The results of the study confirm the long-lasting increased risk for premature death in drug dependent patients. Although the largest risk of drug related death occurred during the first 15 years, the level of such causes of death continued to be high throughout and above the 37-year follow-up period, and premature mortality remained significantly increased up to the age of 69. This stresses the chronic nature of drug abuse and dependence. The age at drug related death in the cohort was 35.7 years, which is close to the mean age of drug induced deaths in some recent European studies [29
Male gender, opiate and barbiturate use at first admission, as well as neurosis were risk factors for premature drug related death and alcohol use for non-drug related death. Premature mortality was lower in women over time, an observation previously reported in other Scandinavian studies of drug users [4
]. Earlier studies reflecting differences between sexes are not conclusive [3
]. However, mortality in women in this study was higher in the younger age groups than for men, even though, with regard to the proportion of substances, the age at first use of drugs and age at first admission showed a similar pattern regardless of sex. The relatively lower body weight in women in combination with a propensity to use doses similar to those used by men, might be one explanation for the greater risk of fatal accidental intoxication.
In the European population aged 15 to 49 years, between 10% and 23% of the mortality is attributed to opioid use [26
]. Not surprisingly, opiate use predicted drug related death in the studied cohort. In a meta-analysis of mortality the death rates among opiate abusers were about 13 times the norm for their age [31
] and 2.4 times higher compared to those of amphetamine users [3
]. Fifty-nine percent of the cohort was poly drug users. Mixing several drugs poses a real danger, since non lethal doses of heroin can become lethal in combination with alcohol and sedatives such as benzodiazepines[32
]. This study started when barbiturate abuse was common. Barbiturates caused several drug related deaths, mostly in combination with opiates. Both barbiturates and opiates cause respiratory depression which is the major mechanism of opiate death [33
]. The use of stimulants had no impact on premature mortality in this cohort. Stimulants do not have the same lethal effects as opiates, but, according to a study of Gossop et al [15
], the use of amphetamine in combination with opiates increased the risk of mortality.
Despite the fact that cannabis use in this study did not reflect "recreational use" but a chronic abuse persisting over several years, the association between cannabis use and drug related death was negative. This finding remains in the present cohort even after controlling for the use of other drugs, and support the results of other studies indicating that cannabis is not associated with increased premature mortality [34
]. It is possible that a passive lifestyle associated with cannabis use in heavy drug abusers exposed these persons to a lesser risk of violent deaths as suicide, homicide and traffic accidents. In support of this suggestion, cannabis abusers from a later cohort from the same hospital showed less risk of committing property and violent crime compared with other types of drug addicts [19
]. In contrast, opiate/heroin abuse requires many activities related to pursuing drugs and money by stealing, prostitution or, in some cases, violent offences and, as Hser et al stated in their follow-up study: "heroin addicts also have extensive involvement in criminal activities even into older age" [[36
], Pp 308]. However speculative, future research will need to address if cannabis use is also generally associated with lowered risk for overdoses among poly drug abusers.
To our knowledge, no other cohort study of patients with different types of abuse (opiates, amphetamine/stimulants, cannabis, barbiturates, sedative/hypnotics and hallucinogens) has tracked causes of death over almost four decades. Cohort studies of mortality in opiate addicts showed a higher percentage of deceased persons, 58% in a Danish study [9
] and 49% in the Californian study by Hser et al [36
] compared to the findings of 36% deceased in the present cohort, which included opiates as well as other drugs. Despite variations in time to follow-up, we conclude that the drug use pattern has the strongest impact on drug related deaths.
Half the cohort was diagnosed with psychiatric disorders at first admission. The prevalence of co-morbidity in substance abusers has been reported to increase over the last two decades or longer [37
]. The rate of psychoses was however, similar between the present cohort and a later cohort of patients treated from March 1978 to June 1995, while depressions, anxiety and personality disorders became more prevalent [38
]. In our cohorts of drug abusers the increase of co-morbidity reflected the more systematic application of diagnostics rather than a general increase in prevalence rates [38
Two patterns remained in the analysis; neurosis predicted drug related premature death and chronic psychoses did not. The explanation is that only a few patients with chronic psychoses in this study used opiates or amphetamine intravenously. Still, the prevalence of psychotic disorder in this cohort was much higher than in the Lundby population study [39
] conducted in the same region. The prevalence of psychoses was at that time 4.2% in the local suburban general population compared to 14.4% in this cohort. The neurosis group included mainly patients with depressive and anxiety symptoms, constituting 15% of the cohort compared to a prevalence of neurosis of 0.4% in the general population [40
]. This group of patients could be expected to use more alcohol and sedatives/hypnotics, prescribed or not, for alleviating psychological suffering as a kind of "self-medication", which in combination with opiates increases the risk of premature death. High levels of anxiety have been shown to increase the risk of premature mortality, and regular use of benzodiazepines predicted overdoses in a prospective study of substance abusers in the UK [15
]. It is possible that intoxication among suicides may have contributed to the association between neurosis and drug-related premature death. However, given the sample size, having more than two risk outcomes for the competing risks model was not feasible. Future research should investigate this question using larger cohorts.
Some researchers found no association between mortality and psychiatric conditions [9
], while others suggest that psychopathology causes increased premature mortality [3
]. Instead of discussing the general impact of the co-morbidity of psychiatric disorders on mortality in drug dependent persons, the case might be that various psychiatric disorders have a differential influence on causes of premature death.
Somatic diseases constituted 70% of the non drug related deaths, and violent death the remaining 30% [41
]. In this study alcohol use predicted non drug related deaths. Alcohol dependence is known to contribute to a wide range of somatic diseases, such as liver failure, cancer, coronary diseases, stroke and diabetes. A J-shaped relationship between alcohol and total mortality was confirmed in both men and women in a meta-analysis from 2006 [42
]. While moderate consumption of alcohol was inversely associated with total mortality, higher consumption was associated with increased mortality. Illicit drugs contributed to death for those who died from liver failure associated with viral hepatitis and/or chronic alcoholism and for those who died from HIV or HIV-induced opportunistic infections and cancers (AIDS).
Among the strengths of this study are the long observation period and the fact that the cohort was reasonably representative for drug abuse patterns in the southern region of Sweden at the time. According to data from the national case finding study from the end of the 1970s, the cohort was reasonably similar in drug use, age and incidence of intravenous abuse to the population of substance abusers at the time [23
]. The slight overrepresentation of women in the clinical cohort was typical for a more pronounced treatment-seeking behavior in women substance abusers compared to substance abusing men [2
]. In the substance abusing population in Sweden at the time some 25% were women, while in clinical settings women constituted 33% [24
]. This was the case also in this cohort.
Causes of death were coded according to ICD-10 classification by a senior consultant physician and an associate professor of forensic medicine, a procedure which eliminated inconsistencies in recording drug related deaths, which are often found when data from national cause of death registers are used as only source. This procedure increased the rate of drug related death by 35% compared to register data only.
There are however some limitations. The first is that the cohort design by necessity provides a more limited number of subjects for analysis, thus restricting its statistical power more than is the case in large epidemiological samples. Secondly, we have not been able to include important aspects of the patients life-situation. Premature death may be predicted by life events like traumas, separation and loss of close friends and relatives, data known to be associated with suicide. Such data were however seldom registered in the patient records in a systematic fashion and have not been included in the analysis.
Thirdly, patients' behavior during treatment as well as their discharge status may be potential indicators of long term risk of premature death. Dropout from treatment is known to increase the risk of death by overdose in opiate abusers [15
]. In this study however no overdose was diagnosed in the few patients who died within three months after premature termination of treatment and no association was found between dropout and dominant substance of abuse. Based on the available data, we cannot determine if discharge status at first admission is a predictor of premature death many years later.
Finally, the categorization of co-morbid psychiatric disorders into three broad groups is another limitation. The psychiatric nomenclature used at the time when the patients entered the cohort (ICD-8) might be considered somewhat dated by today's standards. Neurosis, for example, is today replaced by more refined and specific diagnoses of depression and anxiety disorders. Personality disorders had lower prevalence in the cohort than is the case in more recent clinical materials of substance dependent persons [19
]. It is likely that the low prevalence reflected the critical stance of the 1970s drug addiction treatment towards personality assessment in general and psychiatric diagnostics in particular, as articulated by, for example, Thomas Szasz [43