1 Infectious Diseases Cluster, Department of HIV and STD Research, Municipal Health Service Amsterdam, Amsterdam, the Netherlands.
2 Department of Epidemiology and Information, Municipal Health Service Utrecht, Utrecht, the Netherlands.
Received for publication May 10, 2004; accepted for publication August 24, 2004.
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ABSTRACT |
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behavior; fatal outcome; harm reduction; longitudinal studies; substance-related disorders
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INTRODUCTION |
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Generalization of research findings on long-term outcome is hampered by differences in drug-using patterns, in drug-related policy across countries, and in definitions of abstinence. Moreover, most long-term studies recruit participants through abstinence-oriented treatment centers or criminal justice systems. In Amsterdam, the Netherlands, approximately 6070 percent of heroin users annually receive some type of methadone treatment, mainly in programs that aim not to achieve abstinence but to minimize the harm associated with use of illicit drugs (15). Most participants included in the present study were recruited from these easy-access ("low-threshold") programs (15). However, their study entry and follow-up were independent of any treatment involvement. In the current paper, we describe long-term outcomes regarding death and abstinence among drug users recruited in such a setting of harm reduction.
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MATERIALS AND METHODS |
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Participation in the ACS is voluntary, and written informed consent is obtained prior to data collection. Participation involves returning every 4 months for follow-up visits. At every visit, a standardized questionnaire on drug use and risk behavior is administered, and a blood sample is drawn for human immunodeficiency virus (HIV) testing. In cases of loss to follow-up (e.g., because of leaving Amsterdam or refusal), ACS staff check the participants vital status at regular intervals with the population register in the participants town of residency. In cases of death, the cause of death is ascertained by examining hospital records or obtaining information from the coroners office.
Of the 1,487 ACS participants enrolled during or after 1985 but before January 2001, we selected 1,237 who were still in follow-up on March 1, 1989, or entered the ACS thereafter. From that date, the questionnaire asked about the calendar year of initiation of regular (at least three times per week) use of illicit drugs. Of these persons, we only included 899 Dutch nationals, because vital status could not be validly determined for foreigners. Further analyses demonstrated comparatively high mortality rates and low abstinence rates among the excluded Dutch nationals for whom ACS follow-up was terminated before March 1, 1989 (n = 145). This implies that, in the present analysis, long-term outcome was probably biased in a favorable direction.
Assessment of drug use, type, and frequency
At ACS entry, frequency of use of heroin, cocaine, and/or amphetamines for the preceding 6 months was recorded; at follow-up visits, frequency of drug use was recorded for the time since the preceding visit. At every visit, drug use was categorized as none (i.e., fully abstinent), monthly (i.e., three times per month or less often), weekly (i.e., at least once per week but not every day), or daily. July 1 of the reported calendar year of starting regular use was regarded as the starting point of a participants drug-using career. In a former ACS analysis, it was found that drug users give valid self-reports in a setting where no clienthealth-care-provider relationship is present (16).
Study dropouts
To adjust for the possible bias associated with selective loss to follow-up, we traced a number of participants (188 out of 899) who had dropped out of the study for at least 1 year on June 30, 2001, or September 30, 2001. These participants had not explicitly refused future contact at the time of their withdrawal ("traceable dropouts"). Tracing was done by means of the population register. A questionnaire on current frequency of drug use was sent by mail; if necessary, a reminder was sent. The number of dropout questionnaires that were filled out and returned was 43. Another group of ACS dropouts (58 out of 899) explicitly refused any future contact at the time of their withdrawal ("untraceable dropouts"). All data on the drug-use patterns of dropouts collected during their ACS follow-up were included in the analysis.
Statistical analysis
Mortality
Mortality rates over time since initiating regular use of illicit drugs were calculated by means of Kaplan-Meier product-limit survival estimates for left-truncated data. Survival times were left-truncated at the time of ACS enrollment, since participants entered the ACS after a time interval following their initiation of drug use. The survival times of participants who had been recruited before March 1989 were left-truncated at March 1, 1989, since these participants were not observable at risk of death between their ACS entry and March 1989. However, their data on drug-use patterns collected between study entry and March 1989 were included in the analysis on abstinence (see below). Among HIV-infected participants, deaths were classified as being related to HIV or acquired immunodeficiency syndrome (AIDS) when they did not result from an injury such as overdose, violence, or suicide. Deaths due to such causes and all deaths among non-HIV-infected participants were classified as not related to HIV/AIDS. To avoid a downward biasing of mortality rates due to reporting delay, ACS data files up to January 2003 were used, but the survival times of those alive and in follow-up were censored at the end of July 2002. The survival analysis was performed with EGRET, version 2.0.1 for Windows (Cytel Software Corporation, Cambridge, Massachusetts).
Abstinence
For the present analysis, we divided the individual drug-using-career time scale into 4-month intervals since initiation of regular drug use. The individual drug-using career began in July 1 of the reported calendar year of starting regular use of illicit drugs and ended at death or July 2002. The frequency of drug use, as reported during an ACS visit, was assigned to the end of a predefined 4-month interval that immediately preceded the ACS visit. This could be done for those predefined 4-month intervals to which the data collected in the ACS referredthat is, from 6 months before ACS enrollment to the last ACS follow-up visit or July 2002. In case of a longer interval between two consecutive ACS visits (e.g., 1 year), the data reported at the first visit following such an interval were assigned to all of our predefined 4-month intervals between those two ACS visits.
We estimated the point prevalence of abstinence at the end of all predefined 4-month intervals along the drug-using-career time scale, using three definitions: 1) no use of illicit drugs and no use of methadone since the last visit; 2) no use of illicit drugs, leaving use of methadone out of consideration; and 3) no use of illicit drugs or occasional use only, leaving both monthly use of illicit drugs (or less) and use of methadone out of consideration. For the present analysis, an episode of abstinence was defined as being abstinent minimally since the last visit (i.e., 4 months). A participant who relapsed after an episode of abstinence was reclassified as nonabstinent after that episode. Only participants who were alive and in ACS follow-up at a certain time point in their drug-using career contributed to the estimation of the point prevalence of abstinence for that time point along the career time scale. This resulted in a series of cross-sectional snapshots of the study group based on a varying number of contributing participants. Analyses on abstinence were performed with SAS, version 6.12 for Windows (SAS Institute, Inc., Cary, North Carolina).
We also estimated the point prevalence of abstinence according to definition 1, 2, or 3 with the same data entered into a logistic regression model for binomially distributed data, using the method of generalized estimating equations (GEE) to take into account the correlation between data on the same participant over the course of follow-up (17, 18). For any temporal distance between two of our predefined 4-month intervals (i.e., a distance of 4 months, 8 months, 12 months, etc.), a separate correlation coefficient was estimated. This resulted in a covariance structure with minimal assumptions (stationary M-dependent). Besides time since initiation of drug use and duration of drug use at ACS entry, age at starting regular drug use, gender, calendar year of initiation, and ethnicity were added to the model. A linear relation between time since initiation and the logit of the point prevalence of abstinence was assumed.
Potential sources of bias
Late entry into the study. Partici-pants entered the ACS with various time intervals since initiation of drug use. Because ACS entry was probably associated with an episode of more intense drug use and a lower likelihood of abstinence at that time, and recruitment of participants took place continuously and at various stages since initiation, the prevalence of abstinence might have been underestimated at any point along the drug-using-career time scale. In the descriptive analysis, we took into account this possible source of bias due to continuous selective inflow by stratifying the data according to the participants number of years since drug initiation at the time of his/her ACS entry. We reasoned that the data from participants enrolled comparatively soon after their initiation of drug use permitted the most valid estimation of the prevalence of abstinence at any time point. In the GEE model, however, data from participants who entered the ACS after longer intervals since initiation might still have contributed to the estimation of a time trend in the prevalence of abstinence along the drug-using-career time scale. Additionally, in the GEE model, we included duration of drug use at ACS entry as a covariate in order to meet the biasing effect of continuous selective inflow of drug users during an episode of intense use. Including this covariate in the GEE model made it possible to predict the abstinence rates of a "virtual" cohort of drug users ideally recruited at their time of drug-use initiation.
In addition, we excluded data on frequency of current drug use during the 6-month interval preceding the ACS entry visit from all estimations, in order to further attenuate the possible biasing influence of more intense drug use associated with ACS entry.
Loss to follow-up. The estimated prevalence of abstinence at any time point was adjusted for the possible effect of selective dropping out. This was done by re-allocating the number of dropouts at a certain time point along the drug-using-career time scale over the categories "abstinent" and "nonabstinent." Re-allocation was conducted according to the frequency distribution with respect to current drug use as observed among the dropouts who were traced and returned the dropout questionnaire (n = 43; see table 2). In addition, sensitivity analyses were performed with assumptions of extreme prevalence (i.e., 0 and 100 percent) among all dropouts for whom no dropout questionnaire was available (n = 203). This was done to assess the maximum influence of loss to follow-up on the results.
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RESULTS |
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Determinants of abstinence
A lower age at initiation, a recent calendar year, and a non-Western-European ethnic origin (mainly Surinam and Netherlands Antilles) were unfavorably associated with a lower estimated prevalence of abstinence (table 4).
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DISCUSSION |
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For a sound interpretation of the presented data, sources of potential bias must be acknowledged. First, the majority of participants entered the ACS a considerable number of years after their initiation of drug use. Thus, mortality rates might have been underestimated, since participation was conditional on being alive at the time of study entry (or being in follow-up in March 1989). We addressed this bias by left-truncating the individual survival times, leaving out of consideration the time during which the participant was not observable at risk of death. However, because hardly any participant was enrolled immediately after the initiation of illicit drug use and no deaths were registered during the first 5 years of the drug-using time scale, the estimated mortality rates may still be regarded as being biased downwards. When assuming that the mortality rates as observed from 5 years onwards are similar to the (probably) unobserved mortality rates during the very early stages of the drug-using career, the time axis of the survival graph (figure 1) may be shifted to the right by relating the figures for the 25-year time point to the 20-year time point. This probably yields a more reliable estimate of mortality (38 percent instead of 27 percent at 20 years). Second, "late entry into the study" also implied that the prevalence of abstinence at any time point was underestimated. Therefore, number of years since initiation at ACS entry was included as a covariate in all analyses (see Materials and Methods). Third, study withdrawal in association with high rates of abstinence may cause a further underestimation of the prevalence of abstinence. We addressed this objection by reallocating all dropouts on the basis of current drug use reported by a number of traceable ACS dropouts (table 2). Furthermore, we performed a sensitivity analysis to assess the maximum uncertainty range around the estimations associated with loss to follow-up (table 3).
In a meta-analysis by Cramer and Schippers, data from a large number of follow-up studies on drug-using career outcome were summarized (6, 9, 11). They indicated that approximately 20 percent of the subjects had died after 20 years; among those who were alive, 50 percent had become abstinent and the other 50 percent were still using drugs either on a daily basis or in a less problematic way. The studies were all conducted before the outbreak of HIV, which had a major impact on mortality among injecting drug users. The 16 percent rate of mortality due to HIV/AIDS-nonrelated causes after 20 years that we found in the present study may be regarded as comparatively low but was probably biased downwards (see above). Right-shifting of the time axis by 5 years may yield a mortality rate comparable to that of Cramer and Schippers (21 percent at 20 years; see above). In other Dutch studies conducted before or after the spread of HIV, mortality rates found among drug users in the Netherlands were low in comparison with other countries (19, 20). Since the original aim of the ACS was to monitor the HIV epidemic, participants in the ACS may represent a sample of drug users who experience a higher risk of death in association with a high-risk lifestyle than persons in other drug-using populations in the Netherlands.
The estimated prevalence of abstinence found in our study seems to be less favorable than that found in other studies (6, 911). One possible explanation is that the majority of studies conducted in the 1970s and 1980s involved heroin addicts, while later studies involved users of multiple drugs (12). Cocaine use has increased during the past several decades, and it has been reported that cocaine use is related to a poor treatment outcome, a high relapse rate, and continued use of heroin (2123). We found a trend towards a lower prevalence of abstinence with increasing calendar year of initiation. In-depth analyses, in which the types of drugs used and other drug-related characteristics such as intravenous administration are handled as time-dependent variables, are required in order to obtain insight into important determinants of abstinence and relapse and associated calendar-time trends.
We found a higher prevalence of abstinence associated with a higher age at initiation of drug use, especially when the more stringent definitions of abstinence were used (table 4). This finding in itself supports Winicks theory of the "natural history" of addiction, which is closely related to the life cycle of the addict and the problems associated with adolescence (8). However, the high mortality and low abstinence rates found long-term in the present study do not suggest that "maturing out" is operative among the majority of persons who become severely addicted, as was suggested by Winicks study. Other studies, preferably studies including qualitative interviews, are needed in order to better understand individual motives for continuation of drug use at older ages and whether depraved living conditions may hamper a naturally occurring "maturing out" and associated rehabilitation. On the other hand, the present findings do not rule out a tendency towards less problematic or better "controlled" use in the course of an addiction career (24). This would require analyses not in which drug-use patterns were dichotomized in terms of use versus abstinence but in which a more refined categorization from intense use towards moderate use and abstinence was employed.
Some limitations of our study require consideration. First, our results primarily reflect the addiction careers of persons with opiate addiction and full access to low-threshold methadone treatment programs. Second, the ACS data did not permit us to make a distinction between enforced abstinence during imprisonment or hospitalization and internally motivated abstinence. Precise coincidence of a prison or hospital episode with the interval between two ACS visits is unlikely, and high rates of (noninjecting) use of heroin and cocaine have been reported in Dutch prisons (25). Thus, the influence of episodes of enforced abstinence on our estimated prevalence of abstinence may have been limited. Next, estimations of point prevalence along the drug-using-career time scale do not provide insight into the individual conversion between intense use and abstinence (2). In-depth analyses of the ACS data for the study of individual transitions in frequency of drug use and their associated determinants are currently under way. Finally, the present analysis does not provide insight into how persons with a history of severe addiction became addicted following their first use of illicit drugs. Evidence indicates that initial use of illicit drugs does not necessarily degenerate into loss of control and a marginal lifestyle (26). Further studies are required in order to explore the drug-using careers of persons who become severely addicted versus the careers of those who manage to keep their use within bounds.
In conclusion, we found a favorable trend towards abstinence in this Dutch cohort of illicit drug users. However, the high mortality rates and the low prevalence of abstinence among those who remained alive over the long term indicate that the concept of natural recovery or "maturing out" to a drug-free state does not apply to a substantial portion of the addict population. An older group of drug users who are addicted primarily to opiates may increasingly attract attention from public health service providers in the Netherlands (27). Studies on the primary prevention of addiction and the prevention of relapse deserve high priority.
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ACKNOWLEDGMENTS |
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The authors thank Dr. Ronald B. Geskus and Prof. Dr. Roel A. Coutinho for critically reviewing an earlier version of this article. The authors are indebted to Else te Brake for designing the questionnaire and organizing data collection for the dropout study and to research nurses Maja Totté, Ans Snuverink, and Joke Bax for daily administration of the ACS. The authors also thank Lucy Phillips for final editorial review.
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NOTES |
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REFERENCES |
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