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PubMed1997

Qualitative detection of opiates in sweat by EIA and GC-MS.

Sweat was collected with the PharmChek sweat patch, and drugs were eluted from the collection pad of the patch. A solid-phase enzyme immunoassay (EIA) using microtiter plates was modified for the analysis of opiates in sweat. After opiate administration, sweat contains primarily parent opiate (heroin, codeine) and lipophilic metabolites (6-monoacetylmorphine [6-MAM]). The immunoassay was determined to have a cross-reactivity with codeine of 588%, with hydrocodone of 143%, with diacetylmorphine of 28%, and with 6-MAM of 30% relative to 100% for the morphine calibrators. The optimum cutoff concentration for this modified assay was determined by receiver operator characteristic analysis using 215 patches from 95 subjects to be 10 ng/mL morphine equivalents. At this cutoff concentration the assay had a diagnostic sensitivity of 86.9% and a diagnostic specificity of 92.8% versus gas chromatography-mass spectrometry (GC-MS), which was the reference method. The positive predictive value at a prevalence of 50% was 86%. The intra-assay precision at 10 ng/mL was 7.8%, and the interassay coefficient of variation (CV) was 39%. Analysis of spiked patches around the cutoff gave a percent positive threshold of approximately 50% between 10 and 15 ng/mL and a 95% confidence level for a positive result by the EIA between 20 and 25 ng/mL. Eighteen possible adulterants that could be injected into or under the patch were studied. Two (tile cleaner and detergent) can cause false-positive responses in the immunoassay. Two adulterants reduced response to spiked drug (Visine eye drops and Ben Gay ointment), which could cause a false-negative response. All results were confirmed by GC-MS. The clinical sensitivity and specificity for detecting drug use by analyzing sweat collected from human subjects following known doses of codeine (0, 30, and 60 mg orally) or heroin (20 mg intravenously) were 76 and 100%, respectively.

Calibration↗

PubMedDate not supplied

Acetylcodeine as a urinary marker to differentiate the use of street heroin and pharmaceutical heroin.

Acetylcodeine (ACOD) is a synthesis byproduct present in street heroin but not in pharmaceutical diacetylmorphine (DAM) as used in the Swiss program Heroin-Assisted Treatment for Opiate Dependent Drug Users (HAT). ACOD was evaluated and validated as an urine marker to detect the consumption of street heroin by HAT participants. A gas chromatography-mass spectrometry method allowing the quantitation of ACOD concentrations as low as 0.2 ng/mL urine has been developed. In opiate-naïve subjects, intravenous (i.v.) ACOD showed a plasma elimination half-life of 237 +/- 18 min, urine peak concentrations 2 h after administration, and a detection window of 8 h. Only 0.4 +/- 0.1% was excreted unchanged, with codeine (COD) as the main metabolite. ACOD may be formed by transacetylation when i.v. DAM and oral codeine are co-administered. To avoid false-positive results, the calculation of COD/ACOD ratios is recommended. In a study with 105 HAT participants, 14% of the tested urines were ACOD positive. Only a low correlation was found between the anonymously self-declared consumption of street heroin and the ACOD positive rate.

Acetylation↗

PubMedDate not supplied

Postmortem distribution of heroin metabolites in femoral blood, liver, cerebrospinal fluid, and vitreous humor.

The presence of 6-monoacetylmorphine (6-MAM) is often used to distinguish between heroin (diacetylmorphine) and morphine exposures. 6-MAM, however, is rapidly metabolized to morphine and may not be present in detectable quantities in blood following heroin exposure. Recent studies have shown that 6-MAM may persist in cerebrospinal fluid (CSF) and this specimen may be preferable for establishing heroin exposure. This study reports postmortem distribution of 6-MAM, unconjugated morphine, and codeine in different tissues from 25 deceased individuals. In all cases, 6-MAM was detected in vitreous humor, and in CSF in 16 of the 25 cases (64%). When 6-MAM was detected in blood (13 of 25 cases), the level of 6-MAM in vitreous humor and CSF was higher than in blood, with a mean concentration ratio of 11.3 (range: 1.7-27) for vitreous humor and 6.6 (range: 2.6-17.3) for CSF. 6-MAM was not detected in liver in any of the cases examined. Free morphine levels were highest in liver, followed by blood, CSF, and vitreous humor. The concentration ratios (mean +/- standard deviation) for free morphine in vitreous humor, CSF, and liver to that in blood were 0.36 +/- 0.18, 0.64 +/- 0.27, and 2.99 +/- 2.12, respectively. The liver/blood ratio was consistent with previously reported values for morphine in heart and femoral blood. Codeine levels following heroin overdose were consistently low relative to the morphine concentration. For blood, liver, and CSF, the ratio of codeine to morphine was essentially the same (0.06), whereas the vitreous codeine/morphine concentration ratio was slightly higher (0.19). These results characterize the distribution of heroin metabolites in postmortem tissues. Vitreous humor appears to be a useful specimen for determining 6-MAM and establishing the morphine was derived from heroin.

Aqueous Humor↗

PubMedDate not supplied

Simultaneous identification and quantitation of codeine and morphine in urine by capillary gas chromatography and mass spectroscopy.

An analytical procedure for simultaneous determination of codeine and morphine in urine is described. The detection of codeine and morphine is based on liquid-liquid extraction and derivatization to the acetylated compounds. The acetylated codeine and morphine are separated by capillary gas chromatography and identified mass spectrometrically by selected ion monitoring (SIM). Quantitative determination was carried out by SIM using nalorphine as internal standard. Excellent linearity was obtained over a concentration range of 25 to 800 ng/mL. The overall recovery for codeine and morphine in the extraction was found to be 58% and 40%, respectively. The on-column sensitivity for both compounds was 2 ng at a peak-to-noise ratio of 5:1. The derivatives, acetylcodeine, diacetylmorphine, and diacetylnalorphine were stable at room temperature for 72 hr.

Codeine↗

PubMed1998

Genetic toxicology of abused drugs: a brief review.

Although numerous studies have been conducted on abused drugs, most focus on the problems of addiction (dependence) and their neurotoxicities. Now accumulated data have demonstrated that the genotoxicity and/or carcinogenicity of abused drugs can also be detrimental to our health. In this review, commonly abused substances, including LSD, opiates (diacetylmorphine, morphine, opium and codeine), cocaine, cannabis, betel quid and khat, are discussed for their potential genotoxicity/carcinogenicity. The available literature in the field, although not as abundant as for neurotoxicity, clearly indicates the capability of abused drugs to induce genotoxicity.

Animals↗

PubMed2006

A prospective cohort study on orally administered heroin substitution for severely addicted opioid users.

AIMS: To assess the efficacy and safety of orally administered heroin [diacetylmorphine (DAM)] tablets in substitution treatment of severely addicted opioid users. DESIGN: An open-label, prospective cohort study with two non-randomly assigned treatment arms and historical controls: DAM tablets only versus DAM tablets combined with injected DAM and/or other opioids, with an observation period of 1 year. SETTING: Twenty-one out-patient treatment centres of the Swiss heroin-assisted treatment programme. PARTICIPANTS: A total of 128 patients received DAM tablets only, and 237 patients received a combination of orally and intravenously applied DAM and other opioids. MEASUREMENTS: Retention rate after 1 year; number of serious adverse events; dosage of DAM over time; subjective tolerance of study medication. FINDINGS: In the intention-to-treat analysis, 1-year retention rates after 1 year in the DAM tablets-only group [0.804, 95% confidence interval (CI) = 0.735-0.873] as well as in the subgroup combining oral application of DAM with intravenous application or other opioids (0.843, 95% CI = 0.797-0.889) were higher compared to historical controls (Swiss cohort of patients who had been substituted intravenously with DAM; 1-year retention rate = 0.70). Rates of serious adverse events under study medication (tablets only = 0.038 per application year; tablets in combination = 0.028 per application year) were comparable to the historical rate of the Swiss heroin-assisted treatment (0.043). CONCLUSIONS: DAM tablets seem to be an effective and safe application mode of heroin-assisted substitution treatment. Randomized clinical trials to compare its relative efficacy to other substances are necessary.

Adult↗

PubMed1979

Serum morphine concentration after oral administration of diamorphine hydrochloride and morphine sulphate.

1 Venous blood was obtained from patients with far-advanced cancer receiving either diamorphine (diacetylmorphine, heroin) hydrochloride (65 samples) or morphine sulphate (24 samples) regularly by mouth in doses from 2.5 mg to 90 mg every 4 h. 2 Samples were obtained within 30 min of the 09.00 h drug round. 3 Serial samples were also obtained over a 4 h period from three patients receiving diamorphine hydrochloride. 4 Assay of serum 'morphine equivalents' was by radioimmunoassay using an antibody that cross reacts almost equally with diamorphine, 6-0 monoacetylmorphine and morphine. 5 The serum concentration of opiates expressed as 'morphine equivalents' ranged from 11 ng/ml to 1440 ng/ml. 6 A highly significant positive linear correlation exists between the dose administered and the serum concentration (P less than 0.001) with respect to both drugs. 7 There was no difference between the two drugs in relation to the serum concentration achieved per 10 mg of opiate administered. 8 Higher oral doses of both diamorphine and morphine are now being used when indicated rather than, as before, resorting to injections when an oral dose in excess of 40 mg is indicated.

Adult↗

PubMed1992

Systemic contact dermatitis from subcutaneous hydromorphone.

We report a patient who developed a generalized dermatitis after a period of progressive local intolerance to continuous subcutaneous infusion of hydromorphone for cancer pain. Sensitization to hydromorphone was proved by a positive patch test. Infusions with an equianalgesic dose of diacetylmorphine were well tolerated, without local or systemic side-effects, and prolonged the duration of infusion sites.

Dermatitis, Contact↗

PubMed1984

Morphine diesters. I. Synthesis and action on guinea pig ileum.

3,6-Dipropanoylmorphine (DPM), 3,6-dibutanoylmorphine (DBM), and 3,6-dihexanoylmorphine (DHM) were prepared as prospective long-acting narcotic analgesics. The purity and structure of these compounds were authenticated by high pressure liquid chromatography and direct probe mass spectrometry. In aqueous solution the stability of the HCI salts of these compounds decreased with increasing alkyl chain length such that DHM underwent rapid hydrolysis to 6-monohexanoylmorphine (MHM). A comparison of DPM, DBM, and MHM with morphine (MO) and 3,6-diacetylmorphine (DAM, heroin) in the electrically stimulated guinea pig ileum myenteric plexus longitudinal muscle strip preparation (GUPIL) revealed similar potencies and efficacies for all compounds, but marked differences in the onset of drug action (MO greater than DAM greater than MHM greater than DPM greater than DBM, faster to slower). In a periodically washed GUPIL preparation DBM and MHM were five times longer acting than MO, DAM or DPM.

Animals↗

PubMed1984

Morphine diesters. II. Blood metabolism and analgesic activity in the rat.

The kinetics of hydrolysis of dipropanoylmorphine (DPM) and dibutanoylmorphine (DBM) in human blood fractions and for diacetylmorphine (DAM) and DBM in rat blood fractions were investigated. In each case the hydrolysis of morphine diesters terminated with the production of the corresponding 6-monoester derivative. Generally, decreases in Km and Vmax were observed for the plasma, red blood cell (RBC) cytosol, and RBC membrane esterases responsible for morphine diester hydrolysis as the alkyl chain length of the ester moiety increased. This resulted in an overall decrease in the rate of hydrolysis of morphine diesters by human or rat blood with longer chain homologs of DAM. The analgesic potency and duration of morphine, DAM, and DBM were assessed at various i.v. dosages in the rat by means of the tail-flick latency test. A comparison of equianalgesic doses of morphine, DAM, and DBM indicated that DAM and DBM were 11.5 and 6 times as potent and 0.8 and 1.2 times as long acting, respectively, as morphine.

Analgesics↗

PubMed2006

Combining the tape-lift method and Fourier transform infrared spectroscopic imaging for forensic applications.

Conventional Fourier transform infrared (FT-IR) spectroscopy and microscopy have been widely used in forensic science. New opportunities exist to obtain chemical images and to enhance the spatial resolution using attenuated total reflection (ATR) FT-IR spectroscopy coupled with a focal-plane array (FPA) detector. In this paper, the sensitivity limits of FT-IR imaging using three different ATR crystals (Ge, ZnSe, and diamond) in three different optical arrangements for the detection of model particles is discussed. Model systems of ibuprofen and paracetamol particles having sizes below 32 mum were studied. The collection of drug particles was achieved with the aid of two different tapes: common adhesive tape and a film of polydimethylsiloxane (PDMS). The surface of the film with collected particles was measured directly via ATR-FT-IR imaging. Since the removal of tape from porous surfaces can be difficult, the application of micro ATR-FT-IR imaging directly to the surface of a newspaper contaminated with particles of model drugs is also discussed. In order to assess the feasibility of the chosen method in a forensic case study, the detection of diacetylmorphine hydrochloride traces in PDMS matrix and the finger surface is investigated. The scenarios considered were that of the detection of evidence collected at a crime scene with the tape lift method and the analysis of the finger of an individual after drug handling. The results show broad implications in the detection of drugs of abuse.

Acetaminophen↗

PubMedDate not supplied

Clinical significance of esterases in man.

Esterases, hydrolases which split ester bonds, hydrolyse a number of compounds used as drugs in humans. The enzymes involved are classified broadly as cholinesterases (including acetylcholinesterase), carboxylesterases, and arylesterases, but apart from acetylcholinesterase, their biological function is unknown. The acetylcholinesterase present in nerve endings involved in neurotransmission is inhibited by anticholinesterase drugs, e.g. neostigmine, and by organophosphorous compounds (mainly insecticides). Cholinesterases are primarily involved in drug hydrolysis in the plasma, arylesterases in the plasma and red blood cells, and carboxylesterases in the liver, gut and other tissues. The esterases exhibit specificities for certain substrates and inhibitors but a drug is often hydrolysed by more than one esterase at different sites. Aspirin (acetylsalicylic acid), for example, is hydrolysed to salicylate by carboxylesterases in the liver during the first-pass. Only 60% of an oral dose reaches the systemic circulation where it is hydrolysed by plasma cholinesterases and albumin and red blood cell arylesterases. Thus, the concentration of aspirin relative to salicylate in the circulation may be affected by individual variation in esterase levels and the relative roles of the different esterases, and this may influence the overall pharmacological effect. Other drugs have been less extensively investigated than aspirin and these include heroin (diacetylmorphine), suxamethonium (succinylcholine), clofibrate, carbimazole, procaine and other local anaesthetics. Ester prodrugs are widely used to improve absorption of drugs and in depot preparations. The active drug is released by hydrolysis by tissue carboxylesterases. Individual differences in esterase activity may be genetically determined, as is the case with atypical cholinesterases and the polymorphic distribution of serum paraoxonase and red blood cell esterase D. Disease states may also alter esterase activity.

Albumins↗

PubMed2001

Detection of acetylcodeine in urine as an indicator of illicit heroin use: method validation and results of a pilot study.

BACKGROUND: Acetylcodeine (AC), an impurity of illicit heroin synthesis, has been suggested as an interesting biomarker of illicit heroin use. METHODS: Procedures were developed for quantification of (a) morphine, 6-monoacetylmorphine (6-AM), and codeine in urine and (b) diacetylmorphine and AC in urine. Solid-phase extraction of the analytes was performed, and the extracted analytes were analyzed by selected-ion monitoring with gas chromatography-mass spectrometry. This procedure required prior derivatization with propionic anhydride. RESULTS: Different validation parameters were determined, such as linearity, reproducibility, extraction recoveries, and cutoffs. Seventy-one urine specimens of illicit heroin abusers and 44 urine specimens of subjects in a heroin maintenance program were analyzed. AC was detected in 85.9% of the samples of the first group but not in any of the samples from subjects taking medical heroin. In the two groups, there were 94.4% and 84.1% 6-AM positive urine specimens, respectively. Detection times were determined for AC and codeine by parallel administration of heroin containing various percentages of AC to four voluntary patients in a heroin maintenance program. The measured detection times were 8 and 23 h for AC and codeine, respectively. CONCLUSIONS: These results indicate that, together with detection of 6-AM in urine, AC is a suitable marker of illicit heroin use.

Biomarkers↗

PubMed2001

[The history of heroin].

The discovery of heroin and the development of heroin abuse are introduced. Heroin, the hydrochloride of diacetylmorphine, was discovered by acetylation of morphine. Heroin, in pharmacological studies, proved to be more effective than morphine or codeine. The Bayer Company started the production of heroin in 1898 on a commercial scale. The first clinical results were so promising that heroin was considered a wonder drug. Indeed, heroin was more effective than codeine in respiratory diseases. It has turned out, however, that repeated administration of heroin results in the development of tolerance and the patients become heroin-addicts soon. In the early 1910s morphine addicts "discovered" the euphorising properties of heroin and this effect was enhanced by intravenous administration. Heroin became a narcotic drug and its abuse began to spread quickly. Restrictions on its production, use and distribution were regulated by international treties. The total ban on heroin production was also proposed. As a result of the strict regulations the production and cosumption of heroin showed a significant decrease after 1931. At the same time the underworld recognized the shortage of heroin and started the illicit production and trafficking. The quantity of heroin seized by law enforcement agencies in the past decades rose gradually. As an indicator of the worldwide heroin market, the quantity of confiscated heroin underwent a tenfold increase since 1970. The paper surveys the most important heroin-producing and trafficking countries. Heroin, prepared in clandestine ("kitchen" or "jungle") laboratories, is diluted ("cut") by every member of the illegal heroin distributing chain, i.e. smugglers, traffickers, dealers and vendors.

Heroin↗

PubMed1988

Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine.

Morphine sulfate in doses of 90 to 150 micrograms/3 microliters evoke a prominent behavioral syndrome characterized by 1) periodic bouts of spontaneous agitation during which the rat scratches and bites at the skin of the caudal dermatomes and 2) vigorous agitation, vocalization and coordinated efforts to bite and escape evoked by a light tactile stimulus applied to the flank, suggestive of a pain state (allodynia). The phenomenon is not reversed by naltrexone or is it subject to tolerance. The ordering of activity of an opioid alkaloid related agent in producing this touch-evoked agitation is: noroxymorphone-3-glucuronide, morphine-3-glucuronide, morphine-3-ethereal sulfate, dihydromorphine, noroxymorphone dihydrate, hydromorphone, dihydrocodeine tartrate, morphine sulfate, dihydroisomorphine, morphine-HCl, 6-acetylmorphine, N-normorphine-HCl and (+)-morphine. The following agents were essentially without effect at the highest doses examined: 3,6-diacetylmorphine, N-normeperidine-HCl, nalorphine-HCl, alfentanil, sufentanil, naloxone, naltrexone, methadone, dextrorphan tartrate, meperidine-HCl, oxycodone, levorphanol, oxymorphone, codeine phosphate, thebaine, nalbuphine and naltrexone-3-glucuronide. The observations that the sulfated and conjugated metabolites are 10 to 50 times more potent than their unmetabolized precursor suggest the possibility that, in high concentrations certain phenanthrene opioid alkaloids with a free 3-OH position, an ether bridge and no N-methyl extension will be subject to conjugation and this metabolite will alter the processing of otherwise innocuous tactile stimuli. The fact that the phenomenon appeared at least partially stereospecific may reflect upon the fact that other laboratories have shown that glucuronyl transferase may preferentially convert (-)-morphine to the 3-glucuronide and (+)-morphine to the 6-glucuronide which may be less active.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗

PubMedDate not supplied

An evaluation of TLC systems for opiate analysis.

The authors selected 38 thin-layer-chromatography (TLC) systems described in the available literature published over the last 10 years and evaluated those systems with respect to their suitability for detection and identification of opiates in urine, opium and heroin, as well as adulterants in heroin. A total of 14 substances: 8 opiates (morphine, 6-monoacetylmorphine, diacetylmorphine, codeine, acetylcodeine, noscapine, papaverine and thebaine) and 6 adulterants (ephedrine, quinine, methadone, caffeine, cocaine and strychnine) were used as test samples for this research. Using laboratory-coated plates and pre-coated plates, 15 and 13 TLC systems, respectively, were found to be able to detect and identify morphine and codeine in urine without interference from the remaining 12 substances. For the detection of opiates in opium samples as well as opiates and adulterants in illicit heroin samples the TLC system: chloroform-n-hexane-triethylamine (9:9:4) which was developed by the National Drug Research Centre, Penang, Malaysia, was found to be most suitable on both laboratory-coated and pre-coated plates. In addition, the following two systems, one on laboratory-coated plates--hexane-chloroform-diethylamine (50:30:7)--and the other on pre-coated plates--benzene-dioxane-ethanol-ammonia (50:40:5:5; T-7)--were also found to be among most suitable TLC systems for the analysis of opiates in opium samples. The article also presents the relative cost of each of the 38 evaluated TLC systems.

Chromatography, Thin Layer↗

PubMedDate not supplied

Parameters for determining the origin of illicit heroin samples.

A method has been evolved for assigning the source of supply or origin of illicit heroin samples. The content of morphine, codeine and acetyl products and the ratios of morphine to codeine and heroin to acetylcodeine obtained from opium samples of known origin as well as the content of heroin (diacetylmorphine) and acetylcodeine and their ratios in illicit heroin samples that have been found to belong to the same source of supply as the known opium samples are used as the basic criteria for a comparison to determine the origin of illicit heroin samples. Because the content of alkaloids in opium and heroin samples varies considerably, the number of opium and illicit heroin samples of known origin analysed should be sufficient to determine a representative composition of alkaloids in such samples for a given geographical area and period of production. It was observed that the theoretical ratio of heroin to acetylcodeine increases two-fold at each stage of the chemical conversion in the series opium-morphine-heroin. The ratios of heroin to acetylcodeine obtained from opium samples of known origin showed significant variation, which enabled the author to make distinct composition profiles of the alkaloids for each geographical area studied. Such profiles made it possible to compare heroin samples of known origin with illicit heroin samples of unknown origin and to determine the geographical area from which the latter originated. This method can also be applied in determining the origin of illicit morphine samples.

Chemical Phenomena↗

PubMed1981

[Effect of euphorigenic drugs on emotionally-positive brain systems].

Cocaine (10 mg/kg), amphetamine (1 mg/kg), diacetylmorphine (5 mg/kg), pentobarbital (3 mg/kg) and diazepam (1 mg/kg) caused in rats an activation of the reactions of electrical self-stimulation of the lateral hypothalamus, comparable by their pronouncement. All the drugs changed the pattern of histograms of durations distribution of pauses between self-stimulations, due primarily to a diminished number of long pauses. Psychodepressant drugs increased the number of long and superlong pedal pressings. A number of pairs of parameters with stable correlations was revealed, and their changes under the drugs effect were noted. The results of the study suggest that euphorigenic effect of the drugs is connected with the activation of reward system produced by them.

Amphetamine↗