Factors associated with the transition from abuse to dependence among substance abusers: Implications for a measure of addictive liability
Introduction
Estimation of drugs’ addictive potential has helped clarify how drug use can lead to drug use-related disorders and in the U.S. has informed drug control procedures as well as Food and Drug Administration (FDA) policy. Impressive strides have been made in the last century toward understanding differences in the addictive potential between substances. However, important gaps in the literature remain (Balster and Bigelow, 2003). For example, addictive liability research is mostly based on studies conducted in laboratory settings. Substances that are not developed by pharmaceutical manufacturers, substances that are not regulated by the FDA (e.g., inhalants), “street” uses of prescription medications, settings where drug abuse takes place, and dosages of medications often do not match laboratory settings. In a conceptually related literature, individuals’ liabilities to addiction have been researched in terms of the factors that contribute to persons’ risk for addiction (Tarter et al., 2002) as well as factors that contribute to transitions through levels of addiction (Hasin and Grant, 2004, Ridenour et al., 2003, Schuckit et al., 2001). However, literatures focusing on the addictive liability of drugs and on persons’ liability to addiction have evolved largely in parallel arenas. A measure of substances’ addictive liabilities that could be used in research regarding individuals’ liability for addiction might provide a more widely used bridge between the two literatures.
This study was an initial validity test of a measure that might be useful for post-marketing surveillance of pharmaceutical substances as well as addictive potential research of non-FDA regulated substances, using large samples, or with etiological or clinical foci. The term “abuse potential” is used to describe the concept of a drug's potential to generate addiction in users of the drug. Because the term “abuse” refers to a specific psychiatric diagnosis and the abuse diagnosis is included in the analyses of this paper, the term “addictive potential” is used henceforth. Moreover, the term “abuse potential” refers to the potential for experiencing any of a number of problems due to drug use; the measure examined in the present study is theoretically different from “abuse potential” because it is composed of levels of addiction.
Balster and Bigelow (2003) summarize recent calls for clinically relevant evaluations of addictive liability by arguing that “epidemiological experience—the extent of actual abuse—is the ultimate gold-standard criterion index that other approaches are trying to predict” (p. S26) (Ator and Griffiths, 2003, Fischman and Foltin, 1991, Griffiths et al., 2003). Abuse, defined as DSM-IV substance-related abuse diagnoses, appears to not provide an adequate gauge of addictive potential. Arfken and Cicero (2003) reported that of the 932 Medwatch surveillance reports that were suggestive of tramadol abuse, only 30% could be definitely diagnosed as at least meeting DSM-IV abuse criteria (some users met criteria for dependence). Follow-up data indicated that abuse diagnoses turned out to be “mostly due to transient experimentation” rather than clinically significant abuse or dependence. Ridenour et al. (2003) argued that the environmental element of each abuse criterion makes the abuse criteria impure measures of an individual's misuse of the drug. To illustrate, the abuse criterion of substance use leading to social problems might be avoided by socializing only with persons who misuse substances or do not view drug use as problematic. Using the prevalence of substance use-related dependence diagnoses as an alternative metric for the drug's addictive liability also has limitations. Users of different drugs differ for reasons that do not reflect drug characteristics such as availability, legality, or social acceptability. Hence, alcohol users differ considerably from opiate users and prevalence estimates of dependence for different drugs also are likely to be influenced by factors other than characteristics of the drug. A third alternative for estimating addictive potential of different substances in people is the length of time from first use to the onset of a disorder (e.g., Ridenour et al., 2003, Wagner and Anthony, 2002); however, time from first use to onset of a disorder has similar shortcomings as using prevalence to estimate addictive potential.
Numerous studies have examined sequences between levels of addiction such as (a) initiating use, (b) onset of criteria and diagnoses, and (c) length of time between levels of drug involvement such as abuse or dependence (Hasin and Grant, 2003; Langenbucher et al., 2004, Mackesy-Amiti et al., 1997, Ridenour et al., 2003, Wagner and Anthony, 2002). These studies largely have been limited to addressing nosological issues; investigation of characteristics that might be associated with the rate of transition through levels of addiction has been neglected. However, results from these studies suggest that a fourth alternative to estimating the addictive liability of substances in people may be the length of time between onset of abuse and dependence (LOTAD). Using abuse rather than use as the threshold to select a baseline sample identifies individuals who have already endorsed certain problems due to their use of substances. LOTAD measures the pace that a drug generates dependence, potentially a reflection of drugs’ addictive liability. It is assumed that a greater addictive liability of a drug is indicated by a smaller time lapse between experiencing abuse and experiencing dependence. Hence, very high addictive liability would be indicated if, on average, people experience dependence at about the same time as experiencing abuse (LOTAD = 0), which might be interpreted as: a person experiences dependence on a drug at about the same time his or her functioning within the environment is impeded by use of the drug.
Results from a recent study of the order of onset of abuse and dependence criteria suggested that LOTAD rank orders substances consistently with the addictive potential of different drugs based on animal studies (Ridenour et al., 2003). The general impression of the addictive potential of different drugs from animal studies is that cocaine and opiates have very high addictive liability, followed by alcohol, and cannabis, respectively (Erdtmann-Vourliotis et al., 1999, Gardner, 1997, Stafford et al., 1998, Winger et al., 1983). Table 1 presents the rank orders of drugs based on the four options for estimating addictive liability of substances in people national estimates of prevalences of abuse and dependence, length of time from initiation to abuse and dependence, and LOTAD using survival curves and configural frequency analysis based on data from Ridenour et al. (2003) findings. The first column of Table 1 indicates the rank order of addictive liability of substances based on impressions from animal studies. The median number of years from use to abuse and the survival curve LOTAD most closely match the rank order of animal studies. Results for alcohol were only partly consistent with hypotheses of addictive liability of drugs for people based on animal studies; alcohol LOTAD was longer than the cannabis LOTAD (the opposite order is expected). Alcohol patterns might deviate somewhat from the hypothesized patterns because of its legality, availability, controlled and known dosage (i.e., proof), or social acceptability. For example, persons who do not even sample other drugs might use or abuse alcohol.
There are a number of advantages to using LOTAD, if it proves to be a valid measure of addictive potential in people. Standard criteria are used for comparisons between drugs, LOTAD is clinical in nature because it is based on DSM-IV criteria, large sample studies and clinical studies of addictive potential could be conducted, LOTAD studies could be conducted with numerous existing datasets, and psychiatric interviews on which LOTAD is based have been translated into numerous languages and psychometric estimates of the translations are available (Cottler et al., 1997, Hasin et al., 1997, Pull et al., 1997, Ustun et al., 1997), and LOTAD may prove useful in etiological research on addictive liability or as a clinical trials outcome measure including research regarding interactions between characteristics of drugs, individuals, and drug ingesting environments (as demonstrated in the present study).
However, there are potential shortcomings to using LOTAD to measure addictive liability. Results from Ridenour et al. (2003) study suggest that DSM-IV substance use-related diagnoses could be improved by developing criteria specifically for each substance rather than basing all substance diagnoses on the Alcohol Dependence Syndrome (Edwards and Gross, 1976). Their argument was partly based the very short time lapses between the abuse and dependence diagnoses for cocaine use and opiate use (which is inconsistent with the DSM-IV intent that abuse diagnosis reflects an earlier stage of addiction than dependence). They also argued that abuse criteria inadequately assess problems related to substance use because they dually require environmental conditions. Sizable proportions of persons with DSM-IV dependence on different substances either do not meet criteria for DSM-IV abuse or experience abuse after dependence (Hasin and Grant, 2004, Ridenour et al., 2003). Moreover, longitudinal studies suggest that many persons who meet alcohol abuse criteria do not later qualify for alcohol dependence (Hasin et al., 1997, Schuckit et al., 2001). For these reasons, some of the analyses used by Ridenour et al. (2003) and the present analyses were designed to include all persons with diagnoses, including those with only abuse or only dependence.
Although the DSM-IV criteria appear less than optimal for diagnoses, using the same criteria across different substances may be useful for comparing substances with regard to their relative addictive liability. For example, the rate of transition from onset of use to abuse and to dependence varies greatly between different drugs (Ridenour et al., 2003, Wagner and Anthony, 2002), and therefore, may provide a technique to measure drugs’ relative addictive liability in people. Further evidence that LOTAD might provide a measure of addictive liability of substances in people was Ridenour et al. (2003) finding that LOTAD was not associated with experiencing a different substance use disorder earlier in life, which suggests that individuals’ vulnerability to addiction has relatively little impact on LOTAD.
In the present study, the validity of LOTAD was tested using hypotheses based on animal and human studies. One hypothesis was that LOTAD will be shorter for persons who initiate use of a drug at a young age than other users (Brook et al., 2002, DeWitt et al., 2000). A second hypothesis was based on the finding that, among animals primed for self-administration of an addictive substance, females consume greater volumes of the substance than males (Cicero et al., 2000, Grathwohl et al., 2001). Hence, it was hypothesized that LOTAD will be shorter in women than men. If LOTAD is shorter in women than men, it would demonstrate that LOTAD might improve measurement of addictive liability above substance because greater prevalences of the disorders occur in men than women (Anthony et al., 1994).
Additional analyses were designed to answer the following research questions. Are LOTAD scores for different substances correlated (based on the hypothesis that LOTAD also measures individuals’ vulnerabilities to addiction across many drugs) or uncorrelated (based on the alternative hypothesis that LOTADs generally measure characteristics specific to each drug)? Are there LOTAD differences between races/ethnicities (no differences were expected)? How much do the characteristics that are associated with LOTAD (e.g., gender, early use of a drug) account for differences in LOTAD between different drugs?
Section snippets
Methods
Data collection, reduction, and storage are detailed elsewhere (Cottler et al., 1995). Hence, only a brief description of the sample and methodology is presented below.
Is LOTAD shorter in women than men?
Table 2 presents the configural frequency analyses results regarding gender differences. Smaller proportions of women (compared to men) experienced abuse before dependence for alcohol, cannabis, and opiates. Moreover, a greater proportion of women (than men) experienced dependence before abuse. Nearly two-fold the proportion of women (compared to men) experienced dependence before abuse related to alcohol and cannabis use.
Fig. 1 presents the abuse and dependence survival curves for women and
Discussion
This is the first study to our knowledge to investigate characteristics associated with rates of progression through levels of addiction. The results reported for drugs in general (Ridenour et al., 2003) were replicated for men and women, early users and other users of the drugs, and African–Americans and Caucasians. Consistent with recent animal studies, being female was associated with shorter LOTAD. The finding that early drug use initiation is associated with shorter LOTAD was expected
Acknowledgements
Thanks to James C. Anthony, Ph.D. and three anonymous reviewers for comments on a previous draft of this manuscript. This investigation was supported by grants from NIDA (DA00430, DA00434, DA15984), NIAAA (AA12111), and NIMH (MH17104). Dr. Compton's work on this study was conducted prior to his appointment at the National Institute on Drug Abuse (NIDA). The views presented in this paper are of the authors’ and do not necessarily represent the views of NIDA, the National Institutes of Health or
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