The reinstatement model has generated a large body of data on pharmacological interventions that prevent reinstatement; some of these data are summarized in . How do they compare with homologous data from clinical trials?
Preclinical studies of reinstatement in rats
Currently, almost no such comparisons are possible. A clinical trial homologous to the reinstatement model would enroll former users who are currently abstinent (we leave aside, for now, the question of how abstinence is achieved) and would assess propensity to lapse or relapse. Clinical trials answering to the above description are startlingly rare, and the few that do exist have usually tested medications never tested in the reinstatement model. The lack of overlap can be seen by comparing and . (Space limitations preclude a full discussion of the material in the tables, but the main purpose of the tables is illustrative.)
The closest points of overlap between preclinical and clinical work can be found in the alcohol literature. The findings appear, at first, to be mixed. Naltrexone, which blocks reinstatement (Lê et al. 1999
; Ciccocioppo et al. 2002
), has also been shown to prevent relapse in alcoholics (Streeton and Whelan 2001
; Latt et al. 2002
)—a finding that seems encouraging, except that the effect size is modest. Fluoxetine, which also blocks reinstatement (Lê et al. 1999
), fails to prevent relapse in alcoholics (Kranzler et al. 1995
). A reasonable explanation for the negative finding with fluoxetine, and for the modesty of the findings with naltrexone, is that each medication blocks only particular subtypes
of reinstatement. As shown in , fluoxetine blocks reinstatement when the precipitant is footshock stress, but not when the precipitant is a priming dose of alcohol (Lê et al. 1999
); naltrexone blocks reinstatement when the precipitant is a priming dose of alcohol (Lê et al. 1999
) or an alcohol-associated cue (Ciccocioppo et al. 2002
), but not when the precipitant is footshock stress (Lê et al. 1999
). In the clinical trials cited here, the hypotheses were not precipitant-specific, and the trials were designed, powered, and analyzed accordingly (with no attempt, for example, to separate subtypes of relapse using EMA).2
In the literature on nicotine, cocaine, and heroin, we found no clinical trials assessing the relapse-prevention efficacy of medications that have been shown to block reinstatement.
If the search criteria are broadened to include clinical trials that did not literally examine relapse prevention, there emerges another modestly encouraging overlap between preclinical and clinical data: baclofen, which blocks priming-induced reinstatement of cocaine seeking in rats (Campbell et al. 1999
), has also been shown to decrease cocaine craving and use in outpatients (though this was in an open-label pilot with only ten participants) (Ling et al. 1998
). A more ambiguous case is that of buprenorphine, which appears to block priming-induced reinstatement of cocaine seeking in rats (Comer et al. 1993
), but may not reduce cocaine use in humans (Compton et al. 1995
; Schottenfeld et al. 1997
). This apparent false positive may be explicable in terms of buprenorphine-induced motor deficits in the rats (Y. Shaham, personal communication), or it may turn out not to have been false: data from our clinic support the possibility that buprenorphine slightly reduces cocaine use in methadone-maintained polydrug abusers (Montoya et al. 1996
), and that this effect is statistically dissociable from its effect on heroin use (I.D. Montoya et al. submitted). The baclofen and buprenorphine findings do not strongly support the predictive validity of the reinstatement model, but neither do they constitute the “overwhelming number” of clear predictive failures for which Sarter et al. (1992)
criticized other animal models.
In other clinical trials that did not literally assess relapse prevention, there is possible evidence that the reinstatement model has produced true negatives
. For example, bromocriptine reinstates cocaine seeking in rats (Wise et al. 1990
), and is not
effective against cocaine abuse in clinical trials (Handelsman et al. 1997
; Montoya et al. 2002
). Similarly, the corticosteroid-synthesis inhibitor metyrapone reinstates heroin seeking in rats (Shaham et al. 1997
), and the corticosteroid-synthesis inhibitor ketoconazole is not
effective against cocaine or heroin abuse, perhaps even exacerbating them (Kosten et al. 2002
). The detection of true negatives could support the specificity of the reinstatement model as a medication screen, but the homology between the preclinical and clinical data is incomplete: the clinical trials comprised patients who had not yet become abstinent, and thus they assessed the real-life homolog of self-administration rather than that of reinstatement. In rats, a drug that has no effect on the former may nonetheless block the latter (Shalev et al. 2002
); the same may be true in humans. Therefore, even these negative findings are far from definitive.
If the search criteria are further broadened to include human laboratory studies, there are some additional points of overlap between the reinstatement literature and the human literature, but new complications arise. For example, reinstatement of cocaine seeking in rats is blocked by either ABT-431 (Self et al. 2000
) or SCH 39166 (ecopipam) (Khroyan et al. 2000
; Ciccocioppo et al. 2001
and each of these has been tested in human laboratory studies. However, as shown in , cross-species comparison is impeded by differing administration schedules. For example, ABT-431 blocks reinstatement more effectively after chronic administration (Self et al. 2000
), but the one published human laboratory study used acute administration only, leaving open the possibility that chronic administration would be more effective (Haney et al. 1999
). Conversely, for ecopipam, human chronic-administration data are available (Haney 2001
), but there are no chronic-administration reinstatement data with which they can be compared.
Medication tested in the reinstatement model and in human laboratory studies of cocaine effects
The tendency among preclinical investigators to screen medications with acute administration may be problematic, because in a clinical situation, those medications would be administered chronically. But there is a broader barrier to interpretation of the findings shown in , a barrier that would stand even if all the studies had used comparable schedules of administration. The human laboratory studies rely on surrogate endpoints that have sometimes turned out not to predict human behavior in daily life (Teoh et al. 1994
; Weiss et al. 1995
) or to predict it only weakly (Litt et al. 2000
). Humans are aware that what happens in the laboratory is only a simulation of daily life, and that daily life will continue unchanged when the experiment ends. For a laboratory animal, the laboratory is the whole of life; the choices the animal makes within the context of a model are choices about its own survival. In that sense, a good animal model may be less
far removed from day-to-day human life than a human psychopharmacological experiment is. None of this should be taken to deny the unique advantages of the latter (such as the experimenter’s ability to give verbal instructions and collect verbal responses). But either approach requires a validity check against the gold standard of prospectively monitored day-to-day human behavior.