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

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.     

Are problem drinkers dangerous drivers? An investigation of arrest for drinking and driving,serum gamma glutamyltranspeptidase activities,blood alcohol concentrations,and road traffic accidents: the Tayside Safe Driving Project.

Serum gamma glutamyltranspeptidase activity was measured in 440 drivers at the time of arrest for driving under the influence of alcohol. The results were compared with information gathered by the arresting police officer. One third of drivers over the age of 30 had abnormal gamma glutamyltranspeptidase activities at the time of arrest. Among drivers who required a driving license for their work, and older drivers, a disproportionately high number had raised gamma glutamyltranspeptidase activities indicating problem drinking. In drivers over the age of 30 a strong association was found between gamma glutamyltranspeptidase activities and road traffic accidents but not alcohol concentrations or previous convictions. These findings argue against the Department of Transport''s criteria for high risk offenders and indicate a clear need for new measures against problem drinkers among drinking and driving offenders.     

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.     

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.     

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.     

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.     

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.     

Unacceptable face of private practice: prescription of controlled drugs to addicts.

Self administered questionnaires completed by 69 out of 100 consecutive drug addicts attending two drug dependence clinics suggested that some private general practitioners were easily persuaded to prescribe controlled drugs. These drugs were usually methadone, dipipanone-cyclizine (Diconal), and methylphenidate (Ritalin). Numbers of new narcotic addicts notified to the Home Office confirmed the practice, which may lead to a severe spread of addiction, as occurred in the 1960s with heroin and cocaine. If the General Medical Council or a tribunal set up in accordance with the Misuse of Drugs Act 1971 cannot stop the practice, then the present licensing system should be extended to include all controlled drugs.     

Alcoholic drinkers and road safety in the Republic of Slovenia

In this study we were therefore interested in the percentage of road traffic offenses (RTO) and road traffic accidents (RTA) involving inebriated drivers one year before and one year after the passing of the new Law on Road Traffic Safety (LRTS) as well as measures (referrals, punishments and final decisions on the revoking of driver's licenses due to drunk driving). One year before the passing of the new LRTS, there were 40,702 RTA-s in the Republic of Slovenia (12.2% caused by drunk drivers). The average alcohol concentration in exhaled air for those analysed was 1.19 g/kg. One year after the passing of this law there were 36,479 RTA-s (8.6% caused by drunk drivers). The average alcohol concentration in exhaled air for those analysed was 1.32 g/kg (the differences were statistically significant). In 13.8% cases the reason for performing a measurement of the alcohol concentration in exhaled aier was an RTA with an average alcohol concentration in exhaled air of 1.22 g/kg and in 86.2% of cases an RTO with an average alcohol concentration in exhaled air of 1.25 g/kg (the differences were statistically significant). We found it interesting that the number of events minvolving lower concentrations decreased, but the percentage involving higher alcohol concentrations even increased. The results of this study indicate without a doubt that the law was not successful enough with its repressive and preventative measures in the field of drunk drivers. Experts on alcohol believe that punishment cannot make alcoholics and other drivers abandon their behavioural patterns and stop driving under the influence of alcohol. This can be achieved only by treatment, and the present practice (police--misdenveanour counts--repeat general medical check-up) has been ineffective as prevention among alcoholic drivers. We therefore believe that supplements to the LRTS should be adopted urgently, that would contribute, through better medical selection, to a reduction in the number of drunk drivers behind the wheel, both those who are alcohol dependent (and should be referred to treatment).     

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.     

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     

ADDICTION AND AUTONOMY: CAN ADDICTED PEOPLE CONSENT TO THE PRESCRIPTION OF THEIR DRUG OF ADDICTION?

It is often claimed that the autonomy of heroin addicts is compromised when they are choosing between taking their drug of addiction and abstaining. This is the basis of claims that they are incompetent to give consent to be prescribed heroin. We reject these claims on a number of empirical and theoretical grounds. First we argue that addicts are likely to be sober, and thus capable of rational thought, when approaching researchers to participate in research. We reject behavioural evidence purported to establish that addicts lack autonomy. We present an argument that extrinsic forces must be irresistible in order to make a choice non-autonomous. We argue that heroin does not present such an irresistible force. We make a case that drug-oriented desires are strong regular appetitive desires, which do not compromise consent. Finally we argue that an addict's apparent desire to engage in a harmful act cannot be construed as evidence of irrational or compulsive thought. On these arguments, a sober heroin addict must be considered competent, autonomous and capable of giving consent. More generally, any argument against legalisation of drugs or supporting infringement of the liberty of those desiring to take drugs of addiction must be based on considerations of harm and paternalism, and not on false claims that addicts lack freedom of the will.     

Method for determination of methadone in exhaled breath collected from subjects undergoing methadone maintenance treatment

At present drugs of abuse testing using exhaled breath as specimen is only possible for alcohol. However, we recently discovered that using modern liquid chromatography–mass spectrometry technique amphetamine and methamphetamine is detectable in exhaled breath following intake in drug addicts. We therefore undertook to develop a method for determination of methadone in exhaled breath from patients undergoing methadone maintenance treatment. Exhaled breath was collected from 13 patients after intake of the daily methadone dose. The compounds were trapped by filtering the air through a C18 modified silica surface. After elution of any trapped methadone the extract was analysed by a combined liquid chromatography–tandem mass spectrometry method. Recovery of trapped methadone from the filter surface was 96%, no significant matrix effect was observed, and the quantification using methadone-d3 as an internal standard was accurate (<10% bias) and precise (coefficient of variation 1.6–2.0%). Methadone was indisputably identified by means of the mass spectrometry technique in exhaled breath samples from all 13 patients. Identification was based on monitoring two product ions in selected reaction monitoring mode with correct relative ratio (±20%) and correct retention time. Excretion rates ranged from 0.39 to 78 ng/min. No methadone was detected in 10 control subjects. This finding confirms that breath testing is a new possibility for drugs of abuse testing. Collection of exhaled breath specimen is likely to be more convenient and safe as compared to other matrices presently in use.     

Drinking, substance use and the operation of motor vehicles by young adolescents in Canada

Background

Impaired driving is a recognized cause of major injury. Contemporary data are lacking on exposures to impaired driving behaviours and related injury among young adolescents, as well as inequities in these youth risk behaviours.

Methods and Findings

Cycle 6 (2009/10) of the Health Behaviour in School-Aged Children survey involved 26,078 students enrolled in 436 Canadian schools. We profiled cross-sectionally the reported use of alcohol, marijuana, or other illicit drugs by on-road and off-road vehicle operators when young adolescents (mean age 13.3 (±1.6) years) were either driving or riding as a passenger. Comparisons were made across vulnerable subgroups. Multi-level logistic regression analyses were used to quantify the effects of the driving behaviours on risks for motor vehicle-related injury. Attributable risk fractions were also estimated. A total of 10% (±3%) of participants reported recent operation of an on-road or off-road motor vehicle after consuming alcohol, marijuana, or other illicit drugs, while 21% (±3%) reported riding as a passenger with a driver under the same conditions. Larger proportions of youth reporting these risk behaviours were males, and from older age groups, rural communities, and socio-economically disadvantaged populations. The behaviours were consistently associated with increased risks for motor vehicle-related injury at the individual level (RR 2.35; 95% CI: 1.54 to 3.58 for frequent vs. no exposure as a driver; RR 1.68; 95% CI: 1.20 to 2.36 for frequent vs. no exposure as a passenger) and at the population level (Attributable Risk Fraction: 7.1% for drivers; 14.0% for passengers). The study was limited mainly by its reliance on self-reported data.

Conclusion

Impaired driving is an important health priority among young adolescents in Canada. Inequities in the involvement of younger adolescents in these risk behaviours suggest the need for targeted interventions for specific subgroups such as youth from rural communities, and among socially disadvantaged populations.     

Differential Pharmacological Actions of Methadone and Buprenorphine in Human Embryonic Kidney 293 Cells Coexpressing Human μ-Opioid and Opioid Receptor-Like 1 Receptors

Methadone and buprenorphine are used in maintenance therapy for heroin addicts. In this study, we compared their effects on adenylate cyclase (AC) activity in human embryonic kidney (HEK) 293 cells stably overexpressing human μ-opioid receptor (MOR) and nociceptin/opioid receptor-like 1 receptor (ORL1) simultaneously. After acute exposure, methadone inhibited AC activity; however, buprenorphine induced compromised AC inhibition. When naloxone was introduced after 30 min incubation with methadone, the AC activity was enhanced. This was not observed in the case of buprenorphine. Enhancement of the AC activity was more significant when the incubation lasted for 4 h, and prolonged exposure to buprenorphine elevated the AC activity as well. The removal of methadone and buprenorphine by washing also obtained similar AC superactivation as that revealed by naloxone challenge. The study demonstrated that methadone and buprenorphine exert initially different yet eventually convergent adaptive changes of AC activity in cells coexpressing human MOR and ORL1 receptors.     

ALCOHOL AND DRIVING—Application of a Definition in a Way to Deter Offenders

Increasing speed and congestion of vehicular traffic have made the effect of alcohol on the drivers of motor vehicles a matter of growing concern. It is not possible, using the definition of drunken driving that is now prevalent in California, to establish a rule, based on a stipulated minimum concentration of blood alcohol, that will serve to indict most of the guilty yet free all the innocent. If, instead of comparing the suspected driver with the hypothetical “ordinarily prudent and cautious person” as is now done in California, we accept the more widely prevalent definition of driving under the influence which defines the offense as any appreciable diminution in skill ascribable to alcohol, then a blood alcohol concentration of 150 mg. per 100 cc. or even 100 mg. per 100 cc., could suffice for conviction.For the rule as to alcohol content of the blood to be an effective deterrent of drunken driving, all drivers—not just those involved in accidents or observed to drive erratically—would have to be subject to testing.     

282例海洛因依赖者复吸原因调查分析

目的探讨海洛因依赖者复吸原因,并分析社会因素、心理因素和戒毒后稽延症状对复吸的影响。方法采用在北京大学中国药物依赖研究所编制的16项复吸原因问卷,调查282例海洛因依赖者吸毒、脱毒后复吸情况以及影响复吸的三方面因素。结果出现稽延性戒断症状（81．9％）、失眠（75．5％）是产生复吸的主要身体因素;消除心情烦恼（39．0％）、打发无聊时间（34．4％）以及再享受最后一次（32．6％）是产生复吸的主要心理因素;毒友影响（43．3％）、旧的吸毒环境又引发毒瘾（33．7％）是产生复吸的主要社会因素。讨论吸毒者的心理康复是预防复吸最重要工作的之一;加强对戒毒后回归社会人员的管理,建立家庭社区综合康复机制,是预防复吸的重要手段;加大在广大青少年人群中禁毒的宣传力度。