Methadone maintenance treatment: the balance between life-saving treatment and fatal poisonings.

AIM: To determine the total mortality related to the Stockholm methadone programme during the period 1988-2000, both the mortality related to the treatment and fatal methadone intoxications in the Stockholm area during the same period. METHODS: The study comprised all individuals (n = 848) who had been in contact with the methadone programme in Stockholm during the study period, including those patients who had been discharged from treatment and those opiate users who had applied for but not received methadone treatment. All deaths that had been the subject of medico-legal examination at the Department of Forensic Medicine in Stockholm where methadone was found in blood or urine were also analysed during the same period. RESULTS: The mortality was lower among those opiate users who remained in maintenance treatment and 91% of the deceased individuals had died due to natural causes, in most cases related to HIV or hepatitis C, acquired before admission to the programme. Those who had been discharged from methadone treatment had a 20 times higher risk of dying from unnatural causes compared to the patients who remained in treatment. The majority died due to heroin injections ('overdoses'). Eighty-nine cases of fatal methadone intoxication were found, but in only two of these cases was there evidence of leakage from maintenance treatment. CONCLUSION: The 'high threshold programme' is safe as long as the patients remain in treatment and there are very few deaths due to leakage from the programme. However, there is a high mortality among those discharged from the programme and only a minority of the heroin users in Stockholm had applied for treatment.

Somatic effects of AAS abuse: A 30-years follow-up study of male former power sports athletes.

OBJECTIVES: The aim of the present study was to investigate the association between somatic health and former abuse of AAS in former elite male athletes 30 years after the end of their active sports career. DESIGN: Retrospective follow-up study. METHODS: N=996 former elite male athletes were sent a questionnaire concerning sociodemographic variables, previous and past sport activity and lifetime prevalence of seeking professional help for health problems. N=683 (68.6%) answered the questionnaire. The lifetime prevalence of AAS-abuse was 21% (n=143), while 79% (n=540) did not admit having ever used AAS. RESULTS: Former AAS-abuse was associated with tendon ruptures (p=0.01), depression (p=0.001), anxiety (p=0.01) and lower prevalence of prostate hypertrophy (p=0.01) and decreased libido (p=0.01). Former advanced AAS-abusers had higher anxiety (p=0.004) compared to the former less advanced AAS-abusers. Moreover, former advanced AAS-abusers, compared to AAS-naïves, reported more psychiatric problems (p=0.002), depression (p=0.003) and anxiety (p=0.00). CONCLUSIONS: A former AAS-abuse seems to be associated with some somatic and mental health problem, although a former less advanced AAS-abuse is related to lower incidence of prostate hypertrophy. The results raise the question whether some of these associations might be dose- and frequency dependent. These findings should however be seen as hypothesis generating and further studies are needed.

Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids.

1. The effects of treating groups of rats with four different anabolic androgenic steroids (AAS) (testosterone, nandrolone, methandrostenolone, and oxymetholone) on 5-hydroxytryptamine (5-HT) and dopamine (DA) neurones in different brain regions were examined. The AAS was injected six times with 1 week's interval and the rats were sacrificed 2 days after the final injection. 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. The effect on DA and 5-HT synthesis rate was analysed as the accumulation of 3,4-dihydroxyphenyl-alanine (DOPA) and 5-hydroxytryptophan (5-HTP), respectively, after inhibition of the amino acid decarboxylase with NSD-1015 (3-hydroxy-benzylhydrazine dihydrochloride). Additionally, the monoamine oxidase (MAO) activity was analysed in the hypothalamus. 2. The DOPAC + HVA/DA ratio was increased in the striatum in all treatment groups. However, the synthesis rate of DA was significantly increased only in the methandrostenolone treated group. 3. The 5-HIAA/5-HT ratio was increased in all treatment groups in the hippocampus, in the frontal cortex in the methandrostenolone-treated animals and in the hypothalamus in the testosterone- and oxymetholone-treated rats, while the 5-HT synthesis rate was not affected by the AAS-treatments. 4. The MAO-A activity was increased in the oxymetholone-treated rats while the other treatment groups were unaffected. The MAO-B activity was not changed. 5. The results indicate that relatively high doses of AAS increase dopaminergic and 5-hydroxytryptaminergic metabolism in male rat brain, probably due to enhanced turnover in these monaminergic systems.

Behavioural anxiolytic effects of low-dose anabolic androgenic steroid treatment in rats.

The use of anabolic androgenic steroids (AAS) in supratherapeutic doses has been associated with aggressive behaviour as well as with severe affective and psychotic symptoms. These symptoms usually follow a chronic exposure for several months. However, AAS also may have milder effects with hypomania-like features such as an increase in confidence, energy and self-esteem. We have studied the short-term effects on male rat behaviour in a modified open-field test of the AAS Metenolon administered three times at a low dose (0.01 mg/kg/week x 3). The control rats showed indications of increased timidity and aversive learning following retesting, a reaction that was absent in the AAS-treated rats. The AAS-treated rats showed less fear or anticipatory anxiety compared to control animals. Furthermore, the suppressed marking behaviour and altered morphological allometric relationships were compatible with a modified social and sexual competence in the AAS treated rats.

Histologic appearance of fractured thyroid cartilage and surrounding tissues.

Histological appearances of the fractured superior horns (SH) of the thyroid cartilage and their surrounding tissues were reviewed, with particular reference to signs of vital origin of the fracture. Twenty-nine autopsies with either histories or findings indicating asphyxial neck compression, with a total of 39 fractured SHs, and three autopsies with history of suicidal jump from height with a total of two SH fractures, were examined. Fifteen autopsies with finding of 19 artefactually fractured SHs while removing neck organs at autopsy were used as controls. In the cases of neck compression and victims of jump from height haemorrhages, retraction of fractured SH fragments with invagination or squeezing of the perichondrium, contraction bands, contraction band necrosis and 'opaque fibres', in the adjacent muscle fibres could be seen. Fibrin deposition and/or leucocytic reaction were noted in cases where circumstances of death indicated prolonged death struggle (as in incomplete hanging, resuscitation or homicidal neck compression). However, retraction of fractured fragments and invagination of perichondrium between artefactually fractured SH fragments were observed in both control cases and cases with antemortem trauma to the larynx. Many of these histological findings, including haemorrhages and fractures had not been evident at gross examination. We conclude that histological examination of SHs may not only uncover macroscopically overlooked injuries but also may facilitate the clarification of an injury's vital origin.

Fatal intoxication as a consequence of intranasal administration (snorting) or pulmonary inhalation (smoking) of heroin.

In recent years we have noticed an increasing proportion of mortalities resulting from an overdose of heroin that involve routes of administration other than injection. Of 239 cases of fatal heroin intoxication examined at our department during the period 1997-2000, 18 deaths were associated with non-parental administration. Seven of these fatalities were experienced heroin users who had begun to use more sporadically, seven were recreational "party-users", while the remaining four persons had relapsed into heroin use following long periods of abstinence. The median blood morphine concentration of these non-injectors was 0.095 microg/g (range: 0.02-0.67 microg/g), significantly lower than that of the injectors. Concurrent use of alcohol, other illicit drugs and/or pharmaceutical preparations was observed in 17 of the 18 cases. However, there were no statistically significant differences between the victims of heroin intoxication by injection or by other routes with respect to the proportion who had simultaneously consumed alcohol or benzodiazepines. Pathological alterations like lung fibrosis, liver cirrhosis, endocarditis, etc. were not found to play a significant role in any of the 18 mortalities. We conclude that snorting or smoking heroin probably involves a reduced risk of obtaining high blood concentrations of morphine but still constitutes a considerable risk of lethal outcome due to high variability in blood concentrations. Furthermore, decreased tolerance resulting from periods of reduced or sporadic use appears to be an important risk factor in connection with heroin overdosing by snorting or smoking, which indicate that some heroin addicts may inaccurately assume that these routes of administration are safe when resuming their use of heroin after a period of abstinence.

Alzheimer changes are common in aged drivers killed in single car crashes and at intersections.

With increasing age, diseases affecting the cognitive functions are more frequent. These diseases may increase the risk for fatal car crashes. We analyzed the frequency of neuropathological alterations characteristic of Alzheimer's disease (i.e. neuritic and diffuse plaques, and neurofibrillary tangles) in two association areas of the brain, parietal and frontal cerebral cortex, from 98 fatally injured aged drivers. In the age groups of 65-75 and over 75 years of age, 50% and 72% of the drivers, respectively, had neuritic plaques in either parietal and/or frontal cortex. In 14% of all killed drivers the number of neuritic plaques reached the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) age-related histologic score C, which indicates the diagnosis of Alzheimer's disease (AD), and an additional 33% had score B, which suggests the diagnosis of AD. Neuropathological AD changes were most common in the brains of drivers killed in single vehicle crashes, followed by multivehicle crashes at intersections and least common in multivehicle crashes elsewhere, but the differences did not reach statistical significance. In a great majority (80-85%) of cases the killed aged driver was the guilty party of the crash. The results imply, that incipient AD may contribute to fatal crashes of aged drivers, and therefore the forensic autopsy of these victims should include neuropathological examination.

Cause and manner of death among users of anabolic androgenic steroids.

Medicolegally investigated deaths among 34 male users of anabolic androgenic steroids (AAS) are described. Nine persons were victims of homicide, 11 had committed suicide, 12 deaths were judged as accidental and 2 as indeterminate. In two cases of accidental poisoning, the levels of pharmaceuticals and illicit drugs were considered too low to be the sole cause of death and AAS was considered part of the lethal polypharmacia. Chronic cardiac changes were observed in 12 cases. In two cases of accidental poisonous deaths, these changes were regarded as contributory cause of death. Homicides, suicides, and poisonings determined accidental or indeterminate in manner were related to impulsive, disinhibited behavior characterized by violent rages, mood swings, and/or uncontrolled drug intake. The observations in the present study indicate an increased risk of violent death from impulsive, aggressive behavior, or depressive symptoms associated with use of AAS. There are also data to support earlier reports of possible lethal cardiovascular complications from use of AAS. Furthermore, a contributing role of AAS in lethal polypharmacia is suggested. Finally, the observations indicate that use of AAS may be the gateway of approach to abuse of other psychotropic drugs.

Sudden unexpected death in a female fitness athlete, with a possible connection to the use of anabolic androgenic steroids (AAS) and ephedrine.

The use of anabolic androgenic steroids (AAS) has been associated with different adverse effects, some of which potentially lethal. Most users of AAS are male, but the prevalence of such use appears to be increasing in females. Here we present a sudden unexpected death in a female fitness athlete with a possible connection to use of doping agents.

Anabolic androgenic steroids and violence.

OBJECTIVE: To scrutinize the criminal career among users of anabolic androgenic steroids (AAS) with focus on a possible relationship between use of AAS and violent offences. METHOD: Prospective longitudinal follow-up of police records concerning known users of AAS. RESULTS: The present study describes five young men who started to use AAS with the primary motive of gaining muscle mass and strength and who subsequently got involved in criminal activities, including violent offences. One person showed deviant behaviour suggestive of conduct disorder at an early age. The other persons appeared to have low self-confidence, but had not been acting out during early adolescence. CONCLUSION: Use of AAS may constitute an increased risk of developing an antisocial life style with involvement in criminal violence.

Anabolic androgenic steroids and suicide.

Eight medicolegally examined cases of suicide, in 21- to 33-year-old males, with a history of current or discontinued use of anabolic androgenic steroids (AAS) are described, five of which were approached by means of systematic interviews with survivors. Five suicides were committed during current use of AAS, and two following 2 and 6 months of AAS withdrawal. In one case it was unclear whether the suicide was committed during current use or after recent discontinuation. In five cases family members had noted depressive symptoms associated with AAS withdrawal. After prolonged use, four persons had developed depressive syndromes. Two subjects exhibited hypomania-like symptoms during the time immediately preceding the suicide. Four subjects had recently committed acts of violence while using AAS. In some cases these acts exacerbated the subjects' problems in personal relationships or at work, which in turn seem to have precipitated the suicides. Only one of them had experienced suicidal ideation before starting to use AAS. In all cases examined by psychological autopsy, risk factors of suicidality likely to be independent of the use of AAS were present. In conclusion, this study presents data suggesting that psychiatric symptoms and conflicts resulting from long-term use of AAS may contribute to completed suicide in certain predisposed individuals.

High-dose anabolic androgenic steroids modulate concentrations of nerve growth factor and expression of its low affinity receptor (p75-NGFr) in male rat brain.

The effects of treatment with a high dose of nandrolone or testosterone on nerve growth factor (NGF) levels and NGF low-affinity receptor (p75-NGFr) distribution in the brain were analyzed. Nandrolone, subcutaneously injected in rats for several weeks, caused an increase of NGF levels in the hippocampus and septum and a decrease in the hypothalamus. The number of p75-NGFr-immunoreactive neurons and the p75-NGFr expression levels were reduced in the septum and vertical and horizontal Broca's bands. Testosterone injections caused an increase of NGF levels in the hippocampus, septum, and occipital cortex and induced an upregulation of p75-NGFr in the forebrain NGF target regions. This testosterone effect suggests that nandrolone and testosterone affect brain NGF target cells by a different mechanism(s). Nandrolone may interfere with NGF transport and/or utilization by forebrain neurons, causing an altered p75-NGFr expression and NGF accumulation as a consequence. Since NGF is known to maintain forebrain neurons and to regulate neurobehavioral functions, including memory, learning, and defensive behavior, it is possible to hypothesize that this neurotrophin may play a role in the mechanism of action of anabolic androgenic steroids (AAS) in the brain and be associated with endocrine and behavioral dysfunctions occurring due to AAS abuse.

Risk factors for sudden unexpected death in epilepsy: a case-control study.

BACKGROUND: Sudden unexpected death is substantially more common in people with epilepsy than in the general population. Our objective was to investigate the association between some clinical variables and sudden unexpected death in epilepsy (SUDEP) to identify risk factors. METHODS: This nested case-control study was based on a cohort of people aged between 15 and 70 years, who, during 1980-89, had been admitted to and discharged with a diagnosis of epilepsy from any hospital in the county of Stockholm. The study population was followed up through the National Cause of Death Register until Dec 31, 1991. Cases were individuals who had died, with a diagnosis of epilepsy registered on the death certificate, and who after review of medical and necropsy records were found to meet our SUDEP criteria. Three control participants, who were living epilepsy patients matched for age and sex, were selected from the same cohort for each case. All medical records were examined. Clinical data were collected and analysed on a predesigned protocol. FINDINGS: 57 SUDEP cases were included, of whom 91% had undergone necropsy. The relative risk of SUDEP increased with number of seizures per year. The estimated relative risk was 10.16 (95% CI 2.94-35.18) in patients with more than 50 seizures per year, compared with those with up to two seizures per year. The risk of SUDEP increased with increasing number of antiepileptic drugs taken concomitantly--9.89 (3.20-30.60) for three antiepileptic drugs compared with monotherapy. Other major risk factors were early-onset versus late-onset epilepsy (7.72 [2.13-27.96]), and frequent changes of antiepileptic drug dosage compared with unchanged dosage (6.08 [1.99-18.56]). The association between SUDEP risk and early onset, and SUDEP risk and seizure frequency, was weaker for female than for male patients, whereas frequent dose changes showed a stronger association in female patients. INTERPRETATION: Our data suggest that SUDEP is a seizure-related event, although the pathophysiological substrate that predisposes individuals to SUDEP may be established at an early age, and there may be some sex differences. Improvement of seizure control and possibly the avoidance of polytherapy may be ways to reduce the risk of SUDEP.