Stereochemistry of phase-1 metabolites of mephedrone determines their effectiveness as releasers at the serotonin transporter.

Mephedrone (4-methyl-N-methylcathinone) is a psychostimulant that promotes release of monoamines via the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). Metabolic breakdown of mephedrone results in bioactive metabolites that act as substrate-type releasers at monoamine transporters and stereospecific metabolism of mephedrone has been reported. This study compared the effects of the enantiomers of the phase-1 metabolites nor-mephedrone, 4-hydroxytolyl-mephedrone (4-OH-mephedrone) and dihydro-mephedrone on (i) DAT, NET and SERT mediated substrate fluxes, (ii) determined their binding affinities towards a battery of monoamine receptors and (iii) examined the relative abundance of the enantiomers in human urine. Each of the enantiomers tested inhibited uptake mediated by DAT, NET and SERT. No marked differences were detected at DAT and NET. However, at SERT, the S-enantiomers of nor-mephedrone and 4-OH-mephedrone were several times more potent than the corresponding R-enantiomers. Moreover, the R-enantiomers were markedly less effective as releasers at SERT. S-nor-mephedrone displayed moderate affinities towards human alpha1A, human 5-HT2A and rat and mouse trace amine-associated receptor 1. These results demonstrate that stereochemistry dictates the pharmacodynamics of the phase-1 metabolites of mephedrone at SERT, but not at DAT and NET, which manifests in marked differences in their relative potencies, i.e. DAT/SERT ratios. Chiral analysis of urine samples demonstrated that nor-mephedrone predominantly exists as the S-enantiomer. Given the asymmetric abundance of the enantiomers in biological samples, these findings may add to our understanding of the subjective effects of administered mephedrone, which indicate pronounced effects on the serotonergic system.

Evaluation of an on-site test device for the heroin metabolite 6-acetylmorphine in urine.

Detection of heroin use is an important task in clinical drug testing and can be best performed by using 6-acetylmorphine as the target analyte. This study was performed to evaluate an on-site test for 6-acetylmorphine screening in urine with an assigned cut-off limit at 10 ng/mL. The reference method was a forensic accredited liquid chromatography-tandem mass spectrometry method. The study confirmed that negative controls and negative authentic specimen resulted in negative readings. Low cross-reactivity was recorded from other potential interfering opioids. Prepared standards and commercial calibrators demonstrated that the cutoff level of the test was lower than the assigned value and rather 2 ng/mL. A study using authentic specimens from patients on substitution treatment with methadone, morphine, and buprenorphine confirmed that the real cut-off level was 2 ng/mL. Using this value as cutoff limit the sensitivity and specificity of the test was 100%.

Ultrafast capillary electrophoresis/mass spectrometry of controlled substances with optical isomer separation in about a minute.

RATIONALE: Analysis of forensic evidence by information-rich technologies such as mass spectrometry (MS) is one of the fastest growing areas in forensic analysis. To provide more accurate identification of forensic evidence, in the past few years there has been a growing interest in moving this technology to the field for on-site, real-time analysis. To this end, several portable mass spectrometers have been introduced; however, the analysis of controlled substances could be complicated by the existence of various isomers including optical isomers in which sentencing may depend on the identification of the isomer. To date very few portable separation devices are capable of separating and identifying the optical isomers. METHODS: In this study, the application of the portable ultrafast capillary electrophoresis (UFCE) to the separation of controlled substances is presented and the results are compared with the results obtained from a bench-top CE system. Both a nominal mass ion trap mass spectrometer and an accurate mass orbitrap mass spectrometer were interfaced with CE using a porous tip capillary. RESULTS: A mixture of several controlled substances can be separated and detected using UFCE/MS in about a minute using field strengths of ≥1000 V/cm. Furthermore, separation and detection of underivatized optical isomers of amphetamine, cathinone, nor-mephedrone, and pregabalin using UFCE/MS can be achieved with an analysis time of less than two minutes. Resolutions of 1.3, 3.7 and 3.8 were achieved for pregabalin, cathinone and nor-mephedrone, respectively, under UFCE/MS conditions. CONCLUSIONS: Amphetamine, cathinone, nor-mephedrone and pregabalin were separated and detected in about a minute, demonstrating the utility of the portable CE instrument for the analysis of controlled substances and their optical isomers. Copyright © 2016 John Wiley & Sons, Ltd.

Simultaneous determination of opiates, methadone, buprenorphine and metabolites in human urine by superficially porous liquid chromatography tandem mass spectrometry.

For monitoring compliance of methadone or buprenorphine maintenance patient, a method for the simultaneous determination of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), buprenorphine, norbuprenorphine, opiates (morphine, codeine, 6-monoacetylmorphine) in urine by superficially porous liquid chromatography tandem mass spectrometry was developed and validated. After enzyme digestion and liquid-liquid extraction, reverse-phase separation was achieved in 5.2 min and quantification was performed by multiple reaction monitoring. Chromatographic separation was performed at 40 °C on a reversed phase Poroshell column with gradient elution. The mobile phase consisted of water and methanol, each containing 0.1% formic acid, at a flow rate of 0.32 mL/min. Intra-day and inter-day precision were less than 12.1% and accuracy was between -9.8% and 13.7%. Extraction efficiencies were more than 68%. Although ion suppression was detected, deuterated internal standards compensated for these effects. Carryover was minimal, less than 0.20%. All analytes were stable at room temperature for 16 h, 4 °C for 72 h, and after three freeze-thaw cycles. The assay also fulfilled compound identification criteria in accordance with the European Commission Decision 2002/657/EC. We analyzed 62 urine samples from patients received maintenance therapy and found that 54.8% of the patient samples tested were detected for morphine, codeine, or 6-monoacetylmorphine. This method provides a reliable and simultaneous quantification of opiates, maintenance drugs, and their metabolites in urine samples. It facilitates the routine monitoring in individuals prescribed the drug to ensure compliance and help therapeutic process.

Characterization of the antinociceptive and pronociceptive effects of methadone in rats.

BACKGROUND: Recently, it has been appreciated that in addition to their antinociceptive properties, opioid analgesics also can enhance pain sensitivity (opioid-induced hyperalgesia [OIH]). OIH may enhance preexisting pain and contribute to dose escalation, tolerance, and misuse/abuse of opioids. Better information is needed to determine which opioid or opioid combinations may be least likely to produce OIH and therefore possibly represent better choices for pain management. Herein the authors have examined the hyperalgesic and antinociceptive properties of racemic methadone and its enantiomers alone and in combination with morphine in rats. Methadone is of particular interest because it possesses both micro-receptor agonist and N-methyl-d-aspartate receptor antagonist activities. METHODS: The antinociceptive and hyperalgesic properties of d,l-methadone, l-methadone, and d-methadone were characterized by dose and sex using the thermal tail-flick test (high and low intensity). The responses to l- and d-methadone combinations with morphine were also determined with this model. RESULTS: Antinociceptive and hyperalgesic effects of d,l-methadone were demonstrated. These effects were related to dose but not to sex. The degree of hyperalgesia was greater with l-methadone compared with d,l-methadone. In contrast, d-methadone (N-methyl-d-aspartate antagonist) did not produce hyperalgesia. Furthermore, d-methadone blocked morphine hyperalgesia, enhanced antinociception, and abolished sex-related differences. This seems to be the result of antagonistic activity of d-methadone at the N-methyl-d-aspartate receptor. CONCLUSION: The current findings with methadone are supportive of previous findings implicating mu-opioid and N-methyl-d-aspartate receptor mechanisms in OIH. Better understanding of OIH may help in choosing the most appropriate opioids for use in the treatment of pain.

Stereoselective determination of methadone and its main metabolite in serum and urine from methadone maintenance patients.

OBJECTIVES: A stereoselective HPLC method was developed to separate and quantify both enantiomers of methadone and its main metabolite EDDP in serum and urine. The method was used to establish that there is a relationship between the dose of methadone prescribed and its serum concentration as well as urine excretion of methadone and its metabolite enantiomers. METHODS: The chiral alpha1-glycoprotein stationary phase was used for enantioseparation of (R)-methadone, (S)-methadone and (R)-EDDP (S)-EDDP. The enantiomers of methadone and EDDP were extracted from urine and serum by a simple solidphase procedure. RESULTS: The validated method was applied to the analysis of 31 serum and urine samples obtained from methadone-maintained outpatients (65% male, age 28.8+/-4; methadone dose 146+/-47 mg). A significant correlation (Pearson) r=0.67 (p<0.001) between methadone dose and serum concentration of (R)-methadone was found. Due to the large variation in results obtained from analysis of the subjects' urine specimens, no statistically significant relationship between methadone dose and urine excretion of methadone and EDDP enantiomers was established. The rate of R/S methadone (1.38 in serum, 2.43 in urine) and R/S EDDP (0.83 in urine) confirmed stereoselectivity in methadone metabolism with high individual variability. CONCLUSIONS: The enantioselective evaluation of serum methadone concentration might be an interesting tool in methadone maintenance programme. On the other hand, the urinary excretion of methadone and EDDP enantiomers is not reliable as marker of methadone compliance but could be useful for monitoring individual metabolism or for studying the stereoselectivity in pharmacokinetics and metabolism of methadone.

Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat.

We studied the effects of the commonly used mu-opioid receptor agonists morphine, oxycodone, methadone and the enantiomers of methadone in thermal and mechanical models of acute pain and in the spinal nerve ligation model of neuropathic pain in rats. Subcutaneous administration of morphine, oxycodone, and methadone produced a dose-dependent antinociceptive effect in the tail flick, hotplate, and paw pressure tests. l-methadone, racemic methadone, and oxycodone had a similar dose-dependent antinociceptive effect, whereas the dose-response curve of morphine was shallower. In the spinal nerve ligation model of neuropathic pain, subcutaneous administration of morphine, oxycodone, methadone and l-methadone had antiallodynic effects in tests of mechanical and cold allodynia. l-methadone showed the strongest antiallodynic effect of the tested drugs. d-methadone was inactive in all tests. Morphine 5.0 mg/kg, oxycodone 2.5 mg/kg, and l-methadone 1.25 mg/kg decreased spontaneous locomotion 30 min after drug administration. In conclusion, in acute nociception all mu-opioid receptor agonists produced antinociception, with morphine showing the weakest effect. In nerve injury pain, l-methadone showed the greatest antiallodynic potency in both mechanical and cold allodynia compared with the other opioids. Opioids seem to have different profiles in different pain models. l-methadone should be studied for neuropathic pain in humans.

Fast gas chromatography/mass spectrometric assay for the validated quantitative determination of methadone and the primary metabolite EDDP in whole blood.

A toxicological analysis was developed and validated for simultaneous screening and quantification of methadone (METH) and its primary metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). The method employs microscale liquid-liquid extraction (microLLE) and direct injection of a separated aliquot of the organic layer into a gas chromatography/mass spectrometric (GC/MS) system without any other pre-treatment stages. A fast GC/MS runtime (total 5.8 min; METH, Rt = 3.55 min; EDDP, Rt = 3.40 min) combined with rapid sample preparation allowed cost-efficient and routinely applicable performance with a low amount of manual work. The validated parameters included: linearity (25-1000 ng mL(-1) both; R(METH)2 = 0.998 and R(EDDP)2 = 0.997), accuracy (Bias(METH): from -0.05 to 11.3%, Bias(EDDP): from 1.11 to 4.37%); intra and inter-assay precision (RSD(METH): from 2.4 to 3.9%, from 4.89 to 10.3%; RSD(EDDP): from 4.50 to 6.20%, from 4.57 to 15.2%), extraction efficiency (METH = 95.5%; EDDP = 90.6%), LOQ(Meth,EDDP) = 25 ng mL(-1). Samples were stable for at least 25 h and no selectivity problems or baseline interference were observed. The method should be applicable for identifying and quantitative confirmation of possible misuse and/or illegal use of METH in toxicological cases.

The effects of racemic D,L-methadone and L-methadone in substituted patients--a randomized controlled study.

AIMS: To test the hypothesis that switching from L-methadone to D,L-methadone is associated with more frequent withdrawal symptoms and side-effects than switching from D,L-methadone to L-methadone. DESIGN: Stratified, randomized 2 x 2 crossover study design over a time-period of 8 weeks. At study entry, every second patient was switched from the pre-study substance to the other medication, after 4 weeks all patients were subject to a (re-)switch. SETTING: The study was conducted as a multi-centre trial in three methadone maintenance therapy (MMT) clinics. PARTICIPANTS: Seventy-five patients previously treated with either D,L-methadone or L-methadone for at least 1 year took part in the study. MEASUREMENTS: Intra-individual changes in withdrawal symptoms (Short Opiate Withdrawal Scale, SOWS) and side-effects were defined as primary outcome criteria. Secondary outcome measures included necessity for methadone dose adjustment. FINDINGS: Complete data were available for 68 patients (91%). Sample strata were unbalanced at baseline: 15 patients (22%) were treated with L-methadone and 43 with D,L-methadone (78%). Thirty-five patients were randomized into the group treated with L-methadone and 33 into the group treated with D,L-methadone during the first 4 weeks. There were no significant differences in intra-individual change of withdrawal symptoms and side-effects between groups after crossover. However, patients treated with levomethadone tended to feel less withdrawal symptoms than patients treated with d,l-methadone. CONCLUSIONS: D,L-methadone and L-methadone can safely be replaced by each other on a 2:1 ratio. Withdrawal symptoms or side-effects due to conversion are of transient nature only.

Usos clínicos de la metadona / Clinical uses of methadone

La metadona es un opioide sintético agonista total en receptores micro, y antagonista de los receptores NMDA. Es altamente liposoluble, con una vida media de unas 23 horas, pudiendo variar entre 13 y 54 horas. Es un isómero óptico, cuya forma L es la responsable de la mayor actividad analgésica. Este fármaco ha sido utilizado satisfactoriamente desde hace años para el tratamiento sustitutivo de pacientes drogodependientes, sin embargo, su utilización como analgésico es menos generalizada, a pesar de su perfil farmacológico que podría ser beneficioso en este aspecto. Teniendo esto en cuenta, hemos revisado las principales aplicaciones terapéuticas de la metadona, y su implicación tanto en el dolor agudo como en el dolor crónico. La metadona es una alternativa atractiva para el tratamiento del dolor oncológico y neuropático, dada su buena disponibilidad oral, su larga vida media con escasas dosis diarias y su bajo coste. Las vías intravenosa, intradural, y epidural, se han mostrado eficaces y seguras para el tratamiento del dolor posoperatorio

Methadone is a synthetic opioid that is primarily a micro-opioid agonist, but also a NMDA-antagonist. It is highly liposoluble and has an average lifee in blood of approximately 23 hours, although it can vary from 13 to 54 hours. It is an optical isomer, where l-methadone is the primarily responsible factor for the analgesic effect. Methadone has successfully been used for many years for the treatment of dependence on opioid drugs. However, it has been less used as an analgesic, in spite of its useful pharmacolog ic profile. Bearing this in mind, we have reviewed the main therapeutic uses of methadone, and its effectiveness in treating both acute and chronic pain. Methadone is an attractive alternative for the treating cancer and neuropathic pain, because of its good oral bioavailability, its long average lHe at low daily doses and its oral bioavailability, its long average life at low daily doses and its low cost. Intravenous, intrathecal and epidural viae have shown to be effective and safe for the treatment of postoperative pain

Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs.

The opioid agonist properties of (+/-)-methadone are ascribed almost entirely to the (-)-methadone enantiomer. To extend our knowledge of the pharmacological actions of methadone at ligand-gated ion channels, we investigated the effects of the two enantiomers of methadone and its metabolites R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium perchlorate (EDDP) and R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline hydrochloride (EMDP), as well as structural analogs of methadone, including (-)-alpha-acetylmethadol hydrochloride (LAAM) and (+)-alpha-propoxyphene, on rat alpha3beta4 neuronal nicotinic acetylcholine receptors (nAChRs) stably expressed in a human embryonic kidney 293 cell line, designated KXalpha3beta4R2. (+/-)-methadone inhibited nicotine-stimulated 86Rb+ efflux from the cells in a concentration-dependent manner with an IC50 value of 1.9 +/- 0.2 microM, indicating that it is a potent nAChR antagonist. The (-)- and (+)-enantiomers of methadone have similar inhibitory potencies on nicotine-stimulated 86Rb+ efflux, with IC50 values of approximately 2 microM. EDDP, the major metabolite of methadone, is even more potent, with an IC50 value of approximately 0.5 microM, making it one of the most potent nicotinic receptor blockers reported. In the presence of (+/-)-methadone, EDDP, or LAAM, the maximum nicotine-stimulated 86Rb+ efflux was markedly decreased, but the EC50 value for nicotine stimulation was altered only slightly, if at all, indicating that these compounds block alpha3beta4 nicotinic receptor function by a noncompetitive mechanism. Consistent with a noncompetitive mechanism, (+/-)-methadone, its metabolites, and structural analogs have very low affinity for nicotinic receptor agonist binding sites in membrane homogenates from KXalpha3beta4R2 cells. We conclude that both enantiomers of methadone and its metabolites as well as LAAM and (+)-alpha-propoxyphene are potent noncompetitive antagonists of alpha3beta4 nAChRs.

Selective antibodies to methadone enantiomers: synthesis of (R)- and (R,S)-methadone conjugates and determination by an immunoenzymatic method in human serum.

Selective antibodies to (R)-methadone (Mtd) and to its racemate were produced in rabbits by immunization with conjugates of (R)- or (R,S)-hemisuccinyl-methadol-bovine serum albumin, respectively. A hapten was first prepared by reduction of (R)- or (R,S)-Mtd with sodium borohydride, followed by esterification with succinic anhydride. The conjugation of hapten with albumin was achieved by the mixed anhydride method. After immunization of rabbits, the titers and specificity of each antibody were determined by ELISA. The antibodies obtained were tested with (R)-, (S)-, (R,S)-Mtd, its major metabolite (EDDP), and some drugs of abuse (morphine, codeine, cocaine). The sensitivities of antibodies to (R)- and (R,S)-Mtd were about 1 and 2 ng/ml, respectively. Selective (R)-antibodies recognized (R)-Mtd about 40 times more avidly than the (S)-isomer, while an antiserum against (R,S)-Mtd recognized (R)- and (S)-isomers to about the same degree. Both selective antibodies showed little interference (about 0.5%) with EDDP metabolite and no crossreactivity with morphine, codeine, and cocaine. These two selective antibodies were used to develop an immunoenzymatic method (ELISA) for the determination of (R)- and (R,S)-Mtd in serum samples of patients under maintenance treatment for narcotic addiction.

Producción científica nacional e internacional en drogas de diseño (1988-1997) / National and International scientific production on designer drugs (1988-1997)

Introducción: El conocimiento de las fuentes de información científica es imprescindible para el abordaje del problema del consumo de drogas de diseño. El objetivo de este trabajo es analizar la producción científica nacional e internacional sobre esta conducta, a partir del análisis bibliométrico de las publicaciones. Material y método: La producción científica sobre drogas de diseño se ha obtenido de las bases de datos IME, MEDLINE, ISOC y teseo durante el período 1988-1997. También se revisaron las referencias bibliográficas de los artículos recuperados en la base de datos IME. Los artículos obtenidos se distribuyeron por años, tipo documental, revista de publicación y temática, instituciones y países de procedencia, idiomas y temas tratados. Resultados: En las revistas españolas se publicaron 34 artículos y en las extranjeras 2.181. Los principales aspectos tratados se refieren a la toxicidad, concepto y clasificación y actividad farmacológica de las drogas de diseño. Las áreas temáticas más productivas son la neuropsiquiatría, la farmacología y la medicina general e interna. Conclusiones: El análisis muestra que existen escasos estudios experimentales y epidemiológicos publicados en España. Las revistas son de drogodependencias, temática general, neuropsiquiatría y farmacología, lo que pone de relieve la multidisciplinariedad de esta conducta adictiva. Predominan los estudios sobre la 1-metil-4-fenil-1,2,3,6-tetrahidropiridina y los análogos y derivados de la MDMA (AU)

Pharmacologic treatments for drug and alcohol dependence.

Pharmacotherapy remains a relatively underused strategy for the treatment of patients with psychoactive substance-use disorders. This is partly because of a widely held view among the public and the substance-abuse treatment community that substance-use disorders are non-medical and should be treated through nonpharmacologic means. Furthermore, the pharmaceutical industry has been slow in developing medications for the treatment of patients with these disorders because of skepticism over the potential profitability of such medications. These factors have limited research activity in this area, with much of the impetus for study of these medications coming from the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, where the substantial public health implications of medications development for substance-use disorders have been recognized. Despite limitations, considerable advances in medication development for patients with substance-use disorders have occurred in recent years, and more can be expected in the near future. This is most evident in the treatment of patients with nicotine and opioid dependence, for whom several pharmacologic options exist. Recently renewed interest in the pharmacologic treatment of patients with alcohol dependence is likely to advance that therapeutic area substantially with time. Ongoing efforts should focus on identifying new compounds, systematically assessing them for activity in specific substance-use disorders, and educating the public and the treatment community about the substantial benefits that can accrue from medication development for patients with substance-use disorders.

Screening for drugs of abuse (II): Cannabinoids, lysergic acid diethylamide, buprenorphine, methadone, barbiturates, benzodiazepines and other drugs.

Requirements for the provision of an efficient and reliable service for drugs of abuse screening in urine have been summarized in Part I of this review. The requirements included rapid turn-around times, good communications between requesting clinicians and the laboratory, and participation in quality assessment schemes. In addition, the need for checking/confirmation of positive results obtained for preliminary screening methods was stressed. This aspect of the service has assumed even greater importance with widespread use of dip-stick technology and the increasing number of reasons for which drug screening is performed. Many of these additional uses of drug screening have possible serious legal implications, for example, screening school pupils, professional footballers, parents involved in child custody cases, persons applying for renewal of a driving licence after disqualification for a drug-related offence, doctors seeking re-registration after removal for drug abuse, and checking for compliance with terms of probation orders; as well as pre-employment screening and work-place testing. In many cases these requests will be received from a general practitioner or drug clinic with no indication of the reason for which testing has been requested. This also raises the serious problems of a chain of custody, provision of two samples, stability of samples, and secure and lengthy storage of samples in the laboratory-samples may be requested by legal authorities several months after the initial testing. The need for confirmation of positive results is now widely accepted but it may be equally important to confirm unexpected negative results. Failure to detect the presence of maintenance drugs may lead to the patient being discharged from a drug treatment clinic and, if attendance at the clinic is one of the terms of continued employment, to dismissal. It seems likely that increasing abuse of drugs and the efforts of regulatory authorities to control this, will lead to the manufacture of more designer drugs. Production of substituted phenethylamines was facilitated by the drug makers' cook book, 'PIHKAL' (Phenethylamines I Have Known And Loved) by Dr Alexander Shulgin and Ann Shulgin, and production of substituted tryptamines is promised in their next book, TIHKAL. Looking to the future, laboratories will need to ensure that they can detect and quantitate an ever-increasing number of drugs and related substances. The question of confidence in results of drugs of abuse testing raised in 1993 by Watson has assumed even greater importance as a result of attention focused on the OJ Simpson trial in Los Angeles. Toxicological investigations are likely to be challenged more frequently in the future. Even if analyses have been performed by GC-MS, there is a need to establish the level of match between the spectrum of the unknown substance and a library spectrum which is considered acceptable for legal purposes. It will also be essential to ensure that computer libraries contain spectra for all substances likely to be encountered in drugs of abuse screening.

Quantitative liquid chromatographic thermospray-tandem mass spectrometric analysis of some analgesics and tranquilizers of the methadone, butyrophenone, or diphenylbutylpiperidine groups in whole blood.

The results of a liquid chromatographic-mass spectrometric method for the quantitative determination of some medicaments of the methadone, butyrophenone, or diphenylbutylpiperidine groups in whole blood are presented. The method includes an extraction procedure with Bond Elut columns. The liquid chromatograph is connected to a mass spectrometer by a thermospray interface, and to obtain as high a sensitivity and selectivity as possible, a selected reaction monitoring mass spectrometric technique in the daughter ion mode is applied.

Phenyl-substituted normethadones: synthesis and pharmacology.

Phenyl-substituted normethadone derivatives were synthesized and their affinity (IC50) for opioid receptors was determined by displacement of the specific binding sites of [3H]sufentanyl on rat brain preparations. Substitution resulted in a decrease of affinity in-vitro. These results suggest that normethadone-like compounds may interact with the P subsite of the mu-opioid receptor and that the P subsite has a well-defined cavity shape of stringent dimensions.

Experience with dipipanone elixir in the management of cancer related pain--case study.

The synthetic opioid dipipanone is infrequently used in the UK in the management of malignant pain, principally because of the inflexibility of the Diconal combination preparation (dipipanone 10 mg with cyclizine 30 mg). We present three patients in which dipipanone elixir proved to be their own drug of choice in the management of opioid responsive cancer pain, and our experience with 15 other patients. Dipipanone elixir was formulated 10 mg/5 ml, in single strength chloroform water.

Pharmacokinetics of dipipanone after a single oral dose.

A single oral dose of Diconal (dipipanone HCl 10 mg, cyclizine HCl 30 mg) was given to six volunteers. The mean peak plasma dipipanone concentration was 29 ng ml-1, the time to peak plasma concentration was 1-2 h, the mean elimination half-life was 3.5 h and the mean AUC was 156 ng ml-1 min. Less than 1% of the dose was excreted in urine unchanged over 24 h.