Serum concentrations of macro and trace elements in heroin addicts of the Canary islands

Na, K, Ca, Mg, P, Fe, Cu, Zn and Se concentrations were determined in the serum of 106 heroin addicts and were compared with the concentrations obtained in a control group formed of 186 apparently healthy individuals. Heroin addicts displayed K and Se mean concentrations lower (p < 0.05), and Na, Mg, P mean concentrations and a Cu/Zn ratio higher (p < 0.05) than those mean values observed in the control group. The Mg and P concentrations in the serum of heroin addicts tended to normalize when age increased. The heroin addicts included in the methadone maintenance treatment program had higher serum mean concentrations of K and Mg than the heroin addicts in the detoxification process. The Na, K and Mg concentrations displayed highly significant correlations, with a different behavior for the heroin addicts group and the control group. When applying factor analysis and representing the scores of the first and second factors, the heroin addicts tended to differentiation from the control group. However, methadone substitution treatment was not able to normalize these concentrations.     

Methadone maintenance treatment and drugs

The mental and physical capabilities of drivers in traffic are often seriously challenged these days. Not only do they need to concentrate on driving, predict connections between various phenomena, take appropriate judgements in current situations and foresee the sequence of measures to be taken, but they are also expected to be emotionally stable, etc. The problem with drugs in traffic is often encountered when assessing the actual safe driving capability of a person in a given moment, for example after a car accident or a police check, or medical check-ups that are required for a driving license. The Road Traffic Safety Law considers methadone a drug. Drug addicts do not meet the health standards required of drivers. This research program deals with the attitude of drivers who are in methadone maintenance treatment programs with respect to the driving ability as well as the effects of methadone use in combination with other drugs on driving. It has been established that drivers undergoing the methadone maintenance program, regularly drive not only under the influence of methadone but also under the influence of marijuana (20%) and heroin (18%) and sometimes under the influence of marijuana (58.6%), heroin (55.7%), and alcohol (48.6%). Certain initiatives have been taken by some therapists to give, under certain circumstances, a clean bill of health to responsible methadone maintenance patients who have an adequate level of responsibility for themselves and their deeds, in order to help them obtain a driving license. Since it has been established that methadone maintenance patients use methadone quite commonly in combination with illegal drugs and/or alcohol, the classification of this type of addicts among possible driving candidates remains disputable. Long term interdisciplinary research is still required to determine the basic principles required to asses and possibly admit this type of drivers to participate in traffic, as well as to determine which professional therapists can participate and evaluate the driving capabilities of these patients.     

Ethnic diversity of DNA methylation in the OPRM1 promoter region in lymphocytes of heroin addicts

The μ-opioid receptor is the site of action of many endogenous opioids as well as opiates. We hypothesize that differences in DNA methylation of specific CpG dinucleotides between former severe heroin addicts in methadone maintenance treatment and control subjects will depend, in part, upon ethnicity. DNA methylation analysis of the μ-opioid receptor gene (OPRM1) promoter region was performed on African-Americans (118 cases, 80 controls) and Hispanics (142 cases, 61 controls) and these were compared with a similar Caucasian cohort from our earlier study. In controls, a higher methylation level was found in the African-Americans compared with the Hispanics or Caucasians. Significant experiment-wise differences in methylation levels were found at the −25 and +12 CpG sites in the controls among the three ethnicities. The overall methylation level of the CpG sites were significantly higher in the former heroin addicts when compared with the controls (point-wise P = 0.0457). However, in the African-Americans, the degree of methylation was significantly decreased experiment-wise in the former heroin addicts at the +12 CpG site (P = 0.0032, Bonferroni corrected general estimating equations). In Hispanics, the degree of methylation was increased in the former heroin addicts at the −25 (P < 0.001, experiment-wise), −14 (P = 0.001, experiment-wise), and +27 (P < 0.001, experiment-wise) CpG sites. These changes in methylation of the OPRM1 promoter region may lead to altered expression of the μ-opioid receptor gene in the lymphocytes of former heroin addicts who are stabilized in methadone maintenance treatment.     

Impaired glucose metabolism in heroin and methadone users

Plasma glucose and insulin responses to both oral and intravenous glucose stimulation were evaluated in heroin and methadone addicts, compared to healthy control subjects. Both groups of addicts had an altered response to oral and intravenous glucose load. These phenomena were linked to a reduced insulin response. Moreover, increased fasting insulin levels in both groups of addicts were observed. These data show that both heroin and methadone addiction may alter glucose metabolism, and, furthermore, stress the findings of similarities between opiate addicts and non-insulin dependent diabetics.     

The Use of Propoxyphene Napsylate in the Treatment of Heroin and Methadone Addiction

The use of methadone in the treatment of heroin addiction continues to be controversial. Propoxyphene napsylate (Darvon N®) is a possible alternative and a pilot study was conducted to test its acceptability, safety and clinical efficacy in treating long term, “multi-relapse” heroin addicts.Findings indicate that propoxyphene napsylate suppresses many of the symptoms associated with opioid withdrawal phenomena. It should be viewed as a very promising therapeutic tool to be used in conjunction with psychological counseling and socio-vocational rehabilitation in detoxification and maintenance therapy for heroin or methadone addiction.     

Role of opioid antagonists in treating intravenous cocaine abuse

Intravenous cocaine abuse is a major probel in opioid abusers including those treated in methadone maintenance. Studying 138 opioid addicts, we found that speedballing by combining opioid agonists with cocaine may be blocked by opioid antagonists such as naltrexone and by partial antagonists such as buprenorphine. With both these treatments cocaine abuse was five to eight times less than with methadone treatment.     

Methadone

Methadone and acetylmethadol, although possessing almost all of morphine''s pharmacological properties, differ from other morphine-like drugs in their longer action, more gradual and less intense withdrawal syndrome, and blockade of euphoric effect of other opiates in addicts. A high percentage of patients maintained on methadone are better able to hold employment or to be otherwise socially productive than when dependent on heroin or morphine.A review of published results and procedures used in methadone maintenance treatment programs for heroin dependence is presented. Former heroin addicts are usually maintained on 80 to 120 mg. (high dose) or 20 to 60 mg. (low dose) oral methadone daily. Some programs are reported to have produced 80% success (patients employed or otherwise socially productive). Selection of patients, availability of allied therapeutic and rehabilitative facilities, strict control of supply, record keeping and periodic evaluation are considered essential.Different criteria (“drug-free” vs. “socially productive”) for judging “success” of treatment of heroin-dependent persons by methadone maintenance and administrative problems in large-scale treatment programs constitute the principal aspects of controversy.     

Chronic Hepatitis Associated with Drug Abuse: Significance of Hepatitis B Virus

One hundred and seventy-seven former heroin addicts, consisting of 85 who were newly admitted to a methadone maintenance program and 92 who had received methadone for a mean period of 30 months, were prospectively studied for up to 2 years in order to determine: (1) the effect of heroin withdrawal on the hepatic abnormalities, and (2) the incidence of HBsAg, anti-HBs, and anti-HCc as indices of the frequency of hepatitis B virus infection. Our study indicates that (1) hepatic abnormalities persist when heroin is discontinued and are not temporally related to drug and/or needle usage, and (2) that 71% of subjects had either HBsAg or anti-HBs; anti-HBc was tested for in 16 patients and was present in 100%, although 9 of the 16 were both HBsAg- and anti-HBs-negative. This study suggests that hepatitis B is largely responsible for the liver dysfunction. It is proposed that an abnormality in immune function, induced by heroin, is responsible for the high incidence of chronic hepatitis. Attention is drawn to the similarity between former drug addicts and hemophiliacs, since both develop chronic hepatitis in spite of anti-HBs in the serum.     

Opioidergic modulation of cocaine conditioned place preferences.

Recent studies have begun to assess the utility of opioid agonists and antagonists for the treatment of cocaine addiction. The present studies assess the effects of naltrexone or methadone on cocaine's reinforcing properties using the conditioned place preference (CPP) test. The results indicate that a 56 mg/kg dose of naltrexone, given 4 hr prior to conditioning, attenuates cocaine's CPP. In contrast, methadone (8 mg/kg), given 1 hr prior to conditioning, enhanced cocaine's reinforcing properties. These results support the suggestion that opioid antagonists may have clinical utility in treating cocaine addiction. The results with methadone lead to a possible explanation for the higher rates of cocaine use in methadone-treated heroin addicts.     

Opioid receptors: Some perspectives from early studies of their role in normal physiology,stress responsivity,and in specific addictive diseases

The early history of research on the possible existence of specific opioid receptors and on developing a new form of pharmacotherapy for the treatment of heroin addiction in New York City, from 1960–1973, along with the special relationships between two leading scientists conducting these research efforts, Dr. Eric Simon and Dr. Vincent P. Dole Jr., are presented in a historical perspective. The linkage of these early efforts and the subsequent identification and the elucidation of the effects of exogenous opiates acting at specific opiate receptors in human physiology, including some findings from perspective studies of heroin addicts at time of entry to and during methadone maintenance treatment, are presented in the context of the important clues which thereby were provided concerning the possible roles of the endogenous opioids in normal mammalian physiology. From many of these early clinical research findings and studies in animal models, the hypothesis that the endogenous opioids system may play an important role in stress responsivity was formulated along with the related hypothesis, first presented in the early 1970s, that an atypical responsivity to stress and stressors might be involved in the acquisition and persistence of, and relapse to specific addictive diseases, including heroin addiction, cocaine dependency and alcoholism. More recent studies of the possible involvement of the specific opioid receptors in these three addictive diseases—heroin addiction, cocaine addiction and alcoholism—from our laboratory are discussed in a historical perspective of the development of these ideas from the early research findings of not only Dr. Eric Simon, but his numerous colleagues in opioid research in the United States and throughout the world. Special issue dedicated to Dr. Eric J. Simon.     

Acute Heroin Fatalities in San Francisco Demographic and Toxicologic Characteristics

The mortality rate due to heroin overdosage in San Francisco has increased dramatically since 1968 and now stands as one of the highest in the United States. While the numbers of heroin fatalities in many eastern United States cities have declined substantially in the past few years, the figures for San Francisco and the other West Coast areas continue to increase. The group of heroin overdose victims from the 1970 through 1973 period is more predominantly Caucasian and younger than from the 1963 through 1965 period. In nearly all of the victims, the presence of morphine (a heroin metabolite) was noted in bile or urine, and in about half the results of blood alcohol tests were positive. Measurement of blood morphine concentrations in the victims showed no significant difference from the concentrations noted in a control group of heroin addicts dying from causes other than overdosage.     

Regulation of G Protein-Coupled Receptor Kinase 2 in Brains of Opiate-Treated Rats and Human Opiate Addicts

Abstract: The effects of opiate drugs (heroin, morphine, and methadone) on the levels of G protein-coupled receptor kinase 2 (GRK2) were studied in rat and human brain frontal cortices. The density of brain GRK2 was measured by immunoblot assays in acute and chronic opiate-treated rats as well as in opiate-dependent rats after spontaneous or naloxone-precipitated withdrawal and in human opiate addicts who had died of an opiate overdose. In postmortem brains from human addicts, total GRK2 immunoreactivity was not changed significantly, but the level of the membrane-associated kinase was modestly but significantly increased (12%) compared with matched controls. In rats treated chronically with morphine or methadone modest increases of the enzyme levels (only significant after methadone) were observed. Acute treatments with morphine and methadone induced dose- and time-dependent increases (8–22%) in total GRK2 concentrations [higher increases were observed for the membrane-associated enzyme (46%)]. Spontaneous and naloxone-precipitated withdrawal after chronic morphine or methadone induced a marked up-regulation in the levels of total GRK2 in the rat frontal cortex (18–25%). These results suggest that GRK2 is involved in the short-term regulation of μ-opioid receptors in vivo and that the activity of this regulatory kinase in brain could have a relevant role in opiate tolerance, dependence, and withdrawal.     

Heroin addiction in African Americans: a hypothesis-driven association study

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify gene variants associated with heroin addiction in African Americans. The emphasis was on genes involved in reward modulation, behavioral control, cognitive function, signal transduction and stress response. We have performed a case–control association analysis by screening with 1350 variants of 130 genes. The sample consisted of 202 former severe heroin addicts in methadone treatment and 167 healthy controls with no history of drug abuse. Single nucleotide polymorphism (SNP), haplotype and multi-SNP genotype pattern analyses were performed. Seventeen SNPs showed point-wise significant association with heroin addiction (nominal P < 0.01). These SNPs are from genes encoding several receptors: adrenergic ( ADRA1A ), arginine vasopressin ( AVPR1A ), cholinergic ( CHRM2 ), dopamine (DRD1 ), GABA-A ( GABRB3 ), glutamate ( GRIN2A ) and serotonin ( HTR3A ) as well as alcohol dehydrogenase ( ADH7 ), glutamic acid decarboxylase ( GAD1 and GAD2 ), the nucleoside transporter ( SLC29A1 ) and diazepam-binding inhibitor ( DBI ). The most significant result of the analyses was obtained for the GRIN2A haplotype G-A-T (rs4587976-rs1071502-rs1366076) with protective effect ( P _uncorrected = 9.6E- 05, P _corrected = 0.058). This study corroborates several reported associations with alcohol and drug addiction as well as other related disorders and extends the list of variants that may affect the development of heroin addiction. Further studies will be necessary to replicate these associations and to elucidate the roles of these variants in drug addiction vulnerability.     

Toxicology and pathology of deaths related to methadone: retrospective review

Objectives To clarify the mechanisms and risk factors of methadone toxicity and to describe the findings of deaths related to methadone use Design Retrospective review of case notes in the records of the San Francisco Medical Examiner comparing the findings in cases where methadone was deemed the cause of death with findings in decedents where methadone was an incidental finding, and with 50 age-matched, disease and drug free, trauma victims. Results 38 cases out of the 3317 processed by our office during 1997-1998 were identified in which methadone had been detected. Cases were mostly male 28/38 (74%) and white, 28/38 (74%). In 17 of 38 cases death was deemed to have been caused by methadone toxicity. For the group the mean blood methadone concentration for all 38 patients, was 957 ng/ml SD =.681, SE =.14). The mean blood concentration of the main methadone metabolite (EDDP) was 253 ng/ml, SD = 529 ng/ml, SE =.089. The mean ratio of methadone in the blood to EDDP in the blood was 13.6:1 Values were not significantly different between cases in which methadone toxicity was the cause of death and in those in which it was an incidental finding. Cocaine, or the cocaine metabolite benzoylecgonine, was detected in the blood or urine of 16/38 cases (42%); morphine in one-third (13/38) and methamphetamine in only one. Pulmonary edema was evident in all cases, coronary artery disease in 9/38 (24%) and cirrhosis in 7/38 (18%) of the methadone users. Necrotizing fasciitis was the cause of death in 4 of the 38 methadone users (11%). Nationally, a sizeable percent of methadone deaths are from drugs diverted from treatment programs. Conclusions The presence of methadone is often an incidental finding during postmortem examination which is unrelated to the cause of death. Postmortem measurements of methadone or its metabolite, or both, cannot be used in isolation to identify which deaths are associated with methadone toxicity.The Office on National Drug Control Policy is commited to making methadone treatment programs more widely available; deaths related to heroin use fall when where methadone replacement programs are available.^{1, 2, 3} Unfortunately, methadone is toxic. A total of 552 methadone-related deaths were reported to the government in 1996, making methadone the seventh most frequent cause of drug-related death in the United States (nearly 4000 deaths related to heroin were reported during that same period).⁴Most deaths that are related to methadone occur during the first few weeks of maintenance treatment; they are often the result of the dosage having been increased so quickly that fatal respiratory depression occurs.^5,6 The relative risk of fatal respiratory depression occurring during the first 2 weeks of methadone maintenance treatment is nearly seven times higher than that in untreated heroin addicts and 97.8 times higher than for patients who have been on methadone maintenance for more than 2 weeks.^3,7New opiate users who are using illicitly obtained methadone are also at risk. The amount of methadone diverted from treatment programs, and by inference the number of deaths occurring as a result, is limited because the number of heroin users actually enrolled in methadone programs is comparatively small. There are an estimated 810,000 heroin addicts in the United States but only 115,000 participate in maintenance programs.⁴ If methadone becomes more widely available opportunities for diversion from treatment programs will increase and so will the number of deaths.¹ Some of these deaths might be prevented, especially if the underlying cause of death was better understood. Little is known about the pharmacokinetics of methadone in opiate users. The data that have been published are largely derived from studies of single doses given to healthy volunteers or intravenous doses given to patients with cancer. Whether such studies are relevant to the pharmacokinetics in chronic heroin users is not known. Furthermore, nearly all of these studies were undertaken before differences in the tissue distribution of methadone isomers were understood,⁸ before methadone metabolites could be routinely measured, before chiral (special chemical techniques used to separate dextro- from levo- isomers of the same molecule) separation of methadone isomers was possible ⁹ and before the problem of determining the redistribution of drugs after death was appreciated.¹⁰     

Adipocyte-derived hormones in heroin addicts: the influence of methadone maintenance treatment

Heroin addiction markedly affects the nutritional and metabolic status and frequently leads to malnutrition. The aim of our study was to compare circulating concentration of adipose tissue-derived hormones leptin, adiponectin and resistin in 12 patients with heroin addiction before and after one-year methadone maintenance treatment with the group of 20 age- and body mass index-matched healthy subjects. Basal serum leptin and adiponectin levels in heroin addicts were significantly decreased (3.4+/-0.4 vs. 4.5+/-0.6 ng/ml and 18.9+/-3.3 vs. 33.9+/-3.1 ng/microl, respectively; p 0.05) while serum resistin concentrations were increased compared to healthy subjects (10.1+/-1.2 vs. 4.6+/-0.3 ng/ml; p 0.05). Moreover, positive correlation of serum leptin levels with body mass index was lost in the addicts in contrast to control group. One year of methadone maintenance treatment normalized serum leptin, but not serum adiponectin and resistin concentrations. In conclusion, circulating concentrations of leptin, adiponectin and resistin are markedly altered in patients with chronic heroin addiction. These alterations appear to be relatively independent of nutritional status and insulin sensitivity.     

The quantitative analysis of heroin, methadone and their metabolites and the simultaneous detection of cocaine, acetylcodeine and their metabolites in human plasma by high-performance liquid chromatography coupled with tandem mass spectrometry

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

T-helper 1 and 2 serum cytokine assay in chronic opioid addicts

There are a few studies with conflicting results on the effects of opioids on the functioning of immune system. This study was performed to investigate the in vitro production of interferon-gamma and interleukin-10 after antigenic stimulation of cells using whole blood from opioid addicts. Blood samples were taken from 20 chronically opioid-addicted persons, who voluntarily enrolled for detoxification (10 opium and 10 heroin addicts). Blood samples were also taken from 10 healthy individuals with no history of drug abuse as the control. Cell culture was performed in a whole blood culture assay. Diluted blood samples were stimulated with phytohemagglutinin or with lipopolysaccharide and the supernatants were collected to measure cytokine production. The results demonstrated a significant decrease in interferon-gamma production and an increase in interleukin-10 secretion in heroin addicts, relative to the control group (35.9+/-26.3 versus 110.2+/-60.3 pg/mL, p<0.01 and 71.8+/-28.4 versus 17.1+/-13.5 pg/mL, p<0.01, respectively), however the changes in these values in opium addicts were not significant compared to healthy individuals. The results could suggest that opioid addiction leads to a shift in the Th1/Th2 cytokine balance of peripheral CD4+ cells towards the Th2 response, and opioid addicts demonstrate reduced mitogenic responsiveness of lymphocytes relative to healthy individuals.     

Serum Proteomic Analysis Reveals High Frequency of Haptoglobin Deficiency and Elevated Thyroxine Level in Heroin Addicts

Heroin addiction is a chronic, complex disease, often accompanied by other concomitant disorders, which may encumber effective prevention and treatment. To explore the differences in expression profiles of serum proteins in control and heroin addicts, we used two-dimensional electrophoresis coupled to MALDI-TOF/TOF, and identified 4 proteins of interest. Following validation of the increase in serum transthyretin, we assessed serum levels of thyroid stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4), and observed a robust increase in T4 in heroin addicts compared to controls. In addition, we performed haptoglobin (Hp) phenotyping, and showed that the frequency of Hp0 (serum devoid of haptoglobin) was significantly higher in heroin addicts. Altogether, these findings indicated that: (1) thyroid hormone imbalance is present in heroin addicts; (2) anhaptoglobinemia (Hp0) might a risk factor or a deleterious effect of heroin abuse.     

Idling in Mao’s Shadow: Heroin Addiction and the Contested Therapeutic Value of Socialist Traditions of Laboring

The Chinese government has come under attack by international critics for forcing drug users to labor in the name of treatment. While joining these activists in criticizing conditions in compulsory labor centers, former detainees who congregated at a drop-in center in southern Yunnan also defended the therapeutic potential of socialist legacies of laboring. Shuttling between laboring in state compulsory centers and idling in a market economy, long-term heroin users saw their difficulties in recovering from addiction as inextricably linked to their inability to find suitable work opportunities. Certain drop-in center attendees maintained that earlier Communist laboring projects had helped wayward citizens, including drug addicts, “merge into” society as productive workers. This group evoked the stable long-term jobs and benefits once provided by local state-owned enterprises and the radical revolutionary power of “remolding through labor” they imagined to have existed in the first years of the People’s Republic as powerful alternatives to their recent crisis of idling. The nuanced ways that drop-in center regulars revisited the potential healing power of earlier traditions of socialist laboring as remedies to their contemporary struggles complicates long-standing debates about coercion in treatment and the responsibility of the postsocialist state towards marginalized workers.