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PubMed2003

Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts.

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 (</=200-250 mg) exhibited linear diacetylmorphine, monoacetylmorphine, and morphine kinetics and resulted in sustained diacetylmorphine exposures (bioavailability, 380% +/- 157% [mean +/- SD]) and in lower and delayed peak monoacetylmorphine and morphine concentrations as compared with intravenous administration. Oral diacetylmorphine (</=600 mg) yielded negligible systemic diacetylmorphine and monoacetylmorphine exposures but was associated with linear kinetics and high bioavailabilities for morphine (67% +/- 19%), morphine-3-glucuronide (205% +/- 52%), and morphine-6-glucuronide (180% +/- 61%). In addition, oral diacetylmorphine was absorbed more rapidly and to a greater extent than a concomitant test dose of morphine-d3. CONCLUSIONS: On the basis of the linear pharmacokinetics, the high bioavailability of intramuscular diacetylmorphine, and the rapid and extended morphine absorption from oral diacetylmorphine, the intramuscular and oral routes can be recommended as safe and feasible alternatives to the intravenous route for medical prescription of diacetylmorphine.

Administration, Oral↗
PubMed2001

Arterial and venous pharmacokinetics of intravenous heroin in subjects who are addicted to narcotics.

BACKGROUND: In Switzerland, medical prescription of heroin (diacetylmorphine) is currently being evaluated as a treatment option for heavily dependent addicts. Therefore the diacetylmorphine pharmacokinetics in opioid-addicted patients was studied. METHODS: Three different diacetylmorphine doses (up to 210 mg) and 20 mg deuterium-labeled morphine (morphine-d3) were administered intravenously to 8 heroin-addicted patients. Arterial and venous plasma samples were collected, and diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-d3 plasma concentrations were measured by liquid chromatography-mass spectrometry. RESULTS: Maximal arterial concentrations of diacetylmorphine, monoacetylmorphine, and morphine were 2.4, 5.4, and 1.4 times higher and occurred 2 to 3 minutes earlier than maximal venous concentrations. Venous areas under the concentration-time curves (AUC) of diacetylmorphine and monoacetylmorphine were 35% and 26% lower than arterial AUC values, whereas for morphine the venous AUC was 15% higher. Morphine-3-glucuronide and morphine-6-glucuronide exhibited no arteriovenous differences. AUCs for diacetylmorphine, monoacetylmorphine, and morphine increased linearly with dose. Diacetylmorphine was completely metabolized to morphine. Substantial morphine input into the arterial circulation persisted for up to 90 minutes. The arterial clearances of diacetylmorphine, monoacetylmorphine, and morphine-d3 were 8.7 +/- 2.6, 6.7 +/- 1.6, and 2.3 +/- 0.3 L/min, respectively. The arterial half-lives of diacetylmorphine and morphine-d3 were 2. 4 +/- 0.8 and 88 +/- 21 minutes, respectively. CONCLUSIONS: These data indicate that substantial arteriovenous differences exist for diacetylmorphine and metabolite kinetics, that the pharmacokinetics of diacetylmorphine and metabolites is linear even in the high dose range used by opioid addicts, and that not only diacetylmorphine but also monoacetylmorphine is substantially metabolized peripherally to morphine.

Adult↗
PubMed2005

Pharmaceutical heroin for inhalation: thermal analysis and recovery experiments after volatilisation.

Pharmaceutical heroin for inhalation was developed for a clinical trial on co-prescription of heroin and methadone to chronic treatment-resistant heroin addicts. Diacetylmorphine base was selected as the active pharmaceutical ingredient for this product with caffeine anhydrate added as an excipient. Differential scanning calorimetry and thermogravimetric analysis showed that addition of caffeine resulted in a lower melting temperature and a higher volatilisation rate for the mixture than for diacetylmorphine base alone. Recovery experiments showed that 40.8+/-5.3% of diacetylmorphine base could be found in smoke condensate after volatilisation of diacetylmorphine-caffeine tablets. All of the caffeine from each tablet was recovered unchanged in the fumes, while 85.6% of the diacetylmorphine from each tablet was recovered, either unchanged in the fumes or as non-volatilised residue. Recovery was found to be reproducible and only small differences were found between the tablet types. The experimental set-up was found to efficiently collect the vapours resulting from heating the powder. Under the tested experimental conditions, no evidence was found that degradation products of diacetylmorphine or caffeine, other than 6-acetylmorphine (5.9%) had volatilised, even though a decomposed residue was present after heating diacetylmorphine-caffeine samples. Diacetylmorphine-caffeine was found to be a suitable basis for pharmaceutical heroin to be used by 'chasing the dragon'.

Administration, Inhalation↗
PubMed2001

Acetylcodeine, an impurity of illicitly manufactured heroin, elicits convulsions, antinociception, and locomotor stimulation in mice.

Acetylcodeine is one of the major impurities present in illicitly manufactured heroin (diacetylmorphine). Data on its pharmacology and toxicology are limited and its ability to alter the toxic effects of diacetylmorphine is not known. The first objective of the present study was to compare the acute pharmacological and toxicological effects of acetylcodeine to those of codeine and diacetylmorphine in mice by assessing nociception in the tail-flick test, locomotor stimulation, and convulsive behavior. The second goal of this study was to determine whether acetylcodeine would alter the convulsant effects of diacetylmorphine. The antinociceptive potencies of acetylcodeine and codeine were similar, as reflected by their ED50 (95% confidence limits) values of 35 (29-44) and 51 (40-65) micromol/kg, respectively. Acetylcodeine was somewhat less potent than codeine in stimulating locomotor behavior, with ED50 values of 28 (22-37) and 12 (6-24) micromol/kg, respectively. Diacetylmorphine was considerably more potent than the other two drugs, producing antinociception and locomotor stimulation at ED50 values of 2.4 (1.4-4.1) and 0.65 (0.36-1.2) micromol/kg, respectively. On the other hand, the convulsant effects of acetylcodeine (ED50=138 (121-157) micromol/kg) and diacetylmorphine (ED50=115 (81-163) micromol/kg) were similar in potency and both were more potent than codeine (ED50=231 (188-283) micromol/kg). Finally, a subthreshold dose of acetylcodeine (72 micromol/kg) decreased the convulsant ED50 dose of diacetylmorphine to 40 (32-49). These findings suggest that the convulsant effects of acetylcodeine are more potent than predicted by its effects on locomotor activity and antinociception. The observation that acetylcodeine potentiated the convulsant effects of diacetylmorphine suggests a mechanism for some of the heroin-related deaths reported in human addicts.

Analgesics, Opioid↗
PubMed2005

Development of pharmaceutical heroin preparations for medical co-prescription to opioid dependent patients.

Presently, there is a considerable interest in heroin-assisted treatment: co-prescription of heroin to certain subgroups of chronic, treatment-resistant, opioid dependent patients. In 2002, nine countries had planned (Australia, Belgium, Canada, France, Spain) or ongoing (Germany, The Netherlands, Switzerland, United Kingdom) clinical trials on this subject. These trials (and the routine heroin-assisted treatment programs that might result) will need pharmaceutical heroin (diacetylmorphine) to prescribe to the patients. Research into the development of pharmaceutical forms of heroin for prescription to addicts can benefit from the large amount of knowledge that already exists regarding this substance. Therefore, in this paper we review the physicochemical and pharmaceutical properties of diacetylmorphine and the clinically investigated routes of administration, as well as routes of administration utilised on the street in the context of developing pharmaceutical heroin formulations for prescription to addicts. Patient acceptability of the formulation is essential, because heroin-assisted treatment is aimed at treatment-resistant addicts, who often have to be encouraged to participate (or to maintain participation) in a treatment program. This means that the most suitable products would have pharmacokinetic profiles mimicking that of diacetylmorphine for injection, with rapid peak concentrations of diacetylmorphine and 6-acetylmorphine, ensuring the 'rush effect' and the sustained presence of morphine(-6-glucuronide) creating the prolonged euphoria. Diacetylmorphine for inhalation after volatilisation (via 'chasing the dragon') seems to be a suitable candidate, while intranasal and oral diacetylmorphine are currently thought to be unsuitable. However, oral and intranasal delivery systems might be improved and become suitable for use by heroin dependent patients.

Analgesics, Opioid↗
PubMed1975

Kinetics of heroin deacetylation in aqueous alkaline solution and in human serum and whole blood.

A kinetic study of heroin hydrolysis in alkaline aqueous solution at room temperature was conducted by a gas chromatographic method to measure the consecutive reactions of diacetylmorphine to monoacetylmorphine and of monoacetylmorphine to morphine. A first-order reaction was observed in both instances, and the rate for the deacetylation of heroin was greater than that of monoacetylmorphine. The rates of in vitro hydrolysis of diacetylmorphine in human whole blood and in serum were compared by the same method. Diacetylmorphine was hydrolyzed twice as rapidly in blood as in serum. While morphine was an end product of hydrolysis in the blood, it was absent in the serum.

Alkalies↗
PubMed2005

[Accidental intraartrial injection of diacethylmorphine (heroin) in drug addicts -- three case reports].

Accidental intrarterial injections are not uncommon in medical treatments. This is also true for uncontrolled injections by drug-addicts. Since 2002 a number of 600 heavy opiate addicts in Germany are substituted in a country-wide study with pure diacetylmorphine (Heroine). We report the course and outcome of three cases of accidental intraarterial injections of pure diacetylmorphine under controlled conditions. After initial symptoms of vasospasms, all cases were without symptoms within one hour and no obvious loss of tissue was observed. After discussing the literature about medical literature and treatment options in intraarterial injections it is concluded, that the cause of major complications after intraarterial injections may not be the pure diacetylmorphine but additional substances in impure "street-heroin" samples.

Adult↗
PubMed2003

Five years audit for presence of toxic agents/drug of abuse at autopsy.

OBJECTIVE: To know the frequency of fatal poisoning in Peshawar regarding the toxic agents mostly involved and yearwise percentage. To know the age group and the gender that is most vulnerable to fatal poisoning. DESIGN: Non-interventional (descriptive) type. PLACE AND DURATION OF STUDY: This study was conducted over a period of five years (1997-2001) at Forensic Medicine Department, Khyber Medical College, Peshawar. METHODOLOGY: The study included 3508 autopsies conducted at Khyber Medical College, Peshawar. Out of these, 52 cases were those caused by fatal poisoning. These were analyzed according to age, gender and the toxic agent involved. t-test was applied as the test of significance. RESULTS: Poisoning was the cause of death in 1.48% of the total autopsies conducted during the five years. Males were more involved than the females, 90.38 %. Suicidal poisoning was present in 17.30% of the total cases and accidental poisoning was found in 80.72% cases, while homicidal cases were 1.29% only. Diacetylmorphine (heroin) was the most commonly involved agent, 65.38 %, of the total cases. The incidence of poisoning was more during the third and fourth decades of life. CONCLUSION: Diacetylmorphine (heroin) was the main causative agent involved in young males due to accidental over- dosage. Accidental and suicidal deaths should not be considered as inevitable. More elaborative studies are required in this area of recent research to adopt appropriate and adequate measures to save precious lives.

Adolescent↗
PubMed1975

Congenital malformations of the central nervous system produced by narcotic analgesics in the hamster.

Maternal dose--fetal teratogenic response data were obtained for a variety of narcotic and related compounds by single subcutaneous injections of the drugs into pregnant hamsters during the critical periods of central nervous system organogenesis. The number of abnormal fetuses from females injected with diacetylmorphine (heroin), thebaine, phenazocine, pentazocine, propoxyphene, and methadone increased as the maternal dose of the compounds was increased. By contrast, morphine, hydromorphone, and meperidine produced an increase in the number (per cent) of fetal anomalies only up to a certain maternal dose level. Further increases in maternal dose levels did not produce additional fetal anomalies. Comparative studies of single and multiple maternal doses indicated that diacetylmorphine (heroin) and methadone produced a four- to sixfold increase in fetal anomalies with repetitive doses whereas the percentage of malformed fetuses remained the same with hydromorphone (Dilaudid). The narcotic antagonists nalorphine, naloxone, levallophan, and cyclazocine blocked the teratogenic effects of both single and multiple doses of the narcotics.

Abnormalities, Drug-Induced↗
PubMed1984

Relative cataleptic potency of narcotic analgesics, including 3,6-dibutanoylmorphine and 6-monoacetylmorphine.

Dose-response curves were constructed for duration of significant catalepsy in male Sprague-Dawley rats following i.p. administration of four established and two novel narcotic analgesics. The relative potency of the six drugs was levorphanol greater than monacetylmorphine greater than diacetylmorphine greater than dibutanoylmorphine greater than morphine greater than meperidine. Cataleptic potency correlated with analgesic potency for morphine, diacetylmorphine, and dibutanoylmorphine but not for monoacetylmorphine.

Animals↗
PubMed1997

Simultaneous determination of acetylcodeine, monoacetylmorphine, and other opiates in urine by GC-MS.

In addition to 6-monoacetylmorphine (6-MAM), acetylcodeine (AC) has been suggested as a marker for the use of illicit heroin. We report a sensitive opiate gas chromatographic-mass spectrometric assay that detects AC, diacetylmorphine, and the propionylated derivatives of codeine, morphine, 6-MAM, and norcodeine. The analytes were extracted by solid phase with recoveries from 62 to 98%. The limits of detection (LOD) and quantitation (LOQ) for AC was 0.5 and 1.0 microgram/L. The LOD of the other analytes was 2.0 micrograms/L and the LOQs ranged from 2 to 10 micrograms/L. The assay was linear for each analyte from the LOQ to 200 micrograms/L or 400 micrograms/L (morphine and codeine) with r > or = 0.996, except for diacetylmorphine which was linear to 100 micrograms/L with r = 0.994. The within-run and between-run precision were below 10% CV for all analytes. There was no significant hydrolysis of AC to codeine in urine (pH 4.7 and 8.0) after 23 weeks of refrigeration or freezing. After storage at room temperature in urine of pH 8.0, AC was completely hydrolyzed after 5 weeks, but at pH 4.7, 58% of the AC remained after 15 weeks of storage at room temperature. The sensitivity of this assay was adequate to detect AC in the urine of heroin abusers. In preliminary studies, AC was detected in 6 of 69 opiate positive urines. Concentrations ranging from 1 to 48 micrograms/L were observed. These concentrations were found to be low when compared with the concentrations of 6-MAM, codeine, and morphine also detected in the urines.

Biomarkers↗
PubMed2005

Deuterodiacetylmorphine as a marker for use of illicit heroin by addicts in a heroin-assisted treatment program.

In preparation for a treatment program concerning the medical coprescription of heroin and methadone to treatment-resistant addicts in the Netherlands, we studied a novel strategy for monitoring co-use of illicit (nonprescribed) heroin. A deuterated analogue of heroin was added (1:20) to pharmaceutical, smokable heroin (a powder mixture of 75% w/w diacetylmorphine base and 25% w/w caffeine anhydrate), to be used by inhalation after volatilization ("chasing the dragon"). Plasma and urine samples were collected from nine male patients who had used pharmaceutical, smokable heroin during a four-day stay in a closed clinical research unit, and these samples were analyzed by liquid chromatography coupled with tandem mass spectrometry. Ratios of deuterated and undeuterated diacetylmorphine and 6-acetylmorphine (MAM/MAM-d3) in plasma and urine were calculated from peak areas of these substances in the respective chromatograms. The MAM/MAM-d3 ratios in plasma and urine were normally distributed (with small standard deviations) and independent from concentrations of 6-acetylmorphine and from time after use of pharmaceutical heroin. A MAM/MAM-d3 ratio in urine above 32.8 was considered indicative of co-use of illicit heroin, and this value was associated with a false-positive rate of only 1% (95% confidence interval: -1 to 3%). The MAM/MAM-d3 ratio was detectable in urine for 4-9.5 h after use of pharmaceutical, smokable heroin. Addition of stable, isotopically labelled heroin to pharmaceutical, smokable heroin is considered to be a feasible strategy for the detection of co-use of illicit heroin by patients in heroin-assisted treatment.

Administration, Inhalation↗