Effects of purine nucleotide administration on purine nucleotide metabolism in brains of heroin-dependent rats

ABSTRACT Heroin is known to enhance catabolism and inhibit anabolism of purine nucleotides, leading to purine nucleotide deficiencies in rat brains. Here, we determined the effect of exogenous purine nucleotide administration on purine nucleotide metabolism in the brains of heroin-dependent rats. Heroin was administrated in increasing doses for 9 consecutive days to induce addiction, and the biochemical changes associated with heroin and purine nucleotide administration were compared among the treated groups. HPLC was performed to detect the absolute concentrations of purine nucleotides in the rat brain cortices. The enzymatic activities of adenosine deaminase (ADA) and xanthine oxidase (XO) in the treated rat cortices were analyzed, and qRT-PCR was performed to determine the relative expression of ADA, XO, adenine phosphoribosyl transferase (APRT), hypoxanthine-guaninephosphoribosyl transferase (HGPRT), and adenosine kinase (AK). Heroin increased the enzymatic activity of ADA and XO, and up-regulated the transcription of ADA and XO. Alternatively, heroin decreased the transcription of AK, APRT, and HGPRT in the rat cortices. Furthermore, purine nucleotide administration alleviated the effect of heroin on purine nucleotide content, activity of essential purine nucleotide metabolic enzymes, and transcript levels of these genes. Our findings therefore represent a novel, putative approach to the treatment of heroin addiction.

Polydrug Use and HIV Risk Among People Who Inject Heroin in Tijuana, Mexico: A Latent Class Analysis.

BACKGROUND: Although most people who inject drugs (PWID) in Tijuana, Mexico, primarily inject heroin, injection and non-injection use of methamphetamine and cocaine is common. We examined patterns of polydrug use among heroin injectors to inform prevention and treatment of drug use and its health and social consequences. METHODS: Participants were PWID residing in Tijuana, aged ≥18 years who reported heroin injection in the past six months and were recruited through respondent-driven sampling (n = 1,025). Latent class analysis was conducted to assign individuals to classes on a probabilistic basis, using four indicators of past six-month polydrug and polyroute use: cocaine injecting, cocaine smoking or snorting, methamphetamine injecting, and methamphetamine smoking or snorting. Latent class membership was regressed onto covariates in a multinomial logistic regression. RESULTS: Latent class analyses testing 1, 2, 3, and 4 classes were fit, with the 3-class solution fitting best. Class 1 was defined by predominantly heroin use (50.2%, n = 515); class 2 by methamphetamine and heroin use (43.7%, n = 448), and class 3 by methamphetamine, cocaine, and heroin use (6.0%, n = 62). Bivariate and multivariate analyses indicated a group of methamphetamine and cocaine users that exhibited higher-risk sexual practices and lower heroin injecting frequency, and a group of methamphetamine users who were younger and more likely to be female. CONCLUSIONS: Discrete subtypes of heroin PWID were identified based on methamphetamine and cocaine use patterns. These findings have identified subtypes of heroin injectors who require more tailored interventions to reduce the health and social harms of injecting drug use.

Latent classes of heroin and cocaine users predict unique HIV/HCV risk factors.

BACKGROUND: Patterns of heroin and cocaine use vary and may be associated with unique risk factors for bloodborne infections. METHODS: Latent class analysis identified sub-populations of 552 heroin and cocaine users in Baltimore, Maryland. Using latent class regression, these classes were analyzed for associations with demographic characteristics, risky behaviors, Hepatitis C, and HIV. RESULTS: Three classes were found: Crack/Nasal-Heroin users (43.5%), Polysubstance users (34.8%), and Heroin Injectors (21.8%). Compared to Polysubstance users, Crack/Nasal-Heroin users were almost 7 times more likely to identify as Black (OR=6.97, 95% CI=4.35-11.2). Sharing needles was over 2.5 times more likely among Polysubstance users than among Heroin Injectors (OR=2.66, 95% CI=1.49-4.75). Crack/Nasal-Heroin users were 2.5 times more likely than Polysubstance users to exchange drugs for sex (OR=2.50, 95% CI=1.22-5.13). Crack/Nasal-Heroin users were less likely than Heroin Injectors to have Hepatitis C (OR=0.10, 95% CI=0.06-0.18), but no significant differences were found for HIV. CONCLUSIONS: Subpopulations of cocaine and heroin users differed in demographic classifications, HIV-risk behaviors, and Hepatitis C infection. All subpopulations included substantial numbers of HIV-positive individuals. Findings provide further evidence that non-injection drug users face significant infectious disease risk.

Combined liquid chromatography-coulometric detection and microextraction by packed sorbent for the plasma analysis of long acting opioids in heroin addicted patients.

The sublingual combination of buprenorphine and naloxone (Suboxone(®)) and Methadone Maintenance Therapy have been found effective in treating heroin addiction. A new analytical method suitable for the simultaneous determination of buprenorphine, norbuprenorphine, methadone and naloxone in human plasma by means of liquid chromatography with coulometric detection has been developed. The chromatographic separation was achieved with a phosphate buffer-acetonitrile mixture as the mobile phase on a cyano column. The monitoring cell of the coulometric detector was set at an oxidation potential of +0.600 V. A rapid clean-up procedure of the biological samples using a microextraction by packed sorbent technique has been implemented, employing a C8 sorbent inserted into a syringe needle. The extraction yield values were satisfactory for all analytes (>85%). The calibration curves were linear over a range of 0.25-20.0 ng mL(-1) for buprenorphine and norbuprenorphine, 3.0-1000.0 ng mL(-1) for methadone and 0.13-10.0 ng mL(-1) for naloxone. The sensitivity was also high with limits of detection of 0.08 ng mL(-1) for both buprenorphine and norbuprenorphine, 0.9 ng mL(-1) for methadone and 0.04 ng mL(-1) for naloxone. The intraday and interday precision data were always satisfactory. The method was successfully applied to plasma samples obtained from former heroin addicts treated with opioid replacement therapy.

[Gender heteronomy of heroin addiction in adolescences].

On the model of heroin addiction in adolescents the premises for grounding the concept of gender heteronomy of addictions have been identified. The clinical-dynamic patterns associated with gender--so called gender associated types of disease in which the leading factors of difference formation are biological sex, valuable orientation structure, sexual experience and social status were singled out. The gender-associated types of heroin addiction in boys and girls were specified as dominant, repressive, partner, utilitarian, integrating and independent. Gender-differentiated programs of pharmaco- and psychotherapy are proposed.

A typology of heroin-dependent patients based on their history of self-injurious behaviours.

Self-injurious behaviours (SIB) can provide useful criteria for subtyping heroin-dependent patients, since SIB have been related to an opioid system dysfunction and they hinder patient management. The frequency of nine varieties of moderate/superficial SIB during active heroin use was assessed retrospectively in 164 heroin-dependent patients. A principal component analysis of SIB episodes revealed a four-component solution which accounted for 69.3% of the variance. The components were named as follows (percentage of variance explained by each component is enclosed in parentheses): 'SIB with objects' (27.3%), 'SIB by biting/scratching/hair-pulling' (18.2%), 'SIB by hitting' (12.3%), and 'SIB by picking scabs' (11.5%). A cluster analysis using the results of the principal component analysis enabled us to define three types of heroin-dependent patients, labelled: 'low-occurrence SIB cluster' (59.8%), 'high-occurrence scab-picking cluster' (31.7%) and 'high-occurrence hitting and cutting cluster' (8.5%). SIB by hitting was the most discriminatory component among clusters: its frequency was at a minimum in the low-occurrence SIB cluster, and attained a maximum in the high-occurrence hitting and cutting cluster. However, there were no differences among clusters regarding heroin-use variables. Patients from the low-occurrence SIB cluster, compared with those from the other two clusters, reported fewer episodes of SIB or suicide attempts and were diagnosed less frequently with bulimia. Patients from the high-occurrence scab-picking cluster had a very frequent history of these SIB, while the opposite was true in patients from the high-occurrence hitting and cutting cluster. Patients from this cluster probably presented staff members with the main management problems.

Client matching: a severity-treatment intensity paradigm.

Despite considerable effort to develop matching strategies and client placement protocols, research studies fail to yield compelling results regarding the benefits of matching to treatment. The most consistent findings suggest a matching paradigm, which defines a successful placement as the least treatment intensity required addressing the severity of the disorder. The purpose of the present study is to provide further empirical support for the validity of a severity-intensity paradigm utilizing data from the Drug Abuse Treatment Outcome Studies. A "passive match" approach employed the Client Matching Protocol decision algorithm, which recommended clients to long-term residential or outpatient drug-free treatment. One-year outcomes for clients matched to long-term residential treatment were better on all outcome variables compared to those undertreated in outpatient drug-free treatment. Findings supported the validity of the severity-intensity paradigm in that undertreated clients showed less improvement compared to matched and overtreated clients.

Características de la adicción como factores pronósticos en el tratamiento con naltrexona de la dependencia de opiáceos / Addiction characteristics as prognosis factors in opiate dependence treated with naltrexone

Introducción. Se estudia el valor pronóstico de las características de la adicción en el tratamiento de opiáceos. Para ello se consideran diversas variables relacionadas con la historia previa de consumo de opiáceos (vía de administración, cantidad de sustancia consumida, edad de inicio en la adicción, tiempo de consumo, abuso de otras sustancias). Objetivo. Establecer el valor pronóstico de las características de la adicción en el tratamiento con naltrexona de la dependencia de opiáceos. Métodos. Estudio observacional retrospectivo con diseño de un grupo de tratamiento sin grupo control. Se estudian 945 pacientes dependientes de opiáceos que durante 1991-1995 inician de forma consecutiva tratamiento con naltrexona en el Hospital Ramón y Cajal descriptivas e inferenciales (técnicas de supervivencia). Resultados. Se establecen como variables predictivas de mala evolución el consumo habitual de heroína previo por vía intravenosa, historia prolongada de consumo, edad de inicio en la adicción anterior a los 17 años o posterior a los 25 años y consumo concomitante de otras sustancias, en particular benzodiacepinas y cocaína. Cantidades elevadas de consumo de heroína tienden asimismo asociarse con peor evolución. Conclusiones. Determinadas características de la adicción (duración de la dependencia, vía previa de consumo, edad de inicio, cantidad consumida, consumo de otras sustancias) tienen valor pronóstico en la evolución del tratamiento. Son necesarios estudios posteriores que puedan facilitar la comprensión de la importancia pronostica de la historia adictiva en la evolución del tratamiento (AU)

Introduction. Addiction characteristics as prognostic factors in opiate dependence treatment were studied. Thus, several factors related to previous opiate consumption record were considered (current heroin route, amount of heroin, onset age of heroin consumption, time of heroin consumption, other drug consumption record). Objective. To establish the prognostic value of addiction characteristic in a naltrexone program of opiate dependence. Methods. To achieve this objective, an observational, retrospective study was designed with a design of a treatment group with no control group. 945 subjects diagnosed of opiate dependence who were consecutively hospitalized voluntarily in the naltrexone program of the Hospital Ramon y Cajal of Madrid during 1991-1995 form a part of the study population. Descriptive and survival techniques were used to analyze the data. Results. Previous intravenous heroin route, chronic heroin consumption record, onset age of heroin use younger than 17 or older than 25, and other drug consumption especially benzodiazepine and also cocaine provide a prognostic value for a worse outcome. High quantities of heroin consumption also tend to be associated with a poorer evolution. Conclusions. Several addiction characteristics (current previous route, onset age of heroin consumption, quantity of heroin consumption, time of heroin consumption, other drug consumption) have a prognostic value for treatment evolution. Further studies are necessary to provide a more complete knowledge of addiction characteristics as prognosis factors in opiate dependence treatment (AU)

1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial.

BACKGROUND: The partial opiate-receptor agonist buprenorphine has been suggested for treatment of heroin dependence, but there are few long-term and placebo-controlled studies of its effectiveness. We aimed to assess the 1-year efficacy of buprenorphine in combination with intensive psychosocial therapy for treatment of heroin dependence. METHODS: 40 individuals aged older than 20 years, who met DSM-IV criteria for opiate dependence for at least 1 year, but did not fulfil Swedish legal criteria for methadone maintenance treatment were randomly allocated either to daily buprenorphine (fixed dose 16 mg sublingually for 12 months; supervised daily administration for a least 6 months, possible take-home doses thereafter) or a tapered 6 day regimen of buprenorphine, thereafter followed by placebo. All patients participated in cognitive-behavioural group therapy to prevent relapse, received weekly individual counselling sessions, and submitted thrice weekly supervised urine samples for analysis to detect illicit drug use. Our primary endpoint was 1-year retention in treatment and analysis was by intention to treat. FINDINGS: 1-year retention in treatment was 75% and 0% in the buprenorphine and placebo groups, respectively (p=0.0001; risk ratio 58.7 [95% CI 7.4-467.4]). Urine screens were about 75% negative for illicit opiates, central stimulants, cannabinoids, and benzodiazepines in the patients remaining in treatment. INTERPRETATION: The combination of buprenorphine and intensive psychosocial treatment is safe and highly efficacious, and should be added to the treatment options available for individuals who are dependent on heroin.

Evaluación de tipologías en toxicomanías / Evaluation of a typology for drug addiction

Se presentan los resultados de una investigación sobre una clasificación basada en cuatro tipos de toxicomanías: tipo A (traumática), tipo B (a partir de neurosis actual), tipo C (de transición) y tipo D (sociopática). En este estudio se han analizado las características y recorrido terapéutico con una muestra de 110 heroinómanos que comenzaron tratamiento en cuatro centros de tratamiento ambulatorio y una comunidad terapéutica de la provincia de Sevilla. Los resultados señalan algunas variables que deben ser consideradas en el análisis de la demanda. Se concluye la importancia de establecer tipologías para articular, tanto en el ámbito preventivo como en terapéutico, programas de intervención más específicos (AU)

Differences in severity of heroin dependence by route of administration: the importance of length of heroin use.

To explore differences in the severity of heroin dependence by route of administration, we interviewed 909 heroin users in three Spanish cities. Dependence was measured with the severity dependence scale (SDS). No major differences in the severity of heroin dependence were detected among users with 5 or more years of heroin use (long-term users), but differences were found among newer users (SDS mean scores, 7.3 in heroin injectors; 7.9 in smokers and 4.6 in sniffers; P = 0.006), especially those with fewer than 3 years of use. Similar differences by route of administration were found when frequency of heroin use (days/month) was considered rather than severity of dependence. However, in the latter case major differences were also found among long-term users. These findings suggest that the route of administration probably influences the rate of progression to dependence but has little influence on the long-run level of dependence. They also help explain some aspects of the transition between routes of heroin administration, which is occurring in different areas.

Substance Dependence Severity Scale (SDSS): reliability and validity of a clinician-administered interview for DSM-IV substance use disorders.

No existing diagnostic interview assesses severity of dependence based on DSM-IV criteria across a range of substances. The Substance Dependence Severity Scale (SDSS) was designed to serve this purpose, consisting of substance-specific scales of both severity and frequency of DSM-IV criteria. This study investigated the reliability and validity of the SDSS. The test-retest reliability of the SDSS in 175 (112 male and 63 female) treated substance users ranged from good to excellent for alcohol, cocaine, heroin and sedatives (interclass correlation coefficients (ICCs)=0.75-0.88 for severity, 0.67-0.85 for frequency). Results for cannabis were lower, ranging from fair to good (ICCs=0.50-0.62). Results for joint rating and internal consistency reliability were comparable to test-retest findings. In addition to indicators of concurrent validity, scale applications are presented and discussed.

Concurrent and predictive validity of the Substance Dependence Severity Scale (SDSS).

This study investigated the concurrent and predictive validity of the Substance Dependence Severity Scale (SDSS), a clinician-administered interview designed to assess the severity and frequency of DSM-IV dependence symptoms for a range of substances. A total of 172 (107 males and 66 females) treated substance users participated in the study. Of those, 89% (n=153) received at least one follow-up interview within 1-6 months of an initial assessment. For alcohol, cocaine and heroin, convergent and discriminant validity was supported by significant relationships between SDSS scores at baseline and other baseline measures of substance use consequences, such as the Addiction Severity Index (ASI), as well as significant relationships between SDSS change scores from baseline to follow-up and change scores of other measures of consequences. SDSS scores were significantly associated with time to first post treatment use of alcohol, cocaine and heroin, although the nature of the associations was complex. Scale applications and areas for further study are discussed.

Methadone dosing, heroin affordability, and the severity of addiction.

OBJECTIVES: This study sought to track changes in US heroin prices from 1988 to 1995 and to determine whether changes in the affordability of heroin were associated with changes in the use of heroin by users seeking methadone treatment, as indexed by methadone dose levels. METHODS: Data on the price of heroin were from the Drug Enforcement Administration; data on methadone doses were from surveys conducted in 1988, 1990, and 1995 of 100 methadone maintenance centers. Multivariable models that controlled for time and city effects were used to ascertain whether clinics in cities where heroin was less expensive had patients receiving higher doses of methadone, which would suggest that these patients had relatively higher physiological levels of opiate addiction owing to increased heroin use. RESULTS: The amount of pure heroin contained in a $100 (US) purchase has increased on average 3-fold between 1988 and 1995. The average dose of methadone in clinics was positively associated with the affordability of local heroin (P < .01). CONCLUSIONS: When heroin prices fall, heroin addicts require more methadone (a heroin substitute) to stabilize their addiction--evidence that they are consuming more heroin.

The Severity of Dependence Scale (SDS): psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users.

The Severity of Dependence Scale (SDS) was devised to provide a short, easily administered scale which can be used to measure the degree of dependence experienced by users of different types of drugs. The SDS contains five items, all of which are explicitly concerned with psychological components of dependence. These items are specifically concerned with impaired control over drug taking and with preoccupation and anxieties about drug use. The SDS was given to five samples of drug users in London and Sydney. The samples comprised users of heroin and users of cocaine in London, and users of amphetamines and methadone maintenance patients in Sydney. The SDS satisfies a number of criteria which indicate its suitability as a measure of dependence. All SDS items load significantly with a single factor, and the total SDS score was extremely highly correlated with the single factor score. The SDS score is related to behavioural patterns of drug taking that are, in themselves, indicators of dependence, such as dose, frequency of use, duration of use, daily use and degree of contact with other drug users; it also shows criterion validity in that drug users who have sought treatment at specialist and non-specialist agencies for drug problems have higher SDS scores than non-treatment samples. The psychometric properties of the scale were good in all five samples, despite being applied to primary users of different classes of drug, using different recruitment procedures in different cities in different countries.

Opiates: prevalence and demographic factors.

This paper focuses on the prevalence and profile of opiate use, primarily heroin, in the United States and Europe. Methods include representative population surveys, which understate prevalence, and targeted approaches, which reflect more problematic use. In the United States and Europe, the lifetime prevalence of opiate use reported in surveys remained stable over the 1980s (around 1%), though young adults report higher rates. Estimates for the early 1990s suggest that the prevalence of problematic heroin use in the United States was double the average for western Europe. However, in a few European countries prevalence is now approaching that of the United States. Rates in major cities are considerably higher, especially in the north-east and south-west of the United States. Higher prevalence is often, although not always, associated with socio-economic deprivation. An important trend away from injecting is observed, notably in some European countries. Heroin availability and use, as well as serious heroin-related consequences, are increasing again in many European countries after an apparent pause in the mid-1980s. They are also increasing in parts of the United States. Heroin remains a public health priority, especially among vulnerable populations, including young people in central and eastern Europe.

Modelling transitional and joint marginal distributions in repeated categorical data.

When a repeated measures endpoint classifies people into several categories, marginal and transitional models provide two distinct approaches for data analysis. Marginal models estimate the probabilities of being in different categories over time. Transitional models estimate the probability of changing between any two given states during follow-up visits. This paper develops transitional and marginal models and applies them to a clinical trial of treatments of opiate addiction. The primary outcome was the presence or absence of opiates in a thrice weekly urine test, administered for 17 weeks. Subjects frequently miss visits, however, and in effect respond in one of three ways to a visit: missing, opiates present or opiates absent. Thus we have three possible states. Our transitional model conditions on the current state and models the transition from state k to one of the other (0, ..., K-1) states using a mutinomial logit model. This model generalizes previous work of Muenz and Rubinstein. Significant covariates in this model are predictive of state changes. Our marginal model views the state at each time point, rather than the transitions, as the primary response. Here we model the probability of being in state k with a multinomial logit model. Correlation within individuals over visits can be handled by applying the approach of Zeger and Liang or the bootstrap. Significant covariates in this model can include more 'global' summaries of a person such as extent of previous opiate use. Both marginal and transitional models are needed to provide a complete description of an individual's behaviour over time since global summaries might not affect transitions. Of particular substantive interest is how the opiate treatments affect both the marginal and transition probabilities.

Interviewer severity ratings and composite scores of the ASI: a further look.

The psychometric characteristics of the Addiction Severity Index (ASI) interviewer severity ratings (ISRs) and composite scores (CSs) were examined for a newly trained group of interviewers. The interrater reliabilities of seven raters for 9 methadone maintenance (MM) pilot subjects were determined. These were found to be excellent for the CSs, but only moderate for the ISRs. Regression analyses were performed on the data of 407 methadone maintenance patients entering all of the variables in each area as the independent variables and the ISR as the dependent variable. These analyses indicated that, on average, 55-60% of the variance in ISRs was explained. However, while 63% of the variance was explained for the legal scale only 38% of the variance of the drug scale was explained. The subject's rating of either the need for treatment or the seriousness of the problem accounted for the most variance, with the exception of the drug and alcohol areas. The internal consistency of the composite scores was then examined for this sample using Cronbach's standardized alpha statistic. These were found to be generally satisfactory ranging from 0.62 for the drug scale to 0.87 for the alcohol and psychiatric scales. A mean interitem correlation of 0.11 for the drug scale was obtained suggesting relatively low item homogeneity. Finally, correlations between the CSs and ISRs were calculated for each scale. Moderate to high relationships were found (0.53-0.78) with the exception of the correlation for the employment area which was only 0.08. The findings are discussed in terms of the nature of and limitations of the ISRs and CSs.

The Fifth Edition of the Addiction Severity Index.

The Addiction Severity Index (ASI) is 12 years old and has been revised to include a new section on family history of alcohol, drug, and psychiatric problems. New items were added in existing sections to assess route of drug administration; additional illegal activities; emotional, physical, and sexual abuse; quality of the recovery environment; and history of close personal relationships. No changes were made in the composite scoring to maintain comparability with previous editions. This article discusses the clinical and research uses of the ASI over the past 12 years, emphasizing some special circumstances that affect its administration. The article then describes the rationale for and description of the changes made in the ASI. The final section provides "normative data" on the composite scores and severity ratings for samples of opiate, alcohol, and cocaine abusers as well as drug abusing inmates, pregnant women, homeless men, and psychiatrically ill substance abusers.