Drug related deaths in the Split-Dalmatia County 1997-2007

Drug overdoses are a major cause of mortality for drug users and, in many countries, are the leading cause of death in this group. The aim of the present study is to explore the frequency of all drug related deaths in the Split-Dalmatia County in the period between 1997 and 2007 and to analyze some of the characteristics of these deaths to help target preventive policies. The data on drug related deaths were collected using records from the Department of Forensic Medicine, Clinical Hospital Centre Split, University of Split, School of Medicine. There were 190 drug related deaths in the observed period of 11 years. Statistically significant difference (p = 0.004, chi2-test for trend) was found in the number of deaths in 1997 in comparison with the number of deaths in 2007. The majority of 105 (55%) the decedents were 25-34 years old, and 92.1% (175) of them were male. There was a 94% higher probability of mortality in the 25-34 years group (chi2 = 5.55, p = 0.064). Average age of all dead people was 31.01 +/- 7.59 years (median 31.0 years; range 18-49). Almost three quarters of the decedents were single and more than three fifths hadn't been employed. The most common location of death was at home. Approximately, 80% were autopsied followed by full histological and toxicological analyses. Out of all examined cases, the majority of drug related deaths (93 or 60.8%) were attributed to heroin. Heroin was the sole cause of death in 35 (22.9%) cases. Methadone was cause of death in 24 (15.7%) cases. 3.4-methylenedioxy-methamphetamine (MDMA) deaths were rare (3.3%). Cocaine deaths were also rare (1.3%). Three fifths (55.6%) of the cases involved includes multi-substance use. During the investigation there was an evident trend towards multi-substance abuse patterns. These data suggest that interventions to prevent drug related mortality should address the use of drugs such as heroin and alcohol in combination.     

PMA deaths in Ontario

A new street-drug, para-methoxyamphetamine (PMA), recently made its appearance in Ontario. Between March and August 1973 there were nine deaths of young people in this province that were attributed to the drug. PMA appears to have a powerful hallucinogenic effect as well as a marked toxicity to the central nervous system. The clinical picture resembles that observed in cases of acute poisoning by amphetamine and methylenedioxyamphetamine (MDA).     

A “Krokodil” emerges from the murky waters of addiction. Abuse trends of an old drug

“Krokodil” is the street name for the semi-synthetic opioid derivative desomorphine. Although an old drug, it re-staged on “drug arena” during the last decade causing detrimental effects to its users. Despite the fact that Russia and other former Soviet Republics were the initial plagued countries, “krokodil” arrived in Europe and United States lately, as a substitute of the relative expensive, and in many cases unavailable, heroin. It can be easily manufactured in home-environment from codeine and causes significant health problems, even deaths worldwide. The aim of this review is to summarize the current knowledge about this drug, concerning its chemistry, synthesis, pharmacology and toxicology. Published or reported “krokodil” related cases, fatalities or intoxications, as well as self reports from drug users are reviewed. The existing analytical methodologies for the determination of desomorphine in biological samples as well as its legal status are also presented.     

Heroin users in general practice: ascertainment and features

A case-control study of heroin users in general practice showed a prevalence of roughly two per 1000 of the urban population or four per “average” general practice list of patients. A method of studying heroin users who attend general practice was used that has advantages over existing techniques. Thirty six heroin users had a statistically significantly higher yearly doctor-patient consultation rate than a group of matched controls. More heroin users also failed to attend appointments than controls. When consultations directly related to heroin and its effects were excluded, however, the consultation rates in the two groups were similar. The heroin users did not have an excess of psychiatric disorder or disturbed family background compared with controls but had a noticeable history of dishonest and violent behaviour towards medical staff.A high proportion of heroin users in the study were antibody positive for the human immunodeficiency virus. General practitioners should take advantage of their frequent contacts with heroin users and their families to give them support and counselling about the acquired immune deficiency syndrome.     

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     

Fluoxetine-induced attenuation of amphetamine self-administration in rats

Daily injections of fluoxetine (5.0 mg/kg i.p.) to rats trained to self-administer intravenous d-amphetamine produced marked decreases in drug intake on three successive days of treatment. After fluoxetine injections were stopped, the number of daily amphetamine self-injections was still significantly reduced for an additional 2 days. When trained amphetamine self-administration animals were placed in an apparatus which delivered i.v. saline with each lever press, increased self-injection is observed. Acute fluoxetine injection did not alter this response. However, if fluoxetine is given prior to amphetamine exposure for 1 day and animals are then tested for the saline response, lever pressing activity is significantly reduced. These data might suggest that 5-hydroxytryptaminergic neurons mediate some aversive or negative reinforcing property of amphetamine. If true, this finding could be exploited clinically in cases of human psychomotor stimulant addiction.     

Evaluation of the health status outcome among inpatients treated for Amphetamine Addiction

Amphetamine is one of the most abuser drugs in Saudi Arabia. The aim of this study was to evaluate health status outcome at baseline and after detoxification in amphetamine users through the evaluation of the body mass index, renal function tests, cardiac biomarkers, gonadal hormonal levels, and oxidative stress markers. A cross-sectional study was conducted on 90 participants. Sixty participants were hospitalized patients for treatment of addiction and 30 participants were healthy volunteers. This study was performed at a psychiatric and rehabilitation center, in Qassim region, in the Kingdom of Saudi Arabia. Participants were divided into: group I = control; group II = amphetamine users and group III = amphetamine plus cannabis users. Socio-demographic data was collected. The urinary amphetamine level, Severity Dependence Scale (SDS), body mass index (BMI), vital signs; serum levels of troponin T (TnT), immunoglobulin M (IgM), immunoglobulin G (IgG), luteinizing Hormone (LH), testosterone Hormone (TSTS), urea, creatinine, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured on admission and after detoxification. The results showed that the BMI was significantly decreased while, vital signs such as heart rate, blood pressure and respiratory rate were significantly increased in all abusers and returned to normal values after the detoxification period. The cardiac biomarker troponin T was significantly increased and reversed after detoxification. The immune system was evaluated through assessing serum levels of immunoglobulin (Ig) M and IgG. The immune system remained immunocompromised in drug users, and IgM and IgG levels did not reach the level of control group after treatment. Luteinizing and testosterone hormones were evaluated. Both hormones were increased on admission and improved after the detoxification period. Renal function showed no significant differences between drug users and the control group. In the evaluation of the antioxidant system, there was a significant increase in serum MDA, SOD, GPx, and CAT levels compared to healthy controls. After the detoxification phase, these oxidative stress biomarkers still remained elevated. The current results have shown the addiction of amphetamine and cannabis exert detrimental effects on different body organs and the exert major consequences on the health status of drug users. The present study showed that, there was no improvement in the levels of oxidative stress biomarkers, although an improvement was observed in the other parameters after the detoxification phase.     

Heat and acid tolerance of Clostridium novyi Type A spores and their survival prior to preparation of heroin for injection

Clostridium novyi Type A was implicated as a cause of an outbreak of serious illness and deaths among drug users in the United Kingdom who injected heroin intramuscularly. A contaminated batch of heroin was believed to be the source of infection. To test the ability of the outbreak strain to survive certain processes associated with heroin use, it was tested for its ability to survive a range of temperature and pH and the process used in preparation of "street" heroin for injection. C. novyi spores survived temperatures of up to 100 degrees C in aqueous solution for 5 min and survived pH 2.0 at ambient temperatures for a similar time. However, a combination of low pH and raised temperatures reduced survival times. An experiment reconstructing the "street" preparation of heroin demonstrated that any C. novyi spores present would survive this process and thus be capable of initiating infection under the right conditions.     

Medical facilities used by heroin users.

There is little information about the extent of contact between heroin users and medical facilities. In this study of heroin users from general practice we found an increase in the attendance of patients after the onset of heroin use and that a high proportion of appointments were made at general practices compared with hospital departments.     

Occupational cancer: experience in Ontario.

This paper reviews the experience of the Workmen''s Compensation Board of Ontario in identifying cases of cancer that could be attributed to occupational hazards. Worker''s claims for compensation are allowed if there is reasonable medical evidence that their cancer was caused by exposure to risk factors associated with their occupation. Details of the types of cancer associated with specific carcinogens or fields of employment are discussed. About 50% of the cases were related to exposure in particular industrial operations that functioned for relatively brief periods. The number of deaths from cancer identified as being caused by occupational factors is compared with the total for cancer from all causes in Ontario during the period 1971 through 1975. Although all workers eligible for compensation may not have been identified, the data suggest that less than 1% of cancer is presently caused by occupational factors.     

Problem drug use in a central London general practice.

OBJECTIVE--To describe the profile of problem drug users presenting in general practice and to determine whether they can be cared for in general practice. DESIGN--Study of consultations by problem drug users. SETTING--Central London general practice. SUBJECTS--150 problem drug users presenting over two years. MAIN OUTCOME MEASURES--Stopping drug use, alterations in lifestyle, obtaining paid work, and stopping drug related crime. RESULTS--Of the 150 patients, 111 were men and 39 women, and 106 were unemployed. 121 patients used heroin, 112 of whom injected. 145 patients accepted a methadone reduction programme and 81 completed it. A further 25 were stabilised on reducing doses of methadone, until places became available for them as inpatients at drug dependency units or rehabilitation projects. CONCLUSION--Withdrawal programmes for patients who misuse drugs can be successfully managed in general practice.     

Characteristics of hepatitis C infection in injecting drug users in Zadar County, Croatia

The aim of the study was to determine additional risk factors that could increase the prevalence of hepatitis C (HCV) infection among injecting drug users (IDU). The study included 327 heroin addicts registered in Zadar County, Croatia. The participants were divided into two groups according to their HCV status. HCV-positive and HCV-negative study participants were compared. HCV-positive group started injecting heroin at earlier age (median 18.5 years) than HCV-negative group (median 20.0 years) (p = 0.032) and had been injecting heroin for a significantly longer period (median 5 years vs. median 4 years, respectively; p < 0.001). IDUs in HCV-positive group shared their injecting equipment significantly more often than IDUs in HCV-negative group (p < 0.001; chi2 = 32.7). The main reasons for starting drugs were curiosity, psychological reasons (depression and/or neurosis), and peer or partner pressure in HCV-positive group, and fun, curiosity, and peer pressure in HCV-negative group (p = 0.051; chi2 = 23.6). Earlier onset of heroin use, longer heroin use, sharing injection equipment, curiosity, and psychological problems as reasons for starting drugs were associated with higher prevalence of HCV infection among injecting heroin users in Zadar County.     

Trend of mortality observed in a cohort of drug addicts of the metropolitan area of Bologna, North-Eastern Italy, during a 25-year-period

The aim of our study is to evaluate the temporal trend of deaths in a cohort of i.v. drug users (IVDU) followed in a city of Northen Italy (Bologna), and to assess its relationship with HIV infection and AIDS, and availability of potent anti-retroviral therapy. One thousand and 214 IVDUs (mainly heroin addicts), 916 males and 298 females, attending an out-patient service for treatment and prevention of substance abuse between 1977 and November 1996, were enrolled into our observational cohort, and their vital status was ascertained up to December 31, 2002. The large majority of enrolled subjects were born in the Bologna metropolitan area and surroundings; no extra-European immigrants were present. During the observation period, 271 IVDUs (22.3%) died, 211 males (23.0%), and 60 females (20.1%). No death was recorded before 1984. Main death causes result as follows: AIDS (52.8% of episodes), heroin overdose (22.1%), street accidents (7.4%), decompensated liver cirrhosis (6.3%), and suicide (2.9%). The highest absolute number of deaths was observed between years 1991 and 1996. Crude mortality rate caused by AIDS was 10.0 per 1000 for males and 13.2/1000 for females; the rate of death due to other causes proved 11.1/1000 among males and 5.2/1000 among females. In most recent years, a sharp decrease in the number of AIDS-related deaths, attributable to the increased use of potent antiretroviral regimens, was recorded among IVDUs, although overall mortality rate remained appreciable.     

The human nucleus accumbens is highly susceptible to G protein down-regulation by methamphetamine and heroin

Although the nucleus accumbens is assumed to be a critical brain "pleasure center," its function in humans is unknown. As animal data suggest that a unique feature of this small brain area is its high sensitivity to down-regulation of an inhibitory G protein by drugs of abuse, we compared G protein levels in postmortem nucleus accumbens with those in seven other brain regions of chronic users of cocaine, methamphetamine, and heroin, and of matched controls. Biochemical changes were restricted to the nucleus accumbens in which concentrations of G(alpha)1 and/or G(alpha)2 were reduced by 32-49% in the methamphetamine and heroin users. This selective responsiveness to these abused drugs implies a special role for the human nucleus accumbens in mechanisms of drug reinforcement and suggests that some features of the drug-dependent state (e.g., tolerance) might be related to inhibition of G(alpha)1-linked receptor activity.     

The results of conducting a rapid assessment of the situation in relation to intravenous narcotic abuse in the city of Rostov-on-Don

The main aspects of the spread and intravenous use of drugs in the city, contributing to the transmission of HIV infection among users of intravenous drugs (UID) have been studied. Anonymous questionnaires were distributed among 61 UID; of these, 50 were males (82%) and 11 were females (18%), mainly at the age of 19-35 years. In addition, sociological study was carried out among 582 persons; 61% of them were under 18 years of age, 18% were aged 19-25 years, 13% were aged 26-35 years. The drug users regarded their individual risk of getting HIV infection as insignificant in 23% of cases, slight in 21% of cases, high in 15% of cases, and 15% believed they were at no risk. As shown by the results of the sociological study, 91% of the respondents believed that the problem of drug addiction was topical in the city. The analysis of data obtained from physicians treating drug addicts and from the Head Office of Public Health made it possible to calculate that the number of UID in the city was about 9,000-10,000 persons. Taking into account the results of the rapid evaluation of the situation, the development of the draft program of "diminishing the harm" of the intravenous use of drugs is now in progress.     

Safety of Oral Amphetamine Administered during Positron Emission Tomography Scans in Medically Screened Humans

Changes in endogenous dopamine levels can be detected in humans using positron emission tomography scans by measuring the amount by which a specific D_2/3 radioligand is displaced. In some cases, a challenge drug such as amphetamine is introduced to increase the amount of dopamine released into the synaptic cleft. Although intravenous amphetamine is often utilized, oral amphetamine has been shown to be just as effective in increasing endogenous dopamine levels. Based on our own use of oral amphetamine as a challenge drug, we have retroactively reviewed our study charts to determine the cardiovascular safety of 0.5 mg kg^-1 oral d-amphetamine. Of 172 amphetamine administrations in 144 individuals, only 2.8% of subjects experienced any transient adverse effects. In addition, we found no clinically relevant differences in increases of vital signs between healthy controls and patients. We therefore reaffirm the safety of 0.5 mg kg^-1 oral amphetamine in subjects previously screened for cardiovascular risk factors.     

Genes and Pathways Co-associated with the Exposure to Multiple Drugs of Abuse,Including Alcohol,Amphetamine/Methamphetamine,Cocaine, Marijuana,Morphine, and/or Nicotine: a Review of Proteomics Analyses

Drug addiction is a chronic neuronal disease. In recent years, proteomics technology has been widely used to assess the protein expression in the brain tissues of both animals and humans exposed to addictive drugs. Through this approach, a large number of proteins potentially involved in the etiology of drug addictions have been identified, which provide a valuable resource to study protein function, biochemical pathways, and networks related to the molecular mechanisms underlying drug dependence. In this article, we summarize the recent application of proteomics to profiling protein expression patterns in animal or human brain tissues after the administration of alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine/heroin/butorphanol, or nicotine. From available reports, we compiled a list of 497 proteins associated with exposure to one or more addictive drugs, with 160 being related to exposure to at least two abused drugs. A number of biochemical pathways and biological processes appear to be enriched among these proteins, including synaptic transmission and signaling pathways related to neuronal functions. The data included in this work provide a summary and extension of the proteomics studies on drug addiction. Furthermore, the proteins and biological processes highlighted here may provide valuable insight into the cellular activities and biological processes in neurons in the development of drug addiction.     

Deaths in children with a diagnosis of acute appendicitis in England and Wales 1980-4.

Thirty five children died of acute appendicitis in England and Wales in 1980-4 compared with 204 in 1963-7. Thirteen of the 35 deaths in 1980-4 took place at home or on the day of admission to hospital before operation and a further 18 on the day of operation or the first day after it. Thirty one of the children had peritonitis. A third of the deaths were in children aged 0-4 years, and the hospital fatality rate in this age group was one death in 320 cases compared with one death in 4760 cases in children aged 5-14 years. The fall in the number of deaths between the 1960s and the 1980s was due to improvements in medical care, a reduction in the incidence of appendicitis, and changes in the age structure of the child population. Difficulty and delay in diagnosis and inadequate intravenous therapy are now the main factors contributing to death.