adverse effects of immunosupression following the use of morphine, several reports confirm its potential usefulness as an immunomodulator. In vitro and in vivo animal experiments have demonstrated wide-spectrum effects of morphine, including anti-inflammatory, antifibrotic, antitumour, cardioprotective and renoprotective. Immunomodulation is an important field in modern medicine with rapid advancement in recent years. Though a final statement regarding the clinical relevance of morphine-induced immunomodulation cannot be made at this juncture, nevertheless, it is worthwhile to review current developments. It may encourage further clinical studies to elucidate the influence of morphine treatment on immune regulation in different specialties of medicine.

The aim of this double-blind, placebo-controlled study was to evaluate the efficacy of intravenous magnesium sulphate (MgSO(4)) on the need for chlormethiazole in pure or polysubstance opiate detoxification. Forty-one inpatients suffering from pure and polysubstance opiate dependence were treated with morphine sulphate pentahydrate in a gradual detoxification program. Morphine reduction took about 11 days. Additionally, 5% MgSO(4) was administered intravenously to the intervention group (Mg group, n=22) over 24 h by perfusor (150-200 mg MgSO(4)/h; plasma level of 2.36+/-0.29 mmol/l), whereas NaCl 0.9% was intravenously administered in the placebo group (n=19). In case of withdrawal symptoms (irritability, restlessness, and insomnia), patients received chlormethiazole p.o. Our hypothesis that the need for chlormethiazole would be decreased by adjunctive administration of Mg was not confirmed in our study population (2180 mg/day in the Mg group vs. 2360 mg/day in the placebo group). There was neither a difference in the quantity of chlormethiazole required nor a difference in the severity of withdrawal symptoms measured with the Wang scale between the two comparison groups. We observed that calcium plasma levels decreased and phosphate plasma levels increased significantly during intravenous therapy with Mg. Despite promising pilot studies, the administration of Mg did not enable a dose reduction of tranquilizing medication (chlormethiazole) in pure and polysubstance opiate detoxification.

In preparation for a trial on co-prescription of inhalable heroin and methadone, two methods for inhalation of heroin/caffeine tablets were compared: the commonly used method of 'chasing the dragon' and a standardised procedure for inhalation of volatilised heroin, using a heating device. Five male addicts inhaled a tablet of smokable heroin daily for 5 days, alternating the inhalation method. Plasma concentrations of heroin, 6-acetylmorphine, morphine and morphine-3- and -6-glucuronide were determined using a liquid chromatography method with tandem mass spectrometric detection. The exposure to heroin and its metabolites (expressed as areas under the concentration-time curve) was significantly lower after smoking via the heating device than after 'chasing the dragon': heroin 80% and 6-acetylmorphine 73% lower (p < 0.05). Maximal concentrations of heroin and 6-acetylmorphine were also 80% and 70% lower (p < 0.05) after using the heating device. 'Chasing the dragon' is a more efficient inhalation method than inhalation via the heating device.

The effects of opioids usually parallel the plasma concentrations but with a temporal shift. This temporal shift differs between opioids. It is small with alfentanil or remifentanil and very long with the active metabolite of morphine, morphine-6-glucuronide (M6G). The mathematical and experimental techniques for modeling these pharmacokinetic-pharmacodynamic (PK/PD) relationships were developed in the late 1970s. The delay between plasma concentrations and effects is accounted for by the introduction of a hypothetic effect compartment, which is linked to the plasma compartment by a first-order transfer function with a rate constant k(e0). The effects are then linked to the concentrations at effects site by standard pharmacodynamic models such as sigmoid ("E(max)") models or power models, depending on the actual effect measure. These principles were first applied to the opioids fentanyl and alfentanil in 1985. Since then, PK/PD of opioids have been repeatedly assessed, using EEG derived parameters, pupil size, and experimental and clinical pain as effect measures. The opioids of the fentanyl group, methadone, morphine, and piritramid, are today well characterized with respect to their PK/PD properties. Alfentanil and remifentanil are very fast equilibrating opioids with equilibration half-lives between plasma and effect site of about 1 minute. They are followed by fentanyl and sufentanil, each with equilibration half-lives of about 6 min. Methadone equilibrates with a half-life of about 8 min. Morphine, in contrast, equilibrates with a half-life of 2-3 h. The slowest opioid with respect to plasma-effect site transfer is M6G, with an equilibration half-life of about 7 h. PK/PD modeling has advanced the understanding of the time course of the clinical effects of opioids after various dosing regimens. It may provide a rational basis for the selection of opioids in clinical circumstances. PK/PD modeling of opioids may also be employed for the design and the interpretation of experiments addressing clinical effects of opioids.

Objective: To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery., Design and Setting: Observational study in a level III referral center., Patients and Methods: Pharmacokinetic estimates from 14 neonates undergoing ECMO were compared with findings from a previous study in 0- to 3-year-olds after noncardiac major surgery using a nonlinear mixed effect model. A one-compartment linear disposition model with zero-order input (infusion) and first-order elimination was used to describe all data., Results: Clearance in neonates (age <7 days) at the start of ECMO (2.2 l per hour per 70 kg) was lower than that in postoperative neonates (10.5 l per hour per 70 kg) but increased rapidly (maturation half-life 30 and 70 days, respectively) and equaled that of the postoperative group after 14 days. Clearance was affected by size and age only. Exchange transfusion, when used, contributed only 1.1% (CV 46%) of total clearance. Distribution volume increased with age and was 2.5 times (CV 102%) greater in ECMO children than in postoperative children. The between-subject variability values for volume of distribution and clearance were 49.4% and 38.7%. Weight and age information explained 83% of the overall clearance variability and 60% of overall distribution volume variability., Conclusions: Morphine clearance is reduced in infants requiring ECMO, possibly reflecting severity of illness. Clearance maturation on ECMO is rapid and normalizes within 2 weeks. Initial morphine dosing may be guided by age and weight, but clearance and distribution volume changes (and their variability) during prolonged ECMO suggests that morphine therapy should be subsequently guided by clinical monitoring.

Treating drug users is something that every health professional should be able to do, whether providing brief interventions or harm minimisation advice or providing an assessment and directing the user for further care. Unfortunately, despite a growing problem, few health professionals outside specialist addiction services have the skills, experience and knowledge to provide patients with effective pharmacological interventions. Many of the pharmacological treatment options, such as methadone maintenance, have had extensive research and have been shown to be effective in a number of outcome areas. Newer treatments, such as buprenorphine- and naltrexone-assisted detoxification have a growing research base. This article provides a brief overview of treatments options and the impact of drug use on social and medical care services.

The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

Methadone is a synthetic opioid, used both as an analgesic in severe pain relief and now mainly in the treatment of opiate dependence. Such use of the drug has increased as its advantages have become widely recognized. There are undesirable outcomes from its greater use, including a substantial market in diverted methadone and a high number of deaths where the drug has been implicated. It is important to understand how and why methadone causes death so that such fatalities can be minimized, and to disseminate such information. This paper presents an overview of the chief effects of methadone on the human body, considering its metabolism, drug interactions and tolerance. The principal mechanisms by which methadone causes death are discussed: respiratory depression, aspiration of vomit, pulmonary oedema, bronchopneumonia, cardiac problems and renal failure. Many such deaths are preventable, if drug interactions and polydrug use are avoided, its longer period of metabolism and individuals' tolerance levels are considered. It is hoped that this paper will (a) help guide health professionals in their management and treatment of patients participating in methadone treatment programmes, and (b) provide some basic information for those dealing with individuals who have consumed methadone., (2004 John Wiley & Sons, Ltd.)

Aims: To investigate the possibility that (S)-methadone influences therapeutic and adverse responses to rac-methadone maintenance treatment, by examining how subjective and physiological responses among rac-methadone maintenance patients vary in relation to relative exposure to (S)- vs. (R)-methadone., Methods: Mood states (Profile of Mood States), opioid withdrawal (Methadone Symptoms Checklist), physiological responses (pupil diameter, heart rate, respiration rate, blood pressure), and plasma concentrations (CP) of (R)- and (S)-methadone were measured concurrently 11-12 times over a 24-h interdosing interval in 55 methadone maintenance patients. Average steady-state plasma concentrations (C(av)) and pharmacodynamic responses were calculated using area under the curve (AUC). Linear regression was used to determine whether variability in pharmacodynamic responses was accounted for by (S)-methadone C(av) controlling for (R)-methadone C(av) and rac-methadone dose. Ratios of (S)-:(R)-methadone using AUC(CP) and trough values were correlated with pharmacodynamic responses for all subjects and separately for those with daily rac-methadone doses > or = 100 mg., Results: (S)-methadone C(av) accounted for significant variability in pharmacodynamic responses beyond that accounted for by (R)-methadone C(av) and rac-methadone dose, showing positive associations (partial r) with the intensity of negative mood states such as Tension (0.28), Fatigue (0.31), Confusion (0.32), and opioid withdrawal scores (0.30); an opposite pattern of relationships was evident for (R)-methadone. The plasma (S)-:(R)-methadone AUC(CP) ratio (mean +/- SD 1.05 +/- 0.21, range 0.65-1.51) was not significantly related to pharmacodynamic responses for the subjects as a whole but showed significant positive associations (r) with the intensity of negative mood states such as Total Mood Disturbance (0.61), Tension (0.69), Fatigue (0.65), Confusion (0.64), Depression (0.49) and heart rate (0.59) for the > or = 100-mg dose range., Conclusions: These findings agree with previous evidence that (S)-methadone is associated with a significant and potentially adverse profile of responses distinct from that of (R)-methadone. Individual variability in relative (S)- vs. (R)-methadone exposure may be associated with variability in response to rac-methadone maintenance treatment.

Mu opioid receptors mediate the pharmacological actions of morphine and morphine-like drugs, such as heroin. The mouse and human Oprm genes undergo splicing. In these present studies, we have identified and characterized three new MOR-1 splice variants from the rat Oprm gene. Using an RT-PCR approach, we isolated the new exons 7, 8 and 9 downstream of exon 3. The rat exons 7 and 9 were homologous to the mouse exons 7 and 9 while the rat exon 8 was not. Northern blot analysis with the new exon probes showed distinctive and abundant transcripts of the variants in the rat brain. Full-length cDNA clones containing the new exons, rMOR-1C1, rMOR-1C2 and rMOR-1D were obtained using an RT-PCR approach. Each contained the same exons 1, 2 and 3 as the original rMOR-1, followed by different combinations of the new exons in place of exon 4. In addition, we also isolated another new variant, rMOR-1A, which contains only exons 1, 2 and 3, and is homologous to the human variant MOR-1A previously identified. All the variants were highly mu-selective in binding studies with little difference in affinities for the mu ligands among the variants. However, functional evaluation of assessments of the variants using agonist stimulated [(35)S]GTPgammaS binding assays revealed marked differences among the variants, both in terms of potency and efficacy of the drugs. The relative efficacy of a series of mu opioids to each other varied depending upon the variant studied. Efficacy in the [(35)S]GTPgammaS assay did not correlate with either receptor binding affinity or with potency. Thus, selectivity of opioid action might be achieved by designing compounds with varying efficacies at different MOR-1 variants.

Objective: To review the general principles of pharmacokinetics and pharmacodynamics models by focusing on intravenous anaesthetics (hypnotics and opioids)., Data Sources: Medline references, lectures from the French congress of anaesthesiology and intensive care medicine, abstracts., Data Synthesis: Pharmacokinetic and pharmacodynamic modelling allows simple estimation of becoming of anaesthetic drugs in the body, instead of classical pharmacologic approach. However, pharmacokinetic as well as pharmacodynamic parameters are often considered as resulting from complex mathematic approaches and remain then poorly used in practice by physicians. The aim of this article is to simply expose concepts underlying PK-PD models building and to explain significance of the main PK-PD parameters (first-order rate constants, k(e0), T(1/2)k(e0), T(peak), context-sensitive half-time, context-sensitive decrement times). Clinical consequences for using intravenous anaesthetic drugs (hypnotics and opioids) are exposed either during bolus injection or continuous infusion, when injected alone or co-administered.

Study Objective: To evaluate the potential effect of tenofovir disoproxil fumarate (DF) on the pharmacokinetics of methadone., Design: Phase I, open-label, fixed-sequence, pharmacokinetic drug-drug interaction study., Setting: Clinical research center., Subjects: Fourteen volunteers receiving stable methadone maintenance therapy who were not infected with the human immunodeficiency virus., Intervention: Tenofovir DF was added to the subjects' methadone regimens., Measurements and Main Results: The pharmacokinetics of total, R-, and S-methadone were evaluated at baseline and after 2 weeks of daily tenofovir DF coadministration with a light meal. Steady-state tenofovir DF pharmacokinetics were evaluated at day 15. Bioequivalence testing was conducted of total, R-, and S-methadone area under the serum or plasma concentration-time curve during the 24-hour dosing interval at steady state (AUCss) and maximum concentration in serum or plasma (Cmax). Subjects were evaluated for changes in methadone pharmacodynamics by the Short Opiate Withdrawal Scale (SOWS) and pupillary diameter measurements at frequent intervals. Coadministration with tenofovir DF did not affect the pharmacokinetics of methadone. Geometric mean R-methadone systemic exposures, AUCss and Cmax, differed by 5% or less when methadone was dosed with tenofovir DF. Similar results were observed for S-methadone and for total methadone. Both AUCss and Cmax met the strict criteria for bioequivalence between the two study periods for total, R-, and S-methadone, indicating a lack of drug interaction when tenofovir DF was coadministered with methadone. No significant changes in SOWS scores or pupillary diameter measurements occurred, and no notable clinical adverse events were reported., Conclusion: Tenofovir DF pharmacokinetics were comparable to previously reported values of tenofovir DF in HIV-infected patients. Coadministration of methadone with tenofovir DF did not alter the pharmacokinetics or pharmacodynamics of total, R-, or S-methadone. Tenofovir DF may be given as part of a once-daily antiretroviral regimen in patients receiving methadone maintenance therapy.

A quantitative LC-APCI-MS/MS method for simultaneous measurement of opiates, cocaine, and metabolites in hair was developed and validated. Cocaine and opiates were extracted from pulverized hair via sonication in methanol at 37 degrees C for 3 h. Samples were cleaned up using solid-phase extraction. LC separation was achieved in 20 min with identification and quantification by selected reaction monitoring. Calibration by linear regression analysis utilized deuterated internal standards and a weighting factor of 1/x (R(2) > 0.998). Limits of quantification (LOQ) ranged from 17 to 50 pg/mg for cocaine and metabolites and were 83 pg/mg for opiates. Standard curves were linear from the LOQ to 5000 pg/mg for cocaine and metabolites, except benzoylecgonine (2500 pg/mg). Opiate standard curves were linear from the LOQ to 12500 pg/mg. Accuracy ranged from 84 to 115% for all quantitative analytes. Precision, % relative standard deviation, was less than 11.0% for all analytes. Methanolic sonication produced less than 5% hydrolysis of cocaine and 6-acetylmorphine. The method should be useful for studying cocaine and opiate distribution into hair.

The opportunities for very low birth weight infants (birth weight < 1500 g) and extremely low birth weight infants (birth weight < 1000 g) to undergo surgery are increasing. These infants are prone to prematurity-related morbidities including respiratory distress syndrome, intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity, patent ductus arteriosus and necrotising enterocolitis. Evidence is accumulating that preterm infants are also sensitive to pain and stress. The pharmacokinetics of drugs in preterm infants is not fully understood but smaller doses of anaesthetic drugs are usually required in preterm infants compared to term infants and older children and their effects last longer due to low clearance rates and longer elimination half-lives. Key anaesthetic considerations are (i) inspired oxygen concentration that should be adjusted to avoid hyperoxia, (ii) haemodynamic parameters that should be kept stable and (iii) prevention of hypothermia by using adequate measures to keep the infants warm. These precautions must be continuously taken during the operation and the transport to and from the operating theatre.

This article describes the anaesthetic management and use of total intravenous anaesthesia (TIVA) for neurosurgery in 4 dogs. Propofol in conjunction with morphine was used for the maintenance of anaesthesia. Anaesthesia was induced with either thiopentone or propofol. The program Stelpump (a target-controlled infusion program) was run on a laptop and connected to a syringe driver via an RS 232 cable. The program was found to be reliable and safe for the administration of TIVA in dogs. Invasive monitoring was required in order to monitor cardiovascular changes during surgery. Ventilation was controlled to maintain the end-tidal carbon dioxide below 40 mm Hg. The anaesthesia was characterised by haemodynamic stability. The haemodynamic stability was probably the result of the choice of TIVA and balanced anaesthesia. Intracranial pressure and oedema was controlled with dexamethasone, mannitol and ventilatory management either in combination or alone. Three dogs survived to hospital discharge and 1 dog was euthanased 2 weeks later due to tumour metastasis. The development and characterisation of the anaesthetic effects of TIVA needs to be elucidated in order to provide clinicians with rational guidelines for the appropriate use of TIVA in veterinary medicine.

Background: Characterizing drug interactions using a response surface allows for the determination of the interaction over a complete range of clinically relevant concentrations. Gathering the data necessary to create this surface is difficult to do in a clinical setting and requires the use of volunteer experiments with surrogate noxious stimuli to adequately control the process for data collection. The pharmacodynamic synergy of opioids and hypnotics was investigated using a volunteer study paradigm., Methods: Twenty-four volunteer subjects (12 male, 12 female) were studied using computer-controlled infusions of propofol and remifentanil to create an increasing staircase drug concentration profile in each subject. Three different drug delivery profiles were administered to subjects, one with a single agent and two with combinations of propofol and remifentanil. At each plateau of the staircase profile, drug effect was assessed using four surrogate measures: Observer Assessment of Alertness/Sedation score, tibial pressure algometry, electrical tetany, and response to laryngoscopy. Response surfaces were developed that mapped the interaction of propofol and remifentanil to these surrogate effect measures in all subjects. An interaction parameter was used to assess whether these two drugs behave synergistically to blunt response to noxious stimuli., Results: The response surfaces showed considerable synergy between remifentanil and propofol for blunting response to the noxious stimuli. The interaction index, a measure of synergy, was 8.2 and 14.7 for response to algometry and tetany, respectively (P < 0.001), and 5.1 and 33.2 for sedation and laryngoscopy, respectively (P < 0.001), using the Greco interaction model. The surrogate stimuli mapped to clinically relevant concentrations for these agents in combination., Conclusions: The response surface models reveal the tremendous synergy between remifentanil and propofol. The surface morphologic features give some indication of the relative contribution of sedation and analgesia to blunting subject response. Further, the results of this investigation validate the volunteer study paradigm and use of surrogate effect measures for its clinical relevance.

Aim: To construct a population pharmacokinetic model for methadone enantiomers in the setting of methadone maintenance treatment for opioid dependence., Methods: A population pharmacokinetic model was developed using P-Pharm software for rac-, (R)- and (S)-methadone using data (8-13 plasma samples per subject) obtained from 59 methadone maintenance patients during one interdosing interval at steady state. The patients were randomly assigned to either a development (n = 38) or a validation dataset (n = 21). The model was refined by inclusion of all subjects to construct a final basic model, which was used to construct a covariate model., Results: A population-based two-compartment open model with first-order absorption and lag time was developed and validated for all analytes. The population geometric mean (coefficient of variation) of maximum a posteriori probability Bayesian estimated values for clearance, terminal half-life and volume of distribution at steady-state of the active (R)-enantiomer were 8.7 (42%) l h(-1), 51 (45%) h and 597 (45%) l, respectively. For all analytes, the volume of the central compartment was decreased with increasing plasma alpha(1)-acid glycoprotein concentration and was lower in females, while the delay in absorption was longer at higher doses. No covariates were identified for apparent oral clearance. The apparent oral clearance of (R)-methadone (geometric mean ratio; 95% confidence interval) was 105% (99, 110), that of (S)-methadone (P = 0.19), while (R)-methadone V(c)/F (154%; 151, 157), V(dss) /F (173%; 164, 183), t(1/2beta) (162%; 153, 172) and mean residence time (166%; 156, 176) were significantly greater (P < 0.0001) than for (S)-methadone. The population pharmacokinetic models were able to predict accurately oral clearance values from limited (one or two samples) blood sampling protocols., Conclusions: The substantial stereoselectivity in methadone disposition reinforces the potential for misinterpretation of racemic methadone disposition data. The marked interindividual variability in (R)-methadone clearance, with no covariates identified, highlights the need for alternative methods to determine an individual's metabolic clearance. The ability to predict (R)-methadone clearance from one to two blood samples at steady state may prove clinically useful if a drug-drug interaction or poor adherence are suspected and guide the prescriber in deciding if a client's request for a dose increase is warranted or whether an alternative opioid would be more appropriate.

Aims: There is considerable unexplained interindividual variability in the methadone dose-effect relationship. The efflux pump P-glycoprotein (P-gp) regulates brain access and intestinal absorption of many drugs. Evidence suggests that methadone is a P-gp substrate in vitro, and P-gp affects methadone analgesia in animals. However the role of P-gp in human methadone disposition and pharmacodynamics is unknown. This investigation tested the hypothesis that the intestinal absorption and pharmacodynamics of oral and intravenous methadone are greater after inhibition of intestinal and brain P-gp, using the P-gp inhibitor quinidine as an in vivo probe., Methods: Two randomized, double-blind, placebo-controlled, balanced crossover studies were conducted in healthy subjects. Pupil diameters and/or plasma concentrations of methadone and the primary metabolite EDDP were measured after 10 mg intravenous or oral methadone HCl, dosed 1 h after oral quinidine (600 mg) or placebo., Results: Quinidine did not alter the effects of intravenous methadone. Miosis t(max) (0.3 +/- 0.3 vs 0.3 +/- 0.2 h (-0.17, 0.22)), peak (5.3 +/- 0.8 vs 5.1 +/- 1.0 mm (0.39, 0.84)) and AUC vs time (25.0 +/- 5.7 vs 26.8 +/- 7.1 mm h (-6.1, 2.5)) were unchanged (placebo vs quinidine (95% confidence interval on the difference)). Quinidine increased (P < 0.05) plasma methadone concentrations during the absorptive phase, decreased t(max) (2.4 +/- 0.7 vs 1.6 +/- 0.9 h (0.33, 1.2)), and increased peak miosis (3.2 +/- 1.5 vs 4.3 +/- 1.6 mm (-1.96, -0.19)) after oral methadone. The C(max) (55.6 +/- 10.3 vs 59.4 +/- 14.1 ng ml(-1) (-8.5, 0.65)) and AUC of methadone (298 +/- 46 vs 316 +/- 74 ng ml(-1) h (-54, 18)) were unchanged, as were the EDDP : methadone AUC ratios. Quinidine had no effect on the rate constant for transfer of methadone between plasma and effect compartment (k(e0)) (2.6 +/- 2.6 vs 2.5 +/- 1.4 h(-1) (-3.5, 4.2))., Conclusions: Quinidine increased the plasma concentrations of oral methadone in the absorptive phase and the miosis caused by methadone, suggesting that intestinal P-gp affects oral methadone absorption and hence its clinical effects. Quinidine had no effect on methadone pharmacodynamics after intravenous administration, suggesting that if quinidine is an effective inhibitor of brain P-gp, then P-gp does not appear to be a determinant of the access of methadone to the brain.

Rationale: Methadone maintenance treatment is complicated by the wide variability of efficacy among patients. The large interindividual variability of the plasma concentrations of methadone was previously thought to be responsible for the variable therapeutic efficacy. However, recent studies suggested that methadone may be a substrate of P-glycoprotein (P-gp). Therefore, the function of P-gp in blood-brain barrier (BBB) may affect the concentration of methadone at its site(s) of action in the central nervous system, thereby contributing to its therapeutic efficacy and/or adverse events., Objective: To investigate the effect of P-gp on brain penetration of methadone (R)- and (S)-enantiomers and their major oxidative metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)., Methods: We compared the tissue distribution of methadone (R)- and (S)-enantiomers and EDDP in the Abcb1a-/- gene knockout mice and the Abcb1a+/+ wild-type mice 1 h following intraperitoneal administration of 15 microg Rac-methadone/g mouse., Results: Plasma concentrations of (R)- and (S)-methadone were similar between the two animal groups. However, the brain concentrations of (R)- and (S)-methadone in the Abcb1a-/- mice were markedly higher (15- and 23-fold, respectively, P<0.0001) than those of the Abcb1a+/+ wild-type mice. No statistically significant difference was found for other organs between the mutants and controls. No organ difference was found for EDDP between the mutants and controls., Conclusions: (R)- and (S)-methadone are substrates of P-gp. The P-gp in BBB greatly limits the brain entry of (R)- and (S)-methadone to their central nervous system acting sites. The interindividual variation in expression of P-gp in BBB may represent a source of variation for the access and effects of methadone in the brain.

This paper describes a bioanalytical method involving a simple liquid-liquid extraction for the simultaneous HPLC determination of the enantiomers of tramadol, the active metabolite O-desmethyltramadol (M1), and the other main metabolite N-desmethyltramadol (M2) in biological samples. Chromatography was performed at 5 degrees C on a Chiracel OD-R column containing cellulose tris(3,5-dimethylphenylcarbamate) as chiral selector, preceded by a achiral end-capped C8 column (LiChrospher 60-RP-selected B 5 microm, 250 mm x 4 mm). The mobile phase was a mixture of phosphate buffer containing sodium perchlorate (1 M) adjusted to pH 2.5-acetonitrile-N,N-dimethyloctylamine (74.8:25:0.2). The flow rate was 0.5 ml/min. Fluorescence detection (lambda(ex) 200 nm/lambda(em) 301 nm) was used. Fluconazol was selected as internal standard. The limit of quantitation of each enantiomer of tramadol and their metabolites was 0.5 ng/ml (sample size = 0.5 ml). The chiral conditions and the LC optimisation were investigated in order to select the most appropriate operating conditions. The method developed has also been validated. Mean recoveries above of 95% for each enantiomer were obtained. Calibration curves for tramadol enantiomers (range 1-500 ng/ml), M1 enantiomers (range 0.5-100 ng/ml), and M2 enantiomers (range 0.5-250 ng/ml) were linear with coefficients of correlation better than 0.996. Within-day variation determined on four different concentrations showed acceptable values. The relative standard deviation (R.S.D.) was determined to be less than 10%. This method was successfully used to investigate plasma concentration of enantiomers of tramadol, O-desmethyltramadol and N-desmethyltramadol in a pharmacokinetic study.

Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.

Twelve methadone-maintained HIV-negative subjects were given saquinavir/ritonavir (SQV/rtv) 1600 mg/100 mg once daily for 14 days. Pharmacokinetic evaluations of total and unbound methadone enantiomers (R and S) were conducted before and after SQV/rtv. SQV/rtv was well tolerated, with no ACTG Grade 3-4 adverse events, no evidence of sedation, and no changes in methadone dose. For R-methadone (active isomer), C(max), AUC(0-24 h), and C(min) were unchanged, but percent unbound 4 hours after dosing was reduced by 12%. For S-methadone, no differences in pharmacokinetic parameters of total drug were seen, but unbound concentrations were reduced by 15% and 21% at 4 and 24 hours after dosing, respectively. SQV trough concentrations exceeded the anticipated EC(50) (50 ng/mL) in 10/12 subjects, persisting for at least 6 hours after the final dose in 4/6 subjects. Once-daily SQV/rtv in methadone-maintained subjects is safe and not associated with any clinically significant interaction with methadone during 14 days of concomitant administration.

Background: During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed., Methods: Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated., Results: The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis., Conclusion: This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.

Methadone offers significant therapeutic benefits to the population of pregnant, opiate-dependent women and is currently the treatment of choice for this group. Yet the problem of women who elect to breastfeed while on methadone maintenance frequently vexes providers. Although breast milk offers advantages clearly beneficial to the general population of infants, there is debate about recommending breastfeeding to postpartum women receiving methadone maintenance. Although previous research has shown that amounts of methadone in breast milk appear to be very small, and therefore breastfeeding seems to be safe, women on methadone do not often breastfeed, for a variety of reasons. This article provides an overview of the issues facing providers in treating methadone-maintained women who elect to breastfeed. A comprehensive review of existing literature on the subject is offered, along with clinical advice for practitioners providing care to this population of women and children.

The efflux transporter P-glycoprotein (P-gp) is an important component of the blood-brain barrier (BBB) that limits accumulation of many compounds in brain. Some opioids have been shown to interact with P-gp in vitro and in vivo. Genetic or chemical disruption of P-gp has been shown to enhance the antinociceptive and/or toxic effects of some opioids, although the extent of this phenomenon has yet to be understood. The purpose of this study was to assess quantitatively the influence of mdr1a P-gp on initial brain uptake of chemically diverse opioids in mice. The brain uptake of opioids selective for the mu (fentanyl, loperamide, meperidine, methadone, and morphine), delta (deltorphin II, DPDPE, naltrindole, SNC 121) and kappa (bremazocine and U-69593) receptor subtypes was determined in P-gp-competent (wild-type) and P-gp-deficient [mdr1a(-/-)] mice with an in situ brain perfusion model. BBB permeability of the opioids varied by several orders of magnitude in both mouse strains. The difference in brain uptake between P-gp-competent and P-gp-deficient mice ranged from no detectable effect (meperidine) to >/=8-fold increase in uptake (DPDPE, loperamide, and SNC 121). In addition, loperamide efflux at the BBB was inhibited by quinidine. These results demonstrate that P-gp modulation of opioid brain uptake varies substantially within this class of compounds, regardless of receptor subtype. P-gp-mediated efflux of opioids at the BBB may influence the onset, magnitude, and duration of analgesic response. The variable influence of P-gp on opioid brain distribution may be an important issue in the context of pharmacologic pain control and drug interactions.

Buprenorphine, a partial mu-opioid agonist, has been shown effective for treatment of opioid dependence but also has some abuse potential. A novel formulation of buprenorphine, using a polymer microcapsule depot sustained-release technology, has been developed which may offer effective treatment of opioid dependence while also minimizing risks of patient noncompliance and illicit diversion. This open-label, first-in-human study evaluated the safety and pharmacokinetics of a single-dose buprenorphine depot in physically dependent opioid abusers. The present study also examined the efficacy of depot buprenorphine in suppressing symptoms of opioid withdrawal, attenuating the effects of exogenous opioid challenge, and providing clinical detoxification. Five opioid-dependent volunteers each received a single subcutaneous depot injection containing 58 mg of buprenorphine and were assessed for at least four weeks for signs and symptoms of opioid withdrawal, first residentially and then as outpatients. Depot buprenorphine appeared to provide effective relief from opioid withdrawal, with no participant requiring additional medication for withdrawal relief following depot administration. The depot was safe and well-tolerated, with no significant side effects, signs of intoxication, or respiratory depression. In the opioid challenge sessions, depot buprenorphine appeared to produce substantial opioid blockade that persisted for 6 weeks post-depot administration. Results from the present study suggest that depot buprenorphine offers significant promise for enhancing the delivery of effective opioid agonist treatment while minimizing risk for abuse of the medication.

The roots of the Laboratory of the Biology of the Addictive Diseases are in the development of methadone maintenance for the treatment of opiate addiction. Methadone maintenance therapy continues to be one of the major effective forms of addiction pharmacotherapy and underscores the importance of biological factors in the physiology and treatment of the addictive diseases. Recent work in the Laboratory has focused on the neurobiological, neurochemical, neuroendocrine and behavioral aspects of addictive diseases (principally cocaine and the opiate addictions), using an interdisciplinary approach. The models we have focused on range from in vitro molecular biology and neuroscience, to in vivo animal models, to experiments in normal human populations and patients with specific addictive diseases, and most recently to the human molecular genetics of different addictive diseases. Two long-term corollary hypotheses have guided the Laboratory's work: (1) That the endogenous opioid peptide/receptor systems play a central role in the addictive states and therefore in their treatment. (2) That atypical responsivity to stressors (e.g., in the hypothalamic-pituitary-adrenal axis) plays a role in vulnerability and relapse to specific addictive diseases. This atypical responsivity may be drug-induced, environmentally acquired, and/or due to genetic variation.

Propofol-opioid combinations are widely used in today's anaesthetic practice. Over the past 20-30 years the pharmacology of these agents has been described in increasingly greater detail. Together with novel intravenous administration devices and improved anaesthetic depth monitoring, this has created a basis for the optimisation of the administration of propofol-opioid anaesthesia. This article describes the current strategies regarding the application of this type of anaesthesia, focusing on three strategic tools: (i) application of pharmacokinetic-pharmacodynamic knowledge of propofol and the opioids, with particular attention to pharmacodynamic interactions between them; (ii) the use of state-of-the-art administration techniques; and (iii) the application of bispectral index monitoring. Together, these techniques have improved the level of control, the flexibility and the safety of anaesthetic practice.

Aim: To compare the pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (M1), in male and female rats., Methods: Following a single oral dose of 10 mg/kg trans-T hydrochloride to rats, (+)-trans-T, (-)-trans-T, (+)-M1, and (-)-M1 in plasma were determined by a high performance capillary electrophoresis method., Results: The females showed higher plasma concentrations of (+)-trans-T, (-)-trans-T, and (+)-M1 than the males. The enantiomers of trans-T were absorbed and eliminated more slowly in the females than in the males. (+)-M1 was eliminated more slowly in the females than in the males. All pharmacokinetic parameters but Tmax of the two enantiomers of trans-T were significantly different in both sex rats. The (+)/(-)-enantiomeric ratios of the pharmacokinetic parameters for trans-T in the males were similar to those in the females. The values of Cmax, AUC(0-infinity) of the two enantiomers of M1 were significantly different in both sex rats. The (+)/(-)-enantiomeric ratios of Cmax, AUC(0-infinity) for M1 were lower than 1 in the males, larger than 1 in the females., Conclusions: Systemic exposure of (+)-trans-T, (-)-trans-T, and (+)-M1 was higher in female rats than in male rats. The stereoselectivity in pharmacokinetics of trans-T was similar, and that of M1 was different in male and female rats.

This study examined the accumulation and transport of two related systemic opioids used as antidiarrhoeal drugs and compared their rates of transport with known P-glycoprotein (P-gp) substrates used in our in vitro environment. Cellular uptake and efflux and transcellular transport were all determined using Caco-2 cells after exposure to loperamide or diphenoxylate, with or without a range of efflux inhibitors. Bidirectional transport studies of 5 microM loperamide showed efflux to be fivefold higher than influx (42 x 10(-6) compared to 8 x 10(-6) cm/s); however, this decreased to twofold at 10 microM and was abolished using 100 microM loperamide. An uptake pathway was also discovered when P-gp was inhibited which, in the presence of Ca(2+) channel blockers, was amplified, providing a potential mechanism for central nervous system effects to be increased upon blockage of L-type calcium channels, quite separate from any P-gp inhibition. Diphenoxylate transport, however, showed little sign of P-gp-mediated efflux. Diphenoxylate accumulated readily within cells, yet transport through cells was very low. Additionally, efflux inhibitors had little impact on transport or accumulation, suggesting that diphenoxylate was not a substrate for an efflux mechanism.

The rapid expansion of modern molecular imaging methods since the time of their initial conception in the 1970s has given rise to numerous discoveries of molecular mechanisms that underlie brain function in health and disease. Uses in clinical diagnosis and therapy monitoring are still evolving. Future clinical trials, in which molecular imaging is imbedded and correlated with clinical outcomes, will be critical to advancing new uses for patient management. Receptor occupancy studies are already well integrated into many drug development studies and clinical trials; such studies will provide a basis for new studies that will further advance clinical uses of brain molecular imaging.

Pharmacogenomics, applied as an aspect of molecular autopsy, may be used as an adjunct for certifying methadone fatalities. Methadone is metabolized by cytochrome P-450 (CYP) 1A2, 3A4, and 2D6. We hypothesized that methadone toxicity may be partially due to CYP 2D6 *3, *4, and *5 variant alleles, resulting in poor drug metabolism. A retrospective analysis was performed on covariables and risk factors of 21 methadone cases from the Milwaukee County Medical Examiner's Office (1998-2000). PCR genotyping showed: one heterozygous for 2D6*3, two homozygous for 2D6*4, five heterozygous for 2D6*4, and one heterozygous for both 2D6*3 and *4. This limited number of cases showed that the prevalence of poor metabolizer was higher but not significantly different from that of a control group (n = 23) (P > 0.05, Fisher Exact Test). Thus, CYP 2D6 mutations may not yet be directly associated with methadone toxicity. However, pharmacogenomics, complementing other case findings, served as an adjunct in interpreting methadone toxicity of poor and intermediate metabolizers.

Objective: Mutations in the ABCB1 gene have been associated with decreased expression and net function of P-glycoprotein (P-gp). We investigated the modulation of the central nervous effects of loperamide resulting from ABCB1 genetic variants., Methods: On two occasions, 20 healthy volunteers received 24 mg loperamide suspension orally and, in a double-blind randomized two-way crossover fashion, 800 mg quinidine or placebo orally 1 h before loperamide. Pupil size was measured for 5 h following loperamide administration, and plasma concentrations of loperamide and quinidine were measured for 6 h. Single nucleotide polymorphisms and haplotypes including G2677T(A) (exon 21) and C3435T (exon 26) were analysed for their relation to plasma concentrations of quinidine and loperamide and to the miotic effects of loperamide., Results: Loperamide plasma concentrations with quinidine co-administration were about twice as high as those without quinidine. The ABCB1 haplotype G2677/T3435 was associated with the highest loperamide plasma concentrations, which were about 1.5 times higher than in non-carriers of this haplotype. Plasma concentrations of quinidine did not differ among carriers and non-carriers of genetic variants. When quinidine was co-administered with loperamide, pupil size decreased. Without quinidine it changed only minimally. The ABCB1 TT3435 genotype was associated with the most pronounced increase of the miotic effects of loperamide when quinidine was co-administered. This was accompanied by a tendency toward higher plasma loperamide in TT3435 carriers., Conclusions: Our data support a functional importance of the ABCB1 mutations for plasma concentrations and central nervous actions of the opioid loperamide., (Copyright 2003 Lippincott Williams & Wilkins)

Background: In several countries medical prescription of diacetylmorphine is currently being evaluated as a treatment option for heavily dependent narcotic addicts. Because of damaged veins, many patients administer diacetylmorphine intramuscularly or orally. Therefore we characterized the pharmacokinetics of intramuscular and oral diacetylmorphine in the high dose range usually required in narcotic addicts., Methods: Three intramuscular doses, 3 oral doses, and 1 intravenous dose of diacetylmorphine and oral and intravenous test doses of deuterium-labeled morphine (morphine-N-methyl-d3 [morphine-d3]) were administered to 8 heroin-addicted patients. Arterial plasma concentrations of diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-d3 were measured by liquid chromatography-mass spectrometry., Results: Intramuscularly administered diacetylmorphine (

Whenever an anesthetic is needed during the breast feeding period, potential pharmacological side-effects imposed on the infant by any kind of anesthetic agent used during both general and regional anesthesia are in contrast to the potential beneficial effects of breast feeding for the infant and the mother. Despite an increasing knowledge and understanding of the mechanisms of excretion of drugs and their metabolites through breast milk, information about most anesthetic drugs are still either inconclusive or contradictory. Often it is impossible to decide whether a certain substance that is potentially excreted through breast milk might be harmless or harmful for the breast-fed infant. In addition to that only few anesthetic agents and drugs used in conjunction with an anesthetic are officially approved for use during pregnancy and the period of breast feeding and for medico-legal reasons pharmaceutical companies generally advise against the use of any of those drugs during this period. However, based on the knowledge of pharmacological properties of commonly used anesthetic agents it is reasonable to assume that continuing breast feeding in the immediate postoperative period after a single anesthetic can be considered safe for the infant since no adverse effects caused by or secondary to the single use of those drugs can be expected. Provided there is a careful choice of anesthetic drugs, there is no need to consider that a single general or regional anesthetic is an indication to stop breast feeding. Even planned elective surgical procedures do not need to be postponed. No scientifically based interval between surgery under general or regional anesthesia and resumption of breast feeding can be recommended. Instead current opinion is that breast feeding can be resumed as soon as the mother feels physically and mentally capable to do so.