Benzodiazepine self-administration in humans and ... - Springer Link

Psychopharmacology (1997) 134:1–37

© Springer-Verlag 1997

REVIEW

&roles:Roland R. Griffiths · Elise M. Weerts

Benzodiazepine self-administration in humans and laboratory animals – implications for problems of long-term use and abuse

&misc:Received: 25 October 1996 / Final version: 19 May 1997

&p.1:Abstract Drug reinforcement may represent the primary behavioral-pharmacological mechanism underlying two types of problematic use of benzodiazepines – recreational abuse by polydrug abusers and inappropriate chronic use by patients. High dose polydrug abuse for the purpose of getting high is readily recognized as a significant social problem. Inappropriate chronic benzodiazepine use is more subtle but relatively common: for anxiolytics, 36% of past-year users (3% of the adult population in the US) report using these drugs for 4 consecutive months or longer. The risks of such long-term use are much better documented than the benefits. This paper provides a current review of various problems that have been identified with the long-term use and the recreational abuse of benzodiazepines, including memory impairment, risk of accidents, falls and hip fractures in the elderly, a withdrawal syndrome, brain damage, overuse in the elderly, overuse by chronic pain patients, overuse by alcoholics and recreational abuse among alcoholics and polydrug abusers. A comprehensive review of the literature on benzodiazepine reinforcing effects in humans and laboratory animals is also provided. Drug self-administration studies in humans and laboratory animals provide models of both types of problematic benzodiazepine use. Recreational abuse of benzodiazepines has been modeled in human research with polydrug abusers and in laboratory animal studies, which show that the reinforcing effect of benzodiazepines is intermediate relative to other sedative compounds and is increased in subR.R. Griffiths Department of Psychiatry and Behavioral Sciences, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA E.M. Weerts Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA R.R. Griffiths (✉) Johns Hopkins Bayview, 5510 Nathan Shock Drive, Baltimore, MD 21221-6823, USA&/fn-block:

jects with histories of previous sedative drug self-administration. The problem of inappropriate long-term use of benzodiazepines by people without histories of drug abuse has been partially modeled in human studies showing that benzodiazepines function as reinforcers in subjects with anxiety, insomnia, and histories of moderate alcohol consumption, and in preclinical studies showing stable, low-rate benzodiazepine self-injection with concurrent physical dependence under conditions of continuous availability. Both human and animal research suggests that the drug history and current behavioral context may be important in the establishment of benzodiazepines as reinforcers. Limited human and animal research provides little support for the common belief that physical dependence enhances benzodiazepine reinforcement. &kwd:Key words Benzodiazepine · Reinforcement · Drug self-administration · Abuse · Long-term use · Memory · Accidents · Falls · Hip fractures · Withdrawal · Brain damage · Elderly · Pain · Alcoholics · Drug abusers · Anxious subjects · Insomniacs · Sleeping problems · Social drinking · Normal subjects · Flunitrazepam · Physical dependence · Onset · Drug history · Monkeys · Baboons · Rats&bdy:

Introduction Benzodiazepines, which are among the most widely prescribed of all psychoactive drugs, are extremely safe and effective compounds used primarily for treatment of anxiety and insomnia. Their widespread use has occasionally raised concern about recreational benzodiazepine abuse (i.e. non-medical use for the purpose of getting “high”) and led to the erroneous impression that benzodiazepines have relatively high abuse liability among recreational drug abusers. In fact, the incidence of such abuse of benzodiazepines is modest relative to their widespread legitimate medical use (Woods et al. 1987, 1992; Griffiths and Wolf 1990). However, it is helpful to

2 Table 1 Characteristics of two types of problematic use of benzodiazepines&/tbl.c:& Recreational abuse

Chronic quasi-therapeutic use

Description

Intermittent or chronic use of high doses, often in a pattern of polydrug abuse

Long-term use by patients which is inconsistent with accepted medical practice

Example

High doses of diazepam used in combination with opioids or alcohol

Nightly use of triazolam as hypnotic or daily use of lorazepam as anxiolytic for years despite physician’s recommendation to the patient that medication be stopped

Population

Polydrug abusers; often young males

Patients with and without histories of alcohol or drug abuse; elderly; chronic pain patients

Motive for use

To get “high” (alcohol-like intoxication)

Patients often report that a motive for use is “symptom” treatment; patients may report unsuccessful efforts to cut down use and use to relieve or avoid withdrawal

Dose level

Higher than usual therapeutic doses

Therapeutic doses

Pattern of use

Intermittent or chronic

Chronic

Source of drug

Often illicit

Often licit; however, may involve deception of prescriber to obtain drug (e.g. multiple physicians)

Incidence

Relatively rare relative to rate of prescription, but similar to abuse of other illicit substances such as opioids or cocaine

Relatively prevalent relative to rate of prescription

Associated problems

Involvement in illicit drug culture with associated legal and health risks; memory impairment; risks of accidents; withdrawal syndrome

Memory impairment; risk of accidents; falls and hip fractures in elderly; withdrawal syndrome

&/tbl.:

recognize a second type of problematic use of benzodiazepines which is characterized by long-term drug-taking by patients for a duration which is inconsistent with accepted medical practice (i.e. chronic quasi-therapeutic use). Table 1 outlines the distinguishing features of these two types of problematic benzodiazepine use. From a broad behavioral-pharmacological perspective, both types of benzodiazepine use can be conceptualized as inappropriate self-administration, and thus importantly determined by mechanisms of drug reinforcement. This review begins with a section describing the prevalence, problems and vulnerable populations associated with long-term benzodiazepine use. A second section then reviews the prevalence and problems associated with recreational benzodiazepine abuse by polydrug abusers. A third section explores the rationale for considering drug reinforcement as the mechanism engendering both chronic long-term use and recreational abuse of benzodiazepines. The next two sections present comprehensive reviews of the literature on benzodiazepine reinforcement in both humans and laboratory animals, discussing similarities and differences between these growing clinical and preclinical research domains. A final section discusses implications and future research directions for understanding the problems of inappropriate long-term use and recreational abuse of benzodiazepines.

Long-term use of benzodiazepines: prevalence, problems, and vulnerable populations Benzodiazepine anxiolytics and hypnotics are widely used. A 1990 survey of the general population in the

United States showed that past-year use rates for anxiolytics and hypnotics were 8.3 and 2.5% of the population, respectively (Balter, cited by Woods et al. 1992). The extent of long-term use of these drugs is striking: for anxiolytics, 36% of past-year users (3% of the adult population) reported using these drugs for 4 consecutive months or longer (25% reported continuous use); for hypnotics, 23% of past-year users reported using these drugs for 4 months or longer (14% reported continuous use) (Fig. 1, upper panels). Furthermore, long-term use may be increasing over time. The proportion of the total population using anxiolytics continuously increased about 30% between 1979 and 1990, as did the proportion using 4 months or longer. For hypnotics, increases of about 20 and 30% occurred for those using continuously and for 4 months or longer, respectively. The prevalence of overall and continuous use of anxiolytics in the United States is intermediate relative to eight Western European countries also surveyed in 1990 (E. H. Uhlenhuth, personal communication). By examining the distribution of use in this and similar surveys in the United States (Mellinger et al. 1984a,b; Balter and Uhlenhuth 1992) and assuming that dose does not change with duration of use, it can be calculated that long-term users account for most of anxiolytic and hypnotic drug sold. For example, it can be estimated that almost 90% of anxiolytic drugs and more than 80% of hypnotic drugs sold in 1990 in the United States were consumed by people reporting daily use of 4 months or longer. People using these drugs continuously account for almost 70% of anxiolytic and 60% of hypnotic drug sales. The distributions of the percentage of drug sales as a function of duration of past-year anxiolytic and hyp-

3 Fig. 1 Use and sales of anxiolytics and hypnotics as a function of duration of past year use. Upper left panel presents distribution of the percentage of past-year anxiolytic users as a function of past-year duration of anxiolytic use; upper right panel presents analogous data for hypnotics. Data are from a 1990 survey of the general population in the United States (Balter, cited by Woods et al. 1992). Lower panels present estimates of total drug consumption (i.e. sales) as a function of past-year duration of use&ig.c:/f

notic drug use are presented in the lower panels of Fig. 1. A variety of concerns with long-term use of benzodiazepines have been identified including, uncertain efficacy, memory impairment, risk of accidents, falls and hip fractures in the elderly, a withdrawal syndrome and brain damage. Additional problems associated with benzodiazepines include overuse by the elderly, chronic pain patients and alcoholics. The next portion of this section provides an updated selective review of these areas. Efficacy of long-term use is uncertain Although long-term use of these drugs is substantial and long-term use apparently accounts for the great majority of drug sales (Fig. 1), the efficacy of long-term use of anxiolytics and hypnotics has not been clearly established. Consistent with recommendations in the United States by sleep experts, pharmaceutical manufacturers and the Food and Drug Administration that hypnotics be used only on a short-term basis (National Institutes of Health 1984; Physician’s Desk Reference 1997), there is little evidence supporting long-term efficacy of benzodiazepine hypnotics (Hollister et al. 1993; Grad 1995; Monane et al. 1996) and long-term use of hypnotics is often considered undesirable because of concerns that most chronic use is simply preventing rebound insomnia rather than promoting genuine sleep (Salzman and Watsky 1993; Krska and MacLeod 1995). Likewise, there is little evidence supporting the long-term use of benzodiazepines as anxiolytics (Schweizer et al. 1995). Such use is controversial, but sometimes considered appropriate in some patients and conditions (Hollister et al. 1993; Salz-

man and Watsky 1993; Schweizer et al. 1993; Romach et al. 1995). Provocatively, however, there is evidence from several studies that long-term benzodiazepine anxiolytic users may experience less anxiety on follow-up after drug discontinuation compared to before discontinuation when they were being maintained on benzodiazepines chronically (Ashton 1987; Cantopher et al. 1990; Rickels et al. 1990; Schweizer et al. 1990) or compared to a group of patients in whom drug had not been discontinued (Rickels et al. 1991). Thus, there is concern that some chronic use of anxiolytics may be maintained by preventing rebound anxiety or withdrawal rather than truly reducing anxiety. Finally, consistent with the concern that long-term efficacy may not be responsible for maintaining long-term use, several studies indicate that many long-term benzodiazepines users report unsuccessful efforts to cut down or control benzodiazepine use and taking the benzodiazepine to relieve or avoid withdrawal (Salinsky and Doré 1987; King et al. 1990; Barnes et al. 1993; Romach et al. 1995; Busto et al. 1996b). Memory impairment The ability of benzodiazepines to impair the acquisition of new information after drug administration (i.e. produce anterograde amnesia) has been clearly documented (Curran 1991; Woods et al. 1992). Because this effect was correlated with sedation, and because tolerance to the sedative effects of benzodiazepines was well known, it was often assumed that tolerance developed to these memory impairing effects as well (Ghoneim and Mewaldt 1990; Curran 1991). However, studies in patients (Golombok et al. 1988; Lucki and Rickels 1988; Curran

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1991, 1992; Tata et al. 1994; Gorenstein et al. 1995; Tönne et al. 1995) and healthy volunteers (Ghoniem et al. 1981) have now demonstrated that complete tolerance does not occur to the amnestic and other cognitive effects of benzodiazepines, even after years of chronic use. Since loss of memory has sometimes been a concern of benzodiazepine-using patients (Busto et al. 1986), a persuasive case can be made for considering impaired memory as a risk in both acute and chronic use of benzodiazepine drugs. The case is particularly strong for the elderly (Foy et al. 1995), particularly those who already have reduced levels of cognitive functioning. For example, a single-blind study of elderly nursing home residents showed that those who discontinued chronic benzodiazepines improved on measures of memory and cognitive functioning compared to a group that continued use (Salzman et al. 1992). Two studies observed that discontinuation of chronic benzodiazepine use among elderly nursing home residents resulted in an improved sense of well-being, energy and cognitive functioning that was apparent to family members as well as nursing home staff (Larson et al. 1987; Salzman et al. 1992). The memory impairment phenomenon of transient global amnesia refers to a period of several hours or longer in which individuals report complete memory loss after taking a benzodiazepine hypnotic. Transient global amnesia has been well documented in case reports (usually with triazolam or midazolam); however the phenomenon occurs at very low frequency and has not been characterized experimentally (Woods et al. 1992). Risks of accidents The well-established fact that normal therapeutic doses of benzodiazepines can impair various aspects of psychomotor performance, including simulated and real driving tasks, in both normal and anxious subjects (Woods et al. 1992), raises concerns that benzodiazepine use might be associated with an increased rate of accidents. Epidemiological studies of automobile and other accidents provide largely inconclusive evidence in support of this concern (cf. Oster et al. 1990; Balter and Uhlenhuth 1992; Barnas et al. 1992a; Ray et al. 1992a; Woods et al. 1992) because it has been difficult to provide all the necessary controls. In particular, it is important to compare rates of accidents in benzodiazepine-treated and untreated patients, since untreated patients also may be at increased risk of accident. However, elevated rates of automobile accidents among elderly benzodiazepine users have been clearly documented (Ray et al. 1992a,b) and should be considered in light of the overuse of benzodiazepines among the elderly discussed below.

pounds increase the risk of falls or hip fractures in elderly patients (Sobel and McCart 1983; Hale et al. 1985; Ray et al. 1987, 1989; Sorock and Shimkin 1988; Cumming et al. 1991; Myers et al. 1991; Cummings et al. 1995; Cwikel 1992; Cumming and Klineberg 1993; Ryynanen et al. 1993; Lichtenstein et al. 1994; Herings et al. 1995). Although there are studies that have reported a failure to show this effect or have reported differences among benzodiazepines in producing this effect (cf. Woods et al. 1992), the preponderance of evidence suggests that there is a strong association of falls with use of anxiolytics and hypnotics that should be considered in assessing the risks of prescribing these drugs to the elderly (Berg and Cassells 1990; Grad 1995). Withdrawal syndrome after termination of chronic use A well-documented phenomenon is the emergence of a withdrawal syndrome after termination of chronic benzodiazepine use at either high or normal therapeutic doses (Woods et al. 1992; Hallström 1993; Seivewright and Dougal, 1993). The profile, intensity and time course of signs and symptoms have permitted differentiation of true pharmacological withdrawal from a simple re-emergence of pre-existing anxiety or insomnia. Benzodiazepine withdrawal signs and symptoms include anxiety, insomnia, irritability, headache, gastrointestinal disturbance, depersonalization, a wide range of perceptual changes such as paresthesias and hypersensitivity to light and noise, and, infrequently, seizures and delirium. The proportion of long-term users that are at risk for withdrawal effects has been estimated to be 50%, but is difficult to assess because withdrawal studies have often involved self-selected patients who have previously had difficulty withdrawing from medication (Higgitt and Fonagy 1993). Brain damage High alcohol consumption is known to produce cerebral atrophy (Mutzell and Tibblin 1989), and several investigations have examined whether long-term or heavy benzodiazepine use is also associated with changes in brain morphology. Although abnormalities suggesting cerebral atrophy, usually marginal, have been reported in some studies (Lader et al. 1984; Allgulander et al. 1984; Schmauss and Krieg 1987; Uhde and Kellner 1987; Moodley et al. 1993), other studies have failed to demonstrate such effects (Poser et al. 1983; Perera et al. 1987). Thus, present evidence of benzodiazepine-induced brain damage is questionable.

Risk of falls or hip fractures among the elderly

Overuse among the elderly

A substantial number of recent epidemiological studies suggest that use of benzodiazepines and related com-

The concerns about impaired memory and increased risk of accidents, falls and hip fractures among benzodiaze-

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pine-using elderly has drawn attention to the high use of these compounds by this patient group. Prescriptions filled by the elderly account for a disproportionately large fraction of benzodiazepine prescriptions; in the United States in 1991, persons 65 years or older represented 13% of the population, but received 27% and 38% of all prescriptions for benzodiazepine anxiolytics and hypnotics, respectively (Woods et al. 1992; Woods and Winger 1995). In typical community and outpatient surveys, between 13% and 22% of people 65 or older report current or recent use of benzodiazepines, with most of these patients using these drugs regularly for a year or more (Woods et al. 1987, 1992; Stewart et al. 1989, 1994b; Shorr et al. 1990). Rates of long-term benzodiazepine use among the institutionalized elderly are even higher (Woods et al. 1992), as high as 35–77% in some surveys (Gilbert et al. 1990, 1993; Roberge et al. 1995). Studies also indicate that, compared to younger patients, elderly patients who receive prescriptions for benzodiazepines are less likely to have a diagnosis and reasons for the prescriptions are less likely to be completely documented (Shorr and Bauwens 1992; Woods et al. 1992; Roberge et al. 1995; Thomsom and Smith 1995). Finally, the high rates of prescribing to the elderly cannot be justified by concerns that the elderly are particularly sensitive to withdrawal. Studies of elderly nursing home residents have described procedures for discontinuing chronic benzodiazepines use among the elderly with minimal or no withdrawal effects (Schweizer et al. 1989; Salzman et al. 1992; Gilbert et al. 1993), and one study showed that the severity of withdrawal symptoms was less in the elderly than in younger patients (Schweizer et al. 1989). Overuse among chronic pain patients There has been continuing concern about the overuse of benzodiazepines in chronic pain patients because benzodiazepines have only limited efficacy in treatment of selected pain conditions (King and Strain 1990b; Dellemijn and Fields 1994; Reddy and Patt 1994). Surveys studies have shown that as many as 40–60% of pain patients use benzodiazepines, usually on a long-term basis (Hendler et al. 1980; King and Strain 1990a; Hardo and Kennedy 1991). This rate of benzodiazepine use is much greater than in the general population (Woods et al. 1992). Overuse by alcoholics Studies of alcoholic populations consistently find frequent use of benzodiazepines, with or without a prescription (Woods et al. 1992). Rates of benzodiazepine use exceeding 30% are not uncommon among alcoholics (Busto et al. 1983; Wiseman and Spencer-Peet 1985; Crane et al. 1988; Wolf et al. 1990; Ross 1993) and studies have repeatedly documented use without a prescription (Busto et al. 1983; Bailly et al. 1990; Wolf et al.

1990; Ross 1993). As discussed in more detail in a later section of this review, experimental studies indicate that people with histories of moderate alcohol consumption (deWit et al. 1989; deWit and Doty 1994) and alcoholics (Ciraulo et al. 1988a) show increased sensitivity to the reinforcing effects (deWit and Doty 1994) and positive mood effects (Ciraulo et al. 1988a; deWit et al. 1989) of benzodiazepines.

Recreational benzodiazepine abuse by polydrug abusers: prevalence and problems Although the extent of recreational use (i.e. abuse) of benzodiazepines in the general population is substantially lower than for some drugs (e.g. alcohol and marijuana), it is by no means trivial. For example, 7.1% of the high school class of 1995 reported having used tranquilizers non-medically (mostly benzodiazepines) (NIDA Press Office 1995), with about half of users reporting that they usually got “high” from tranquilizers (Johnston et al. 1993). This rate of abuse is higher or at about the same rate of abuse as heroin, other opioids, cocaine and barbiturates, and all these compounds are perceived as being roughly similarly available for abuse (NIDA Press Office 1995). Although the extent of benzodiazepine abuse within the illicit drug culture is difficult to estimate, it is clear that oral and sometimes IV abuse of benzodiazepines among injecting drug users represents a major clinical and public health problem (DuPont 1988; Seivewright et al. 1993; Strang et al. 1993; Darke 1994). The problem is international in scope, having been reported most extensively in the United States, Europe and Australia (Darke 1994). The best information is provided by clinical observations of professionals working with drug abuse patients and by surveys of drug use at drug abuse treatment clinics. Clinical observations of the illicit drug culture indicate that, like barbiturates that preceded them, benzodiazepines are most frequently abused via the oral route by polydrug abusers and alcoholics (Mitchelson et al. 1970; Smith and Marks 1985; Wolf et al. 1990; Strang et al. 1993). Benzodiazepines are frequently, although not exclusively, abused in combination with other drugs rather than as a primary drug of abuse (Smith and Marks 1985; San et al. 1993b; Strang et al. 1993; Darke et al. 1994). A recurring observation, which has been supported by several surveys, has been the relatively high rate of abuse of benzodiazepines by heroin abusers and methadone maintenance patients (Barnas et al 1992b; Iguchi et al. 1993; Seivewright et al. 1993; Strang et al. 1993; Darke et al. 1995; Busto et al. 1996a; Williams et al. 1996). These individuals often report using relatively high doses of benzodiazepines in abusive (i.e. non-therapeutic) patterns to “boost” the effects they obtain from the opioid drug. A double-blind clinical pharmacology study showed that diazepam does indeed enhance some subjective and physiological opioid effects in methadone maintenance patients while concurrently

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producing sedative-like subjective effects (Preston et al. 1984). Use of benzodiazepines among drug abusers who abuse drugs IV has been associated with a higher incidence of HIV risk-taking behavior (e.g. needle sharing), drug abuse and other psychosocial problems (Klee et al. 1990; Darke et al. 1992, 1993). Although most abuse of benzodiazepines is via the oral route, there have been sporadic reports from several different countries of abuse via IV injection of a variety of different benzodiazepines, including temazepam, diazepam and triazolam (Green et al. 1992; Strang et al. 1992, 1993, 1994; Darke et al. 1995). In the late 1980s, extensive IV abuse of temazepam was reported in several regions across the United Kingdom (Strang et al. 1992). The most abused formulation of temazepam was soft capsules which contained temazepam liquid which could easily be drawn into a syringe and injected. The manufacturers of temazepam reformulated the drug in tablets or in capsules as a hard gel in what appears to be a partially successful attempt to discourage IV abuse (Launchbury et al. 1989; Rubin and Morrison, 1992; Strang et al. 1994). There is substantial additional evidence that there are meaningful differences among the benzodiazepines with respect to their attractiveness to drug abusers (cf. Griffiths and Wolf, 1990 for review). This evidence is based on: human laboratory studies of subjective and reinforcing effects in drug abusers (Griffiths and Roache 1985; Griffiths et al, 1984a,b), interviews with drug abusers (Barnas et al, 1992b; Iguchi et al, 1993), clinical judgement of medical professionals specializing in drug abuse treatment (Griffiths and Wolf 1990), and epidemiological studies (Griffiths et al. 1984b; Bergman and Griffiths 1986; Griffiths and Wolf 1990). Diazepam, in particular, has a greater abuse liability than many of the other benzodiazepines, while oxazepam and halazepam are relatively low in this regard. Diazepam appears to be a particularly popular drug of abuse among heroin abusers and methadone maintenance patients (Barnas et al. 1992b; Iguchi et al. 1993; Darke et al. 1995). As with diazepam, flunitrazepam (Rohypnol) is a popular drug of abuse, especially among opioid abusers (Navaratnam and Foong 1990; Barnas et al. 1992b; San et al. 1993a; Darke et al. 1995). Flunitrazepam is a hypnotic benzodiazepine marketed worldwide, but not in the United States. In examining data on illicit activities associated with benzodiazepines worldwide, the World Health Organization noted that after adjustment for the level of production, the number of reports of illicit activities associated with flunitrazepam was higher than for any other benzodiazepine (World Health Organization 1995). On the basis of a recommendation by the World Health Organization to regulate flunitrazepam more closely under international law, in 1995 the United Nations Commission on Narcotic Drugs moved flunitrazepam from Schedule IV to the more restrictive Schedule III of the Convention on Psychotropic Substances, 1971. Although flunitrazepam was recognized as a drug abuse problem in many countries for years, there were few re-

ports of abuse of flunitrazepam in the United States, undoubtedly due in part to the fact that flunitrazepam is not sold in the United States. That situation has changed in recent years, with new federal legal penalties imposed in November 1996 on flunitrazepam in response to a substantial recent rise in flunitrazepam abuse. Data compiled by the US Drug Enforcement Administration (DEA) between 1994 and March 1997 show there have been over 4000 encounters (i.e. seizures or undercover purchases) of flunitrazepam by federal, state and local law enforcement agencies in 37 states (DEA 1996; James Tolliver, DEA, personal communication). As implied in the above descriptions of recreational benzodiazepine abuse, perhaps the most serious problem with such use is the almost inevitable involvement in the illicit drug culture with sharply increased associated legal and health risks. In addition to these risks, the previously described risks of memory impairment, accidents and a withdrawal syndrome are also of relevance to recreational benzodiazepine abuse.

Drug reinforcement as a mechanism engendering both chronic long-term use and recreational abuse of benzodiazepines This section considers the hypothesis that drug reinforcement may be involved in both chronic long-term use and recreational abuse of benzodiazepines. A stimulus is said to be a positive reinforcer if its presentation increases the likelihood of responses that produce it (Catania 1991). Drug reinforcement commonly refers to the process of a drug increasing the likelihood of behaviors that produce it by virtue of the drug’s CNS activity. Drug reinforcement, which has been widely studied in both laboratory animals and in humans using drug self-administration and choice procedures, is among the most robust behavioral-pharmacological mechanisms to emerge from 40 years of behavioral pharmacology research (Griffiths et al. 1980a; Henningfield et al. 1986; Branch 1991; Meisch and Lemaire 1993). It should be noted that the definition of drug reinforcement does not make assumptions about the mechanism(s) underlying drug reinforcement, other than it is centrally mediated. Thus, drug-taking induced solely by instructions and/or expectations would not qualify as drug reinforcement, as, for example, in the case of a patient complying with a physician’s instructions to take an antibiotic drug. It should also be noted that the definition does not differentiate between presumed motives for use. For example a patient might claim that he/she uses a benzodiazepine to feel good, to avoid anxiety, or to avoid drug withdrawal symptoms – all are instances of drug reinforcement. Likewise, a drug abuser might claim that he/she uses a benzodiazepine to get high, to reduce tension, or to avoid drug withdrawal symptoms – again, all are instances of drug reinforcement. It seems likely that drug reinforcement is a principal mechanism underlying both the chronic long-term use of

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benzodiazepines and the recreational abuse of benzodiazepines. With regard to long-term use, from the broadest perspective, most centrally active drugs that engender chronic daily self-administration in a significant portion of the population that are exposed to them (e.g. nicotine, caffeine and alcohol) have also been demonstrated to be reinforcers in laboratory animals and humans (cf. Woods et al. 1971; Mello 1989; Griffiths and Mumford 1995; Henningfield et al. 1996). Likewise, benzodiazepines have been shown to function as reinforcers under a broad range of conditions: in laboratory animals, in drug abusers, and in normal humans with histories of moderate alcohol drinking, anxiety or insomnia (cf. subsequent sections of this review). Thus, it is quite plausible that drug reinforcement underlies chronic daily benzodiazepine self-administration. Because the definition of drug reinforcement does not differentiate therapeutic efficacy from a more generalized reinforcement mechanism, it is interesting to speculate about the extent to which long-term use of benzodiazepines in patients might be due to therapeutic efficacy. First, it should be noted that there are other centrally-acting, therapeutically efficacious drugs (e.g. chlorpromazine, buspirone) that do not readily function as reinforcers in animals and humans (Griffiths et al. 1979, 1981, 1991; Troisi et al. 1993; Evans et al. 1996) and do not readily sustain self-administration, even in populations for which they are efficacious and prescribed (Goa and Ward 1986; Rickels 1990; Csernansky and Newcomer 1995). Although it seems likely that drugs like chlorpromazine or buspirone function as reinforcers and maintain long-term self-administration in some patients solely because they are therapeutically efficacious, overuse of these drugs by patients rarely occurs because these drugs function as reinforcers only under a very narrow range of conditions. Thus, therapeutic efficacy alone appears insufficient to explain widespread long-term use. Consistent with a more generalized reinforcement mechanism underlying long-term use of benzodiazepines, many long-term benzodiazepines users develop a classic drug dependence syndrome (cf. Hughes 1993) which is characterized by a persistent desire or unsuccessful efforts to cut down or control benzodiazepine use, the benzodiazepine is taken over a longer period of time than intended, and the benzodiazepine is taken to relieve or avoid withdrawal (Salinsky and Doré 1987; King et al. 1990; Barnes et al. 1993; Romach et al. 1995; Busto et al. 1996b). The observations that many long-term users report difficulty controlling benzodiazepine use and report using to avoid withdrawal, when coupled with the fact that longterm therapeutic efficacy of benzodiazepines has not been clearly demonstrated (cf. previous section), suggest that a more generalized reinforcement mechanism may provide a more satisfactory explanation for much of long-term use than therapeutic efficacy. The case for drug reinforcement underlying recreational abuse of benzodiazepines is also compelling. Considerable data show a good correspondence between those drugs that maintain self-administration behavior in

laboratory animals, those that produce self-administration, choice and subjective drug liking in drug abusers, and those that are actually abused by recreational drug abusers (e.g. Johanson and Balster 1978; Griffiths et al. 1979, 1980a). This relationship is strong enough that regulatory agencies consider animal drug self-administration studies and human studies that provide either direct or indirect assessment of drug reinforcement to be an important part of an “abuse liability” assessment of centrally acting compounds (Vocci 1989). With regard to sedative drugs in particular, animal studies and studies in people with histories of drug abuse have shown that sedative drugs considered to have high abuse liability in recreational polydrug abusers (e.g. pentobarbital) are generally more efficacious reinforcers than classic benzodiazepines; benzodiazepines, in turn, are more efficacious reinforcers than drugs such as chlorpromazine or buspirone, which are considered to have little or no abuse liability in polydrug abusers (cf. subsequent sections of this review).

Reinforcing effects of benzodiazepines in humans The reinforcing effects of benzodiazepines have been widely studied in both human subjects and in laboratory animals using variations on drug self-administration procedures. This section will review the human research assessing the reinforcing effects of benzodiazepines, while the following section will review such effects in laboratory animals and point out similarities and differences between the human and animal data. Tables 2 and 3 summarize 26 published papers which have examined the reinforcing effects of benzodiazepine drugs in subjects with and without histories of drug abuse. These studies clearly indicate that benzodiazepines can serve as reinforcers. As elaborated below, these studies also indicate several important determinants of benzodiazepine reinforcement: the history of the subject, the speed of onset of drug effect and the behavioral context in which drug is made available for self-administration. Benzodiazepines are reinforcers in subjects with histories of drug abuse but not in normal subjects without histories of moderate drinking, anxiety or insomnia Comparisons within and across studies in Tables 2 and 3 suggest that the most important single determinant of whether or not a benzodiazepine will function as a reinforcer is the history of the subject. Studies with subjects with histories of drug abuse almost invariably have shown that benzodiazepines function as reinforcers (cf. Table 2). These studies have demonstrated the reinforcing effects of alprazolam (Mumford et al. 1995a,b), diazepam (Griffiths et al. 1979, 1980b, 1984b; Roache and Griffiths 1989), oxazepam (Griffiths et al. 1984b) and

Diazepam (2, 5, 10 mg/ingestion) Pentobarbital (30–90 mg/ingestion) Ethanol (1.86–11.14 g/ingestion)

Diazepam (10 mg/ingestion) Pentobarbital (30 mg/ingestion)

Diazepam (10 and 20 mg/ingestion) Pentobarbital (30 and 90 mg/ingestion) Chlorpromazine (25 and 50 mg/ingestion) Placebo Diazepam (50–400 mg) Pentobarbital (200– 900 mg) Placebo

Diazepam (2–40 mg/ingestion) Pentobarbital (30 or 50mg/ingestion)

Diazepam (40, 80, 160 mg) Oxazepam (480 mg) Placebo

Griffiths et al. (1976)

Bigelow et al. (1976)

Griffiths et al. (1979)

Healey and Pickens 1983

Griffiths et al. (1984b)

Roache and Diazepam (40 or 80 mg) Griffiths (1989) Triazolam (1 or 2 mg) Placebo

Griffiths et al. (1980b)

Drugs and doses

Reference

Male drug abusers (n=8)


Male and female drug abusers (n=10)

Male drug abusers (n=9, diazepam)



Male drug abusers n=2, diazepam)

Subjects Number of diazepam ingestions self-administered increased with increases in doses and decreased with increases in minimum interingestion interval. Similar results were obtained with pentobarbital and ethanol. Number of diazepam and pentobarbital ingestions selfadministered decreased with increasing work requirements.

Results

After a sampling day, one ingestion was available for self-administration for 6 consecutive days. Ingestion selfadministration was dependent on riding an exercise bicycle and the duration of riding required increased over days.

Both diazepam and triazolam were self-administered more than placebo, with selfadministration decreasing across days.

Diazepam self-administration increased with increasing doses. Under similar conditions, chlorpromazine was not self-administered and pentobarbital maintained more selfadministration than diazepam. Diazepam (200 mg) was chosen over placebo. Higher doses of diazepam were not consistently chosen over lower doses. Under similar conditions pentobarbital (400 mg) was chosen over both placebo and diazepam (200 mg). Drug was available 24 h/day with a Diazepam was consistently selfminimum inter-ingestion interval of 30 administered, but no consistent min. On choice days two different doses dose preference was demonsor drugs were available throughout the trated between diazepam doses day. or between diazepam and pentobarbital. After sampling days, discrete two-option Diazepam was chosen over choices occurred across days: diazepam placebo on every occasion. versus placebo, oxazepam versus Oxazepam was chosen over placebo, and diazepam versus oxazepam. placebo on 79% of occasions. High doses of diazepam were chosen over oxazepam.

Ten ingestions of drug were available daily for 5–15 consecutive days. On the first day ingestions were available on request. On subsequent days each ingestion was dependent upon riding an exercise bicycle for 15 min; different drug and dose conditions were tested. After sampling days, discrete two-option choices occurred across days.

20 ingestions of drug were available daily, each dependent upon riding an exercise bicycle for a specified duration. Required riding duration was varied across days from 2 to 20 min per ingestion.

12 or 16 ingestions of drug were available per day, each dependent upon riding an exercise bicycle for 20 min. Dose per ingestion and minimum interingestion interval was varied over days.

Method

Table 2 Reinforcing effects of benzodiazepines in human subjects with histories of drug abuse a,b&/tbl.c:

Diazepam and oxazepam were reinforcers. The reinforcing effects of diazepam increased with dose. Diazepam was a more efficacious reinforcer than oxazepam, based on choice results in combination with various subjective measures. Diazepam and triazolam were reinforcers.

In absence of a placebo comparison, drug reinforcement cannot be concluded.

Study was not double-blind. In absence of a placebo comparison, drug reinforcement cannot be concluded, although maintenance of long durations of exercise bicycle riding were suggestive of drug reinforcement. Diazepam was a reinforcer with the higher dose more efficacious than the lower dose. Diazepam was a less efficacious reinforcer than pentobarbital. Chlorpromazine was not a reinforcer. Diazepam was a reinforcer but was less efficacious than pentobarbital.

Study was not double-blind. In absence of a placebo comparison, drug reinforcement cannot be concluded, although dose-related increases in selfadministration were suggestive of drug reinforcement.

Comment

8


Alprazolam (1, 2, 4 mg) Abecarnil (10, 20, 40 mg) Placebo

Alprazolam (0.5, 1, 2 mg) Pazinaclone (8, 16, 32 mg) Placebo

Alprazolam immediate reMale drug abusers lease preparation (1, 2 mg) (n=14)

Mumford et al. (1995a)

Mumford et al. (1995b)

Mumford et al. (1995c)

Alprazolam extended release preparation (2, 3 mg) Placebo Triazolam (0.125 Male drug abusers or 0.25 mg/ingestion) (n=6) Placebo

Alprazolam was a reinforcer. The reinforcing effects were an increasing function of dose dose.

Alprazolam was a reinforcer. The reinforcing effects were an increasing function of dose.

The number of triazolam capsules self-administered generally exceeded the number of placebo capsules in four of six subjects. The number of triazolam capsules self-administered was inversely related to dose.

Triazolam was a reinforcer in four of six subjects.

Significantly greater monetary The immediate release values were associated with 1 preparation of alprazolam was a and 2 mg alprazolam immediate reinforcer. release preparation than with placebo.

Significantly greater monetary values were associated with 2 mg alprazolam than with placebo.

Significantly greater monetary values were associated with 4 mg alprazolam than with placebo and all doses of abecarnil.

In both experiments, subjects always chose triazolam with relaxation; in expt 2 subjects usually chose d-amphetamine in the vigilance context.

In absence of a placebo comparison, it is not clear if lorazepam was a reinforcer and/or buspirone was a punisher; but subjective effect data suggested that lorazepam was a reinforcer. Triazolam was a reinforcer in a relaxation but not a vigilance context. d-Amphetamine was a reinforcer in a vigilance but not a relaxation context.

Boissl et al. 1983). These studies have not been summarized in the Table because they did not provide interpretable information about drug reinforcement: they lacked a placebo control and results were not replicated across the two studies&/tbl.

After sampling sessions, 18 ingestions of triazolam or placebo were available for self-administration during daily 3-h sessions for 7–10 consecutive days. Ingestions were available upon verbal request according to a fixed-interval 10-min schedule. On this schedule triazolam and placebo were concurrently available as mutually exclusive options. In a different phase, triazolam dose per ingestion was varied in two subjects.

Expt 1: after sampling sessions, subjects repeatedly choose whether they would ingest triazolam or placebo before a relaxation or vigilance activity. expt 2: subjects choose whether they would receive triazolam, d-amphetamine or placebo before a relaxation or vigilance activity. After each double-blind exposure to each dose condition, subjects completed a drug versus money multiple-choice procedure which was reinforced on the last session. After each double-blind exposure to each dose condition, subjects completed a drug versus money multiple-choice procedure which was reinforced on the last session. After each double-blind exposure to each dose condition, subjects completed a drug versus money multiple-choice procedure which was reinforced on the last session.

After sampling sessions, a single choice Seven of eight subjects day involved choosing between choose lorazepam. lorazepam (4 mg/70 kg) versus buspirone (60 mg/70 kg). These doses produced similar ratings of drug strength.

a Drug administration was oral in all studies and was double-blind in all studies, except as noted b Two studies of similar experimental design used a choice procedure to examine preference between triazolam and zolpiclone in alcoholic inpatients (Bechelli et al. 1983;

Roache et al. (1995)


Silverman et al. Triazolam (0.25 mg) (1994) d-Amphetamine (15 mg) Placebo



Lorazepam (4 mg/70 kg) Buspirone (60 mg/70 kg)

Troisi et al. (1993)

9

Lorazepam (0.5, 1, 2 mg) Diazepam (5 mg) Placebo

Flurazepam (15 and 30 mg) Normal subjects Placebo (n=12)

Diazepam (5 and 10 mg) d,l-Amphetamine (5 mg) Placebo

Diazepam (5 and 10 mg) d,l-Amphetamine (5 mg) Placebo

Diazepam (7 capsules of 4 mg each on choice days) Placebo (7 capsules on choice days)

deWit et al. (1984a)

deWit et al. (1984b)

deWit et al. (1985)

deWit et al. (1986)

deWit et al. (1989)

Light social drinkers (n=18); Moderate social drinkers (n=12)

Anxious subjects (n=11); subjects with generalized anxiety disorder (n=13); normal subjects(n=12)

Normal younger (21–35 years) subjects (n=12 and n=13) Normal older (40–55 years) subjects (n=11)

Normal subjects (n=12)

Normal subjects (n=10)

Diazepam (2, 5, 10 mg) d-Amphetamine (5 mg) Placebo

Johanson and Uhlenhuth (1980)

Subjects

Drugs and doses

Reference

Choice tests consisted of 4 sampling days (2 for each of two drug conditions) followed by 3 choice days on which subjects made a mutually exclusive choice between the two conditions.

Choice tests consisted of 4 sampling days (2 for each of two drug conditions) followed by 5 choice days in which subjects chose which one of the two conditions would be ingested.

Choice tests consisted of 4 sampling days (2 for each of two drug conditions) followed by 5 choice days in which subjects chose which one of the two conditions would be ingested. Choice tests consisted of 4 sampling days (2 for each of two drug conditions) followed by 5 choice days in which subjects chose which one of the two conditions would be ingested. Choice tests consisted of 4 sampling days (2 for each of two drug conditions) followed by 5 choice days in which subjects chose which one of the two conditions would be ingested.

Choice tests consisted of 4 sampling days (2 for each of two drug conditions) followed by 5 choice days on which subjects chose which one of the two conditions would be ingested.

Method

Table 3 Reinforcing effects of benzodiazepines in human subjects without histories of drug abuse a&/tbl.c:

In light social drinkers diazepam tended to be preferred to placebo (66% diazepam choice); in moderate social drinkers diazepam was preferred to placebo (100% diazepam choice).

Placebo was preferred to 5 and 10 mg diazepam (estimated mean 10 mg diazepam choice was 28% of choice sessions); 5 mg d,l-amphetamine was preferred to placebo; (estimated mean 5 mg d,l-amphetamine choice was 73% of choice sessions); no significant differences between subject groups.

Placebo tended to be preferred to 10 mg diazepam (diazepam choice was 25%, 32% and 38% of choice sessions); 5 mg diazepam versus placebo were equally preferred; 5 mg d,l-amphetamine tended to be preferred to placebo (d,lamphetamine choice was 80%, 54% and 71% of choice sessions); no significant differences between subject groups.

Placebo was preferred to 5 mg and 10 mg diazepam (diazepam choice was 28% and 27% of choice sessions, respectively); 2 mg diazepam vs placebo were equally preferred; 5 mg damphetamine was preferred to placebo (76% choice sessions); 5 mg damphetamine was preferred to 2 mg diazepam (75% choice sessions). Placebo was preferred to 2 mg lorazepam (lorazepam choice was 16% of choice sessions); .5 mg lorazepam vs placebo, 1 mg lorazepam versus placebo, and 1 mg lorazepam versus 5 mg diazepam were equally preferred. Placebo was preferred to 30 mg flurazepam (flurazepam choice was 20% of choice sessions); 15 mg flurazepam versus placebo were equally preferred.

Results

Diazepam was not a reinforcer; collapsing data across groups, 10 mg diazepam functioned as a punisher c,d and d,l-amphetamine functioned as a reinforcerc,d; time of capsule administration (morning versus afternoon) and age of subjects did not affect choice outcome. Diazepam was not a reinforcer in normal subjects or those with anxious mood or generalized anxiety disorder; collapsing data across groups, 5 and 10 mg diazepam functioned as a punisherb and 5 mg d,l-amphetamine functioned as a reinforcerb. Using a cumulative dosing procedure, diazepam was a reinforcer in moderate social drinkers but not in light social drinkers c.

Flurazepam was not a reinforcer; 30 mg flurazepam functioned as a punisherb,c,d.

Lorazepam was not a reinforcer; 2 mg lorazepam functioned as a punisher b.

Diazepam was not a reinforcer; 5 and 10 mg diazepam functioned as a punisher b,c; 5 mg damphetamine functioned as a reinforcer b,c.

Comment

10



Triazolam (0.25, 0.5 mg) Placebo

deWit (1991)

Johanson and deWit (1992)

Roehrs et al. (1992)

Chutuape and deWit (1995)

Diazepam (7 capsules of 4 mg each on choice days) Placebo (7 capsules on choice days) Ethanol (7 doses of 0.16 g/kg)

deWit and Doty Diazepam (20 mg) (1994) Placebo Ethanol (0.5 g/kg)

Diazepam (10 mg) Placebo

McCracken et al. (1990)

Choice tests consisted of 4 sampling days (2 for each of two drug conditions) followed by 5 choice days in which subjects chose which one of the two conditions would be ingested. Subjects with first- Choice tests consisted of 4 degree alcoholic sampling days (2 for each of two relative (n=14); drug conditions) followed by 3 subjects without choice days on which subjects alcoholic relatives made a mutually exclusive (n=13) choice between the two conditions. Normal subjects Choice tests consisted of 4 (n=43) sampling days (2 for each of two drug conditions) followed by 3 choice days on which subjects made a mutually exclusive choice between the two conditions; subjects were tested under social and/or solitary conditions. Normal subjects Subjects were exposed to three (n=7) conditions in which they Subjective sometimes ingested a pill before insomniacs (n=7) bed; two conditions involved 6 Objective nights of forced exposure to insomniacs (n=7) triazolam (either 0.5 mg/night or 0.5–0.125 mg/night) followed by 6 nights of optional self-administration of 0.25 mg triazolam; the other condition involved 6 nights of forced exposure to placebo followed by 6 nights of optional self-administration of placebo. Light social Choice tests consisted of 4 drinkers (n=13) sampling days (2 for each of two Moderate social drug conditions) followed by 3 drinkers (n=14) choice days on which subjects made a mutually exclusive choice between the two conditions; subjects were tested with diazepam vs placebo and ethanol versus placebo in separate counterbalanced choice tests. Anxious subjects Choice tests consisted of 4 meeting DSM-IIIR sampling days (2 for each of two diagnostic criteria drug conditions) followed by 3 (n=22) choice days on which subjects Normal subjects made a mutually exclusive (n=23) choice between the two conditions; subjects were tested with diazepam versus placebo and ethanol versus placebo in separate counterbalanced choice tests.

Anxious subjects seeking treatment for anxiety (n=14)

In light social drinkers placebo tended to be preferred to diazepam (40% diazepam choice); in moderate social drinkers diazepam tended to be preferred to placebo (73% diazepam choice); this difference between light and moderate drinkers was significant; ethanol tended to be preferred to placebo in light social drinkers (63% ethanol choice) and was preferred (83% ethanol choice) in moderate social drinkers. Diazepam choice was 65% of choice sessions in anxious subjects and 45% in normal subjects; ethanol choice was 52% of choice sessions in anxious subjects and 53% in normal subjects; although not different in number of sessions, anxious subjects consumed more doses of diazepam than did normal control subjects.

Placebo and triazolam were selfadministered at similar rates; insomniacs self-administered pills more frequently than normal subjects.

Placebo tended to be preferred to diazepam, with no difference across the subject groups (diazepam was chosen on 38% and 48% of choice sessions in family-history negative and familyhistory positive groups, respectively). Placebo tended to be preferred to diazepam, with no difference between the social and solitary conditions (diazepam was chosen on 33% of choice sessions).

Placebo tended to be preferred to diazepam (diazepam choice was 37% of choice sessions).

That diazepam functioned as a reinforcer in anxious subjects was suggested by a marginally significant preference for diazepam (P=0.06)c,d; anxious subjects also consumed more more diazepam doses than normal control subjects; diazepam was not a reinforcer in normal subjects.

Both 20 mg diazepam and 0.5 g/kg ethanol functioned as reinforcers in moderate social drinkers but not in light drinkers c,d.

Triazolam was not shown to be a reinforcer in either insomniacs or normal subjects.

Diazepam was not a reinforcer in normal subjects; drug administration in social or solitary context did not affect drug choice.

Diazepam was not a reinforcer in subjects with and without family histories of alcoholism.

Diazepam was not a reinforcer in severely anxious subjects seeking treatment for anxiety; 10 mg diazepam functioned as a punisher c.

11

Drugs and doses

Diazepam (7 capsules of 4 mg each on choice days) Placebo (7 capsules on choice days) Buspirone (7 capsules of 4 mg each)

Diazepam (4 mg/capsule; up to 8 capsules per day, PRN) Placebo (up to 8 capsules per day, PRN)

Triazolam (0.125,0.25 mg) Placebo

Triazolam (0.25 mg) Placebo

Reference

Evans et al. (1996)




Table 3 (continued)a&/tbl.c:

Objective insomniacs (three groups of n=8)

Subjective insomniacs (n=9) Objective insomniacs (n=9)

Female subjects with generalized anxiety disorder (n=4)

Moderate social drinkers (n=55)

Subjects Choice tests consisted of 4 sampling days (2 for each of two drug conditions) followed by 3 choice days on which subjects made a mutually exclusive choice between the two conditions; 30 subjects were tested with diazepam versus placebo and 25 subjects were tested with buspirone versus placebo. Subjects visited the clinic 3 days/week for 6 weeks; choice and self-administration tests consisted of 2 sampling weeks (1 each for diazepam and placebo) followed by 4 weeks on which they made 12 mutually exclusive choices (3 times/week) about which drug condition to selfadminister “as needed.” Subjects were exposed to two conditions in which they ingested 0–3 capsules before bed; in the triazolam condition, a single capsule containing 0.25 mg triazolam was available on 3 sampling nights followed by 4 nights on which 3 capsules were available for optional selfadministration each night (0.25, 0.125, 0.125 mg); the placebo condition was similar except all capsules contained placebo. Subjects were assigned to one of three conditions in which they sometimes ingested a capsule before bed; each condition consisted of 4 sampling nights followed by 7 self-administration nights; the triazolam and placebo conditions involved triazolam and placebo capsules, respectively; the choice condition consisted of sampling triazolam and placebo on 2 nights each followed by a choice between triazolam and placebo on each of 7 nights.

Method

In the choice condition, subjects chose to self-administer triazolam on 86% of the nights; in the triazolam-alone and placebo-alone conditions, subjects selfadministered capsules on 77% and 80% of the nights, respectively.

Triazolam was self-administered as many nights as placebo, but the number of triazolam capsules self-administered was significantly less than placebo; compared to the subjective insomniacs, the objective insomniacs selfadministered capsules on more nights and self-administered more capsules.

Three subjects showed exclusive diazepam preference; 2 subjects selfadministered diazepam in an orderly temporal pattern that was consistent with self-medication of anxiety.

Subjects in the diazepam group chose active drug on significantly more sessions (64% of choice sessions) and ingested significantly more capsules with active drug than did subjects in the buspirone group (27% of choice sessions).

Results

Triazolam was a reinforcer in insomniacs when they had a choice between triazolam and placebo self-administration; triazolam and placebo were not differentially self-administered in conditions in which only one capsule was available each night.

Triazolam was not shown to be a reinforcer in insomniacs.

Diazepam was a reinforcer in patients with generalized anxiety disorder.

Diazepam was a reinforcer and buspirone was a punisher in moderate social drinkers c,d; also measured by choice, diazepam was relatively more reinforcing than buspirone in moderate drinkers b.

Comment

12

Significant based on a one-tailed t-test comparing the average percentage drug choice with the percentage expected by chance (50%)&/tbl.

d

Drug administration was oral and double-blind in all studies Significant based on statistics presented in the original article Significant based on a one-tailed z-test comparing the percentage of the group that were drug choosers (i.e. those who chose drug >50%) with the percentage expected by chance (50%)

a b c


Alprazolam (0.5 mg) Placebo

Subjects with generalized anxiety disorder or panic disorder (n=14)

Subjects visited the clinic once Eleven of 14 subjects showed clear weekly for 6 weeks; choice and alprazolam preference; most subjects self-administration tests took capsules at low stable rates. consisted of 2 sampling weeks (1 each for alprazolam and placebo) followed by 4 weeks on which they could self-administer “as needed.”

Alprazolam was a reinforcer in patients with generalized anxiety disorder or panic disorder.

13

triazolam (Roache and Griffiths 1989; Silverman et al. 1994; Roache et al. 1995). Variations in dose have shown that higher benzodiazepine doses are usually associated with greater reinforcing effects than lower doses (Griffiths et al. 1976, 1979, 1984b; Mumford et al. 1995a,b). Comparisons with non-benzodiazepines have shown that benzodiazepines were less efficacious reinforcers than pentobarbital (Griffiths et al. 1979, 1980b), but were more efficacious reinforcers than chlorpromazine (Griffiths et al. 1979), buspirone (Troisi et al. 1993) or abecarnil (Mumford et al. 1995a). As described in more detail below, comparison across benzodiazepines indicated that diazepam was a more efficacious reinforcer than oxazepam (Griffiths et al. 1984b). Finally, behavioral manipulations have shown that, like other abused sedativehypnotic drugs, benzodiazepine self-administration is reduced as an increasing function of the operant work requirement necessary to obtain drug (Bigelow et al. 1976), as well as reduced as an increasing function of the minimum interval imposed between ingestions within a daily session (Griffiths et al. 1976). In contrast to the consistent demonstration of benzodiazepine reinforcement in subjects with histories of drug abuse, studies in subjects without histories of drug abuse have produced mixed results, with reinforcement only being demonstrated in some subpopulations (moderate drinkers and subjects with anxiety or insomnia) (Table 3). When choice between a benzodiazepine (diazepam, lorazepam or flurazepam) versus placebo has been examined in normal subjects (light drinkers without anxiety or insomnia), the benzodiazepine has been consistently shown not to function as a reinforcer (e.g. Johanson and Uhlenhuth 1980; deWit et al. 1984a,b, 1985, 1986). In several but not all of these studies, choice of a benzodiazepine versus placebo was significantly lower than choice of placebo, thus indicating that the benzodiazepine was functioning as a punisher (Johanson and Uhlenhuth 1980; deWit et al.1984a,b, 1985). The pharmacological specificity of the lack of benzodiazepine reinforcing effect in normal subjects is suggested by the observation that amphetamine functions as a reinforcer under similar choice conditions (Johanson and Uhlenhuth 1980; deWit et al. 1985, 1986). Benzodiazepines are reinforcers in subjects with histories of moderate social alcohol drinking Three studies demonstrate the reinforcing effects of benzodiazepines in normal subjects with histories of moderate alcohol drinking but without histories of drug or alcohol problems (deWit et al. 1989; deWit and Doty 1994; Evans et al. 1996) (Table 3, Fig. 2). Two of these studies (deWit et al. 1989; deWit and Doty 1994) showed that diazepam functioned as a reinforcer in moderate drinkers but not in light social drinkers (mean of 12 and four drinks/week, respectively). The third study demonstrated the pharmacological specificity of benzodiazepine reinforcement in moderate drinkers by showing that

14 Fig. 2 Diazepam is a reinforcer in subjects with histories of moderate social drinking. Data are from three studies (deWit et al. 1989; deWit and Doty 1994; Evans et al. 1996) in which double-blind exposure to the capsule conditions (diazepam and placebo) was followed by 3 choice days on which subjects made a mutually exclusive chose as to which one of the two capsule conditions would be ingested that day. Bars indicate percentage of moderate drinkers showing diazepam preference (choice of diazepam on 2 or 3 of 3 choice days) and placebo preference (choice of placebo on 2 or 3 of 3 choice days). Diazepam preference was significantly greater than placebo preference in all three studies (cf. Table 3)&ig.c:/f

Fig. 3 Diazepam can function as a reinforcer in anxious subjects. Data are from a study (Roache et al. 1996) in which anxious subjects made repeated mutually exclusive choices between self-administering capsules containing diazepam or capsules containing placebo. Cumulative number of diazepam capsules are plotted as a function of time over week 3 of the study for the three subjects who showed exclusive diazepam preference&ig.c:/f

diazepam functioned as a reinforcer in contrast to the non-benzodiazepine anxiolytic buspirone which functioned as a punisher under identical conditions (Evans et al. 1996). These results are relevant to a substantial portion of the general population since it has been estimated that about 30% of 20- to 40-year-olds meet or exceed the criteria for moderate drinking (Cahalan et al. 1969; deWit et al. 1989). Although not investigated prospectively, a related factor that may be associated with benzodiazepine reinforcement among normal subjects is a history of low frequency recreational drug use that does not meet the diagnostic criteria for abuse and dependence. In both studies in which diazepam was a reinforcer in moderate but not in light drinkers, the moderate drinkers had a significantly higher rate of weekly marijuana use than the light drinkers (deWit et al. 1989; deWit and Doty 1994). Across the three studies demonstrating diazepam reinforcement in moderate drinkers, weekly marijuana use averaged 26% in moderate drinkers (deWit et al. 1989; deWit and Doty 1994; Evans et al. 1996). One further study has implicated a role for non-problematic recreational drug use in benzodiazepine reinforcement. Chutuape and deWit (1994) reported a meta-analysis of previous diazepam choice studies in normal subjects to characterize differences between diazepam choosers versus diazepam non-choosers. Although subjects were

screened to exclude those with histories of substance abuse or dependence, diazepam choosers reported greater current use of marijuana and a greater life-time use of stimulant drugs. Benzodiazepines can function as reinforcers in anxious subjects Five double-blind studies which investigated the reinforcing effects of diazepam in anxious subjects produced mixed results (Table 3). In two studies (deWit et al. 1986; McCracken et al. 1990) that showed that diazepam did not function as a reinforcer, subjects were required to ingest diazepam or placebo in the morning as a single bolus dose and return to their normal daily activities. In contrast, the three studies providing evidence of drug reinforcement gave subjects more control over the time and total dose self-administered (Chutuape and deWit 1995; Roache et al. 1996, 1997). In the study by Chutuape and deWit (1995), choice sessions were conducted in the evenings in a laboratory setting. After making a mutually exclusive choice between self-administering placebo or diazepam, subjects could decide whether or not to ingest a capsule every 30 min for a total of seven capsules (total of 28 mg diazepam). Anxious subjects chose diazepam over placebo on 65% of the opportunities, which was marginally significant (Table 3). The study also showed that anxious subjects self-administered

15

more capsules than normal control subjects. The most convincing demonstration of the reinforcing effects of a benzodiazepine in anxious subjects was provided in two studies (Roache et al. 1996, 1997) which more closely approximated the usual clinical use of benzodiazepine drugs. After 2 weeks in which subjects sampled, under double-blind conditions, capsules containing placebo or a benzodiazepine (either diazepam or alprazolam in different studies), subjects had 4 continuous weeks during which they made choices between self-administering the benzodiazepine or placebo. Importantly, subjects were instructed to self-administer capsules “as needed” for anxiety, with the restriction that they should not exceed eight capsules a day. Under these conditions, most subjects in both studies developed low stable rates of selfadministration and showed a strong preference for the benzodiazepine over placebo (>90%). In the study with diazepam, three of four subjects chose to self-administer diazepam exclusively. Figure 3 shows the relatively orderly patterns of diazepam self-administration that occurred in these subjects during week 3 of the study in which they could choose between diazepam and placebo capsules. The conclusion that benzodiazepines can function as reinforcers in some anxious subjects is consistent with the clinical observation that patients with anxiety disorders do indeed self-medicate with benzodiazepines. Benzodiazepines can function as reinforcers in insomniac subjects A clear demonstration of a benzodiazepine functioning as a reinforcer when administered before bed to insomniacs was provided in a recent study in which subjects sampled the triazolam and placebo and then had 7 nights involving a mutually exclusive choice between ingesting triazolam or placebo (Roehrs et al. 1997). These results were similar to those of two older studies in which a verbal preference (actual drug choice was not measured) for triazolam (Fabre et al. 1976) or flurazepam (Jick et al. 1966) over placebo was demonstrated after blind sampling. In contrast to the clear results obtained using mutually exclusive choice procedures, several studies have failed to demonstrate triazolam reinforcement in insomniacs using optional self-administration procedures which have resulted in a high rate of placebo self-administration (placebo self-administered >60% of nights) which was not different from triazolam (Roehrs et al. 1992, 1996, 1997). Contextual determinants of benzodiazepine reinforcing effects: dose self-control and behavioral requirements following drug ingestion Drug reinforcement, like reinforcement by non-drug consequences, may be importantly determined by the behavioral context in which drug is made available for selfadministration. As suggested by the preceding discussion

Fig. 4 Contextual control of triazolam and d-amphetamine reinforcement in humans. The percentage of the eight subjects who chose to take placebo, 15 mg d-amphetamine, and 0.25 mg triazolam, when the vigilance (upper panel) and relaxation (lower panel) contexts were scheduled. The asterisks to the right of the bars indicate which drug choice was significantly controlled by environmental context according to the binomial probability distribution (P≤0.002). Data are from Silverman et al. (1994)&ig.c:/f

of the studies in anxious subjects, control over amount and/or time of drug ingestion may be an example of a contextual determinant of benzodiazepine reinforcement. Although not investigated prospectively, a comparison of studies in Table 3 in subjects without histories of drug abuse suggests that benzodiazepines are more likely to function as reinforcers or less likely to function as punishers when the study design allows the subjects to control the time and total dose self-administered. More specifically, in many of the studies in Table 3 which failed to demonstrate benzodiazepine reinforcement, subjects received a single bolus dose of drug during their normal working day (e.g. Johanson and Uhlenhuth 1980; deWit et al. 1984a,b). In contrast, studies that provided subjects with multiple opportunities to self-administer small doses of benzodiazepine generally showed greater preference for the benzodiazepine (cf. deWit et al. 1989; Chutuape and deWit 1995; Roache et al. 1996). A clear example of contextual control over benzodiazepine reinforcement comes from a study that experimentally demonstrated that the reinforcing effects of both a benzodiazepine and a stimulant could be modulated by the behavioral requirements following drug ingestion (Silverman et al. 1994). Subjects with histories of drug abuse were initially exposed to three drug conditions (placebo, 0.25 mg triazolam and 15 mg d-amphetamine) in the context of two different behavioral tasks (a relaxation task or a computer vigilance task). The drug conditions were administered in color-coded capsules using double-blind procedures. After exposure to the conditions, subjects were given repeated opportunities to choose to ingest one of the three color-coded capsule drug conditions before engaging in prolonged sessions involving the relaxation task or the vigilance task. As shown in Fig. 4, all eight subjects reliably chose triazolam before the relaxation task and no subject chose tri-

16

azolam before the vigilance task. Seven of eight subjects chose d-amphetamine before the vigilance task. Thus the reinforcing effects of both triazolam and d-amphetamine were determined by the behavioral requirements following drug ingestion. A final example of contextual control over benzodiazepine reinforcement is that provided in a study by Roehrs et al. (1997), which showed that triazolam functioned as a reinforcer under a mutually exclusive drug versus placebo choice procedure, but not under conditions using optional self-administration procedures which resulted in high rates of placebo self-administration. Rapid speed of onset of drug effect enhances benzodiazepine reinforcing effects Research in operant behavior has shown that reinforcement becomes less effective as the time from response to subsequent reinforcement increases (Catania 1991). It is widely believed that the reinforcing efficacy of a drug is partly determined by the speed of onset of drug effects. Anecdotally, drug abusers appear to prefer routes of administration resulting in rapid central nervous system effects (e.g. IV, inhalation, snorting), and one study with cocaine abusers showed that euphoria increased with increases in cocaine infusion rate (Fischman and Schuster 1984). Several double-blind studies demonstrate that the efficacy of sedatives, including benzodiazepines, to function as reinforcers or to increase positive subjective effects (sometimes used as an indirect measure of drug reinforcement) is partly determined by the speed of onset of drug effects after oral administration. One study examined the subjective and behavioral effects of diazepam after a single oral dose (fast onset) versus a series of smaller oral doses administered at 30-min intervals (slow onset) in healthy social drinkers (deWit et al. 1993). The two dosing conditions produced comparable peak plasma levels of drug, with the peak occurring earlier in the fast onset condition than in the slow onset condition (61 min versus 220 min). Compared to the slow onset condition, subjects in the fast onset condition reported more euphoria and showed more behavioral signs of intoxication and greater psychomotor performance impairment. These findings with diazepam were consistent with the results of a similar study from this same laboratory with pentobarbital (deWit et al. 1992). A more recent study by Mumford et al. (1995c) extended these findings to another benzodiazepine by evaluating the effects of placebo, immediate-release alprazolam and extended-release alprazolam in subjects with histories of drug abuse. Mean peak alprazolam plasma levels occurred at 1.7 h after the immediate-release alprazolam and 9.2 h after the extended-release alprazolam. Consistent with the deWit findings with diazepam, the immediate-release formulation generally produced greater increases in positive subjective effects (e.g. ratings of liking and good effects), greater increases in drug reinforcement as assessed by a drug versus money multiple choice procedure, as well as

greater impairment of psychomotor and cognitive performance. In addition to these studies that have compared different dosing regimens or release rates of the same compound, the importance of speed of onset of drug effects as a determinant of reinforcing effects and increased positive subjective effects has been supported in doubleblind studies in drug abusers showing that sedative compounds with rapid onset of effects, such as diazepam and pentobarbital, produce a range of positive subjective effects, suggesting greater abuse liability than congeners with slower onsets of effects, i.e. phenobarbital (Fraser and Jasinski 1977) and oxazepam (Griffiths et al. 1984a,b). The most thoroughly characterized comparison was that which evaluated a wide range of doses of diazepam and oxazepam (Griffiths et al. 1984a,b). Diazepam was associated with a more rapid onset of effect than was oxazepam, and this rapid onset of effect was repeatedly cited by subjects in written comments as being a desirable feature of the drug effect. Diazepam also produced greater liking and euphoria and was judged to be of greater monetary street value than oxazepam. The subjective effects of diazepam were categorized as being similar to barbiturates more frequently than were those of oxazepam. Finally, behavioral choice tests showed that diazepam was a more efficacious reinforcer than oxazepam. Consistent with these laboratory-based findings, compared with oxazepam, diazepam was associated with increased retrospective evaluation of drug “high” in sedative drug abusers (Iguchi et al. 1993), increased perception of abuse liability in the clinical judgement of medical professionals treating drug abusers (Griffiths and Wolf 1990), and increased epidemiological data on abuse and drug thefts which cannot be accounted for by differences in prescription rates (Griffiths et al. 1984b; Bergman and Griffiths 1986; Griffiths and Wolf 1990).

Reinforcing effects of benzodiazepines in laboratory animals: relationship to human data The preceding section reviewed research on the reinforcing effects of benzodiazepines in human subjects. This section will review analogous research conducted in laboratory animals and will discuss the relationship of these preclinical findings with the human data. In laboratory animals, benzodiazepine reinforcement via the IV, intragastric and oral routes has been studied using drug selfadministration procedures. Typically, animals are given access to a manipulandum, responding on which activates an injection pump or provides access to a drug solution via a drink spout. Table 4 summarizes the results of 24 studies in nonhuman primates and rats which examined IV benzodiazepine self-injection. As with the human studies in drug abusers, these studies clearly indicate that benzodiazepines can serve as reinforcers. These studies show that benzodiazepines can function as reinforcers in drug naive as well as drug experienced animals and that benzo-

Drugs and dosesb

Diazepam (0.005–0.5 mg/kg)

Hoffmeister (1974, 1977)

Method

Rhesus monkeys

A three-lever choice procedure was used in which injections of drug or saline were dependent upon completion of a shock avoidance lever pull requirement. Initial selection of drug was promoted by requiring a lower response requirement for drug than saline. Initially, the shock avoidance/drug choice trials were presented automatically every 3 (or 4) h, but monkeys could initiate trials more frequently by pressing a separate lever. Male and female Drug injections were continuously drug naive rhesus available and dependent on pressing a monkeys lever. First saline self-injection was (diazepam, n=4) characterized for 1–2 weeks, a test drug (chlordiazepoxide, was then substituted for 4 or more weeks. n=4)

Male rhesus monkeys (n=2)

Subjects

A summary of self-injection testing of several drugs is provided. Drug injections were dependent on responding under an FR 10 schedule during 3-h sessions. Stable self-injection was established with codeine (0.05 mg/kg) and then saline or drug doses were substituted for 6 days. Codeine self-injection was reestablished before each dose substitution. Self-injection was also examined when the FR requirements were varied. Details of procedures were not included in the review. Yanagita et al. Clorazepate dipotassium Male rhesus Drug injections were dependent on lever (1977b)c (0.25–2.0 mg/kg) monkeys press responses. Saline was available (n=2 self-injection for 1 week, then drug was available for naive) up to 14 weeks. Doses were varied and (n=2 self-injection during some periods, monkeys were experienced) exposed to non-contingent injections of clorazepate (e.g. 1 mg/kg every 2 h) in addition to 1.0 mg/kg injections that were available for self-injection.

Diazepam (0.4 mg/kg) Chlordiazepoxide (1 mg/kg)

Yanagita and Takahashi (1973)

Non-human primates Findley et al. Chlordiazepoxide (1972) (0.5–2.0 mg/kg per injection)

Reference

Table 4 Intravenous reinforcing effects of benzodiazepines in animals a&/tbl.c:

Diazepam self-injection (8–10 mg/kg per day) was maintained in three out of four monkeys. Chlordiazepoxide self-injection (10–20 mg/kg per day) was maintained in three out of four monkeys for 4 weeks, then gradually declined to two to four injections/day. Under comparable conditions, pentobarbital maintained selfinjection in eight of eight naive monkeys. Diazepam and pentobarbital maintained self-injection above vehicle, but at lower rates than codeine. Chlorpromazine and imipramine did not maintain self-injection. Increasing the FR requirement (FR 1–10) produced a monotonic decrease in self-injections with diazepam and pentobarbital, but cocaine self-injection remained stable. Both drug self-injection experienced monkeys and one of two naive monkeys was considered to have self-injected clorazepate significantly more than saline. Within the 14-week period daily self-injection rate dropped to low pre-drug saline levels.

Monkeys initiated trials and chose drug more frequently than saline.

Results

Clorazepate was a reinforcer, but self-injection was inconsistent.

Diazepam was a reinforcer.

Diazepam and chlordiazepoxide were reinforcers.

Chlordiazepoxide was a reinforcer.

Comment

17


Hackett and Hall (1977)

Rhesus monkeys (n=3)

Subjects

Method

Drug injections were dependent on lever presses under an FR 2 schedule during 4-h sessions. Stable levels of codeine (0.05 mg/kg) self-injection were established. A dose of diazepam (0.05, 0.1, or 0.4 mg/kg) was substituted for 3 days, followed by a different diazepam dose (0.1, 0.2 or 0.4 mg/kg, respectively) for 3 more days. Codeine self-injection was reestablished and then saline was substituted. Johanson and Flurazepam Rhesus monkeys A brief summary is provided of IV drug Balster (1978) Chlordiazepoxide self-injection results from different laboratories. Drug injections were dependent on responding under an FR schedule. Self-injection was established with a baseline drug (e.g. cocaine or codeine) and doses of benzodiazepines were substituted for a number of sessions. Reinforcement was defined as self-injection above vehicle in more than 50% of monkeys tested. Griffiths et al. Clonazepam Male baboons Drug injections were dependent on lever (1981) (0.01–10 mg/kg) (clonazepam, n=2) pulling under an FR 160 schedule; a Clorazepate dipotassium (clorazepate, n=6) time-out period of 3 h followed each (0.01–5.6 mg/kg) (diazepam, n=3) injection for a maximum of 8 injecDiazepam (flurazepam, n=2) tions/day. Self-injection (6–8 injec(0.032–17.8 mg/kg) (medazepam, n=4) tions/day) of cocaine (0.32 mg/kg) was Flurazepam (midazolam, n=5) established and then drug doses or vehicle dihydrochloride were substituted for 12–15 days. Cocaine (0.1–30 mg/kg) self-injection was re-established before Medazepam each dose substitution. hydrochloride (0.01–10 mg/kg) Midazolam maleate (0.032–10 mg/kg) Balster and Chlordiazepoxide Male rhesus Drug injections were dependent on lever Woolverton hydrochloride monkeys responses under an FR10 schedule (1982) (0.01–0.3 mg/kg) (chlordiazepoxide, during 2-h daily sessions. SelfClorazepate dipotassium n=2) injection responding was established monohydrate (clorazepate, n=2) with 0.1 mg/kg cocaine and (0.03–1.0 mg/kg) then was maintained with 0.03 mg/kg cocaine. Each drug dose or vehicle was substituted for six consecutive sessions. Cocaine selfinjection was reestablished before each drug dose substitution.

Drugs and doses

Reference

Table 4 (continued)&/tbl.c:&

Flurazepam and chlordiazepoxide were reinforcers. Only a brief summary of data was provided.

Midazolam clearly functioned as a reinforcer. The other benzodiazepines were modest reinforcers; they were more efficacious than chlorpromazine but maintained lower rates of self-injection than amobarbital, pentobarbital and secobarbital.

Flurazepam met the criterion for drug reinforcement in one laboratory. Chlordiazepoxide met the criterion for drug reinforcement in one laboratory but not in a second laboratory.

All benzodiazepines maintained moderate mean numbers of selfinjections that were higher than vehicle control, but were lower than cocaine. In some baboons, midazolam maintained numbers of self-injections that were comparable to cocaine. Under comparable conditions, chlorpromazine did not maintain self-injection whereas amobarbital, pentobarbital and secobarbital maintained high rates similar to cocaine control.

Chlordiazepoxide and clorazepate Chlordiazepoxide and clorazepate did not reliably maintain selfwere not reinforcers. injection above vehicle control. Buspirone also did not maintain self-injection above vehicle control in the same four monkeys tested with clordiazepoxide and clorazepate.

Diazepam was not a reinforcer.

Comment

Diazepam did not maintain self-injection behavior above that maintained by saline in codeine-trained monkeys.

Results

18

Male cynomolgus monkeys were either drug naive (n=4/group) or had histories of pentobarbital selfinjection (n=5)

Midazolam (0.003–0.3 mg/kg) Triazolam (0.001–0.03 mg/kg) Chlordiazepoxide (0.03–3.0 mg/kg) Flurazepam (1.0–3.0 mg/kg)

Diazepam (1.0 mg/kg)

Estazolam (0.003–0.3 mg/kg) Flurazepam hydrochloride (0.003–1 mg/kg) Lorazepam (0.003–0.3 mg/kg)

Kubota et al. (1986)c

Yanagita (1987)

Johanson (1987)

Male (n=2) and female (n=4) rhesus monkeys

Rhesus monkeys (n=4–5)


Bergman and Diazepam Johanson (0.012–0.4 mg/kg) (1985)

Continuously available drug or saline injections were dependent on lever responses under an FR 100 schedule. The ratio requirement was increased each injection until responding was suppressed below a criterion level. Drug self-injection was tested when monkeys had been pretreated with programmed IV administration of diazepam (1 mg/kg) or saline every 2 h for 4 weeks. Drug injections were dependent on lever responses under an FR 5 or FR 10 schedule during daily 3-h sessions. Stable self-injection of pentobarbital (0.25, 0.5 mg/kg) was established. Vehicle was substituted until responding declined to low levels. Pentobarbital self-injection was reestablished and then doses of benzodiazepines were substituted for the same numbers of sessions as vehicle substitutions. Pentobarbital selfinjection was reestablished before each dose substitution.

Drug injections were dependent on lever presses under an FR 1 limited access schedule or under an FR 10 schedule for 6 h. After establishing self-injection with pentobarbital, a drug dose was substituted for at least 5 days. Pentobarbital self-injection was reestablished before each drug dose substitution. In a within day progressive-ratio schedule test, the response requirement was doubled after each injection. In drug naive monkeys, saline, midazolam or triazolam were available for 14 days at each of several doses.

Drug injections were dependent on lever responses under an FR1 or FR10 schedule during 1- to 3-h daily sessions. After establishing self-injection with pentobarbital (0.25–0.5 mg/kg) or cocaine (0.1 mg/kg), a diazepam dose or vehicle was substituted for 5–14 days. Cocaine or pentobarbital self-injection was reestablished before each drug dose substitution.

Diazepam maintained self-injecDiazepam was a reinforcer when tion above vehicle control when substituted for pentobarbital. substituted after pentobarbital in Diazepam was an inconsistent reinall five monkeys tested, but only in forcer when substituted for cocaine. three of 11 monkeys when substituted after cocaine under the FR 10 schedule of drug delivery. Diazepam did not maintain selfinjection above vehicle under the FR 1 schedule. When substituted for pentobarbital Midazolam and triazolam under FR 1 and FR 10 schedules, functioned as reinforcers, but were midazolam and triazolam both less efficacious than pentobarbital. maintained self-injection in four Chlordiazepoxide was an inconsistent out of five monkeys. Using similar reinforcer and flurazepam was not a procedures with the FR 1 schedule, reinforcer. chlordiazepoxide and flurazepam maintained self-injection in two of five and none of four monkeys, respectively. On the progressiveratio test, midazolam and triazolam maintained self-injection only weakly and more weakly than pentobarbital. In drug naive monkeys midazolam and triazolam maintained self-in-jection in three of four and two of four animals, respectively. Pento-barbital maintained high rates of self-injection in four of four naive animals. The final ratio maintained by Diazepam was a reinforcer. Chronic diazepam was higher than that pretreatment with diazepam, maintained by saline in four of four presumably producing physical monkeys. Pretreatment with dependence, did not increase the diazepam did not reliably increase reinforcing effects of diazepam. or decrease the final ratios maintained by diazepam. Using similar procedures, chronic pretreatment with codeine increased final ratios maintained by codeine in three of three monkeys. Flurazepam maintained numbers Flurazepam, lorazepam and of self-injections that were higher estazepam were reinforcers. than vehicle control in all six monkeys tested. Lorazepam and estazolam maintained numbers of self-injections above vehicle in the majority of monkeys tested.

19

Sannerud et al. Abecarnil Male baboons 1992 (0.032–1.0 mg/kg) (n=3) Triazolam (0.01 mg/kg)

Male rhesus monkeys (n=2; one experimentally naive and one selfinjection experienced)


Subjects Monkeys were trained to respond on a lever under an FR 1–10 schedule of diazepam (0.03 mg/kg) delivery during daily 2-h sessions. Substitution of various doses of diazepam, saline and cocaine were examined.

Method

Drug injections were dependent on lever pulling under an FR 80 or 160 schedule; a time-out period of 3 h followed each injection for a maximum of eight injections per day. Self-injection (6–8 injections/day) of cocaine (0.32 mg/kg) was established and then drug

Cocaine (0.1 mg/kg) substitution procedure under conditions of satiation (free feed) and food-deprivation (75–85% free feed body weight). Drug injections were dependent on lever presses under an FR 10 schedule during 3 h daily sessions. Diazepam doses or vehicle were substituted until 3 consecutive days of stability. Cocaine self-injection was reestablished between each drug dose. Nader et al. Brotizolam Male (n=2) and Drug injections were dependent on lever (1991) (0.0001–0.03 mg/kg) female (n=5) responses under an FR 10 schedule during Diazepam rhesus monkeys. 130-min sessions; two sessions were sche(0.001–0.1 mg/kg) Each drug was duled daily and methohexital and saline Methohexital sodium tested in 3 were each available during approximately (0.01–0.3 mg/kg) monkeys half the sessions. Various doses of Pentobarbital sodium methohexital, pentobarbital, diazepam and (0.01–0.3 mg/kg) brotizolam were substituted for methohexital for a single session. Each dose was tested twice in three monkeys. Griffiths et al. Alprazolam Male baboons Drug injections were dependent on (1991) (0.01–3.2 mg/kg) (alprazolam, n=4) lever pulling under an FR 80 or 160 Bromazepam (bromazepam, n=3) schedule; a time-out period of 3 h (0.032–3.2 mg/kg) (chlordiazepoxide, followed each injection for a maximum Chlordiazepoxide n=3) of eight injections per day. Self-injection hydrochloride (lorazepam, n=4) (6–8 injections/day) of cocaine (0.032–3.2 mg/kg) (triazolam, n=4) (0.32 mg/kg) was established and then Lorazepam drug doses or vehicle were substituted (0.001–3.0 mg/kg) for 15 days. Cocaine self-injection was Triazolam reestablished before each dose substitution. (0.0001–0.32 mg/kg)


Grant and Johanson (1987)

de la Garza Diazepam and Johanson (0.025–0.4 mg/kg) (1987)

Drugs and doses

Reference

Table 4 (continued)&/tbl.c:&

Triazolam, lorazepam, chlordiazepoxide, alprazolam, bromazepam were reinforcers but maintained lower rates of self-injection than methohexital, but higher rates than phenobarbital and buspirone.

All benzodiazepines maintained mean rates of self-injections that were higher than vehicle control (usually >2 injections/day), but less than cocaine (7–8 injections/day). Maximal mean injections/day were: Triazolam (5.6), lorazepam (4.8), chlordiazepoxide (4.3), alprazolam (4.1), bromazepam (3.1). Similar data for comparison compounds were: methohexital (6.1), phenobarbital (1.8), buspirone (1.3). Abecarnil maintained mean rates of self-injections that were similar to vehicle control. Under comparable conditions triazolam and other benzodiazepines maintained higher rates of self-injection than abecarnil.

Abecarnil is not a reinforcer in contrast to classic benzodiazepines such as triazolam.

Diazepam and brotizolam were reinforcers, but maintained lower rates of self-injection than methohexital or pentobarbital.

Diazepam was an equivocal reinforcer and food deprivation did not increase self-injection.

The variation in saline responding makes it difficult to interpret whether diazepam functioned as a reinforcer.

Comment

Diazepam maintained self-injections in all three monkeys at rates higher than self-injection of saline, but below rates maintained by methohexital and pentobarbital. Brotizolam also maintained selfinjection in all three monkeys but rates were lower than diazepam.

Diazepam maintained self-injection that was higher than saline administered prior to diazepam, but was comparable to saline administered after diazepam (i.e. extinction). Cocaine maintained higher rates of self-injection. Saline responding after cocaine rapidly returned to low levels, whereas saline responding after diazepam remained high. Diazepam maintained selfinjections significantly above vehicle control in the one selfinjection experienced monkey. In contrast to d-amphetamine selfinjection, the self-injection of diazepam was not increased by food deprivation.

Results

20

doses or vehicle were substituted for 15 days. Cocaine self-injection was reestablished before each dose substitution. Griffiths et al. Zolpidem tartrate Male baboons Drug injections were dependent on Zolpidem and triazolam both main- Zolpidem and triazolam were rein(1992) (0.01–1.0 mg/kg) Zolpidem (n=8) lever pulling under an FR 80 or 160 tained self-injection but rates main- forcers. Triazolam Triazolam (n=12) schedule; a time-out period of 3 h tained by zolpidem were consis(0.0001–0.32 mg/kg) followed each injection for a maximum tently higher and near maximal of eight injections per day. Self-injection for the procedure. Maximal mean (6–8 injections/day) of cocaine (0.32 injections/day were: zolpidem mg/kg) was established and then drug (6.9) and triazolam (5.5). doses or vehicle were substituted for 15 days. Cocaine self-injection was reestablished before each dose substitution. In another experiment doses of zolpidem and triazolam which maintained maximal self-injection rates were alternatively substituted for one another for 7 or more days. Winger et al. Flunitrazepam (0.0001– Rhesus monkeys Drug injections were dependent on lever All three monkeys self-injected Flunitrazepam was a reinforcer. (1992) 0.032 mg/kg) (n=3) responding under an FR 10 schedule flunitrazepam at higher rates during 210-min sessions or until a than saline. Rates were intermediate maximum of 150–200 injections were in two monkeys and similar to delivered. A 15-s timeout followed the methohexital in one monkey. completion of the response requirement. Sessions were conducted twice daily with at least 4 h between sessions. Stable selfinjection was established with methohexital (0.1 mg/kg); saline was substituted for approximately half of the sessions. Then doses of flunitrazepam were substituted for one session. Each dose was tested twice. Ator and Midazolam maleate Male baboons Drug injections were dependent on lever Midazolam maintained high rates Midazolam was a reinforcer. Griffiths (0.0032– (n=2) pulling under an FR 160 schedule; a time- of self-injection (6–8 injections/day). (1993) 0.32 mg/kg) out period of 3 h followed each injection for a maximum of 8 injections per day. Self-injection (6–8 injections/day) of cocaine (0.32 mg/kg) was established and then saline was substituted. Cocaine was then reinstated and midazolam 0.32 mg/kg was substituted for at least 13 days, followed by substitution of progressively lower doses of midazolam. Weerts et al. Midazolam maleate Male baboons Continuously available drug or saline Midazolam (1.0 mg/kg) maintained Midazolam was a reinforcer. (1997) (0.004–2.0 mg/kg) (n=6, two self-in- injections were dependent on lever an orderly spaced within-day pattern jection experienced, pulling under an FR 30 schedule; a of injections and low but stable four naive) time-out period of 5 min followed each rates of self-injection (e.g. 5 d Article is in Japanese. Summary is based on English abstract, tables and figures e Ten or fewer self-administrations per day&/tbl.:

Drug infusions were continuously available and dependent on a lever press response under an FR 1 schedule. Seven rats tested with 10 mg/kg per injection for 6– 19 days were compared to four rats tested with vehicle for 14 days. Rats were 23-h water deprived. Drug infusions were dependent on a lick response to a water tube during 10-min sessions. Drug concentrations were increased over 10 days. Drug infusions were dependent on lever presses under an FR 1 schedule during daily 10-h sessions. In expt 1 groups of rats were exposed to saline for one day and then saline or different chlordiazepoxide doses for 8 days. In expt 2, a second lever was added: one lever activated a buzzer and resulted in drug injection; the other lever had no programmed consequence.

Continuous self-administration for 20 weeks b

Continuous self-administration for 10–12 weeks b

All animals were surgically implanted with chronic intragastric catheters Yanagita and colleagues have used similar methods across most studies. Drug infusions were continuously available and dependent on a lever press response. First, vehicle was available, typically for 1 week. Then drug was available for 4–22 weeks. During this period, different doses were examined. Sometimes response-independent infusions were given in addition to infusions that were available for self-administration. Sometimes vehicle was substituted

a b

Diazepam

Walton and Deutsch (1978)

Medazepam

Lormetazepam

Yanagita et al. (1985)d

Rats Götestam (1973)

Quazepam

Yanagita (1985)

25

Drugs

Diazepam Midazolam

Alprazolam Diazepam Midazolam Triazolam

Triazolam

Alprazolam Triazolam

Stewart et al. (1994a)

Meisch et al. (1996)

Kautz and Ator (1995)

Kautz and Ator (1996)

Non-human primates Ator and Diazepam Griffiths Triazolam (1992)b Ethanol

Reference

Baboons (n=3)

Baboons (n=3 self-administration experienced; n=3 self-administration naive)

Rhesus Monkeys (n=2 or 3/group)

Rhesus Monkeys (midazolam, n=4) (diazepam, n=3); all were selfadministration experienced and food-restricted (75–91% free feed body weights)

Baboons (n=1 experimentally naive; n=3 selfadministration experienced)

Subjects

Table 6 Oral reinforcing effects of benzodiazepines in animals a&/tbl.c:

Availability of drug solution was dependent on a mouth contact response during 3-h sessions. A foodinduced drinking procedure was used to establish initial drinking under one spout conditions. One spout conditions and two spout choice (drug and vehicle) conditions were studied after the original inducing conditions ended. Later, each drink was dependent on completing a lever-press response requirement under the one spout procedure. Availability of drug solution was dependent on mouth contact responses under an FR 8 –32 schedule during 3-h sessions. Water was concurrently available under identical conditions from a second spout. Drinking was initially maintained with an 8% ethanol solution. Midazolam was initially substituted for ethanol. After ethanol drinking was reestablished, midazolam concentration was gradually increased and the ethanol concentration decreased until only the drug solution was present. Diazepam was substituted for midazolam. Published as abstract: methods presumed to be similar to Stewart et al. (1994a). Diazepam drinking was estabished using an ethanol-fading procedure. High dose versus low dose choice tests were conducted with both diazepam and midazolam. Alprazolam and triazolam were substituted for midazolam. Availability of drug solution was dependent on a mouth contact response during 3-h sessions. A food-induced drinking procedure was used to establish initial drinking. Data on drug reinforcement was from the first hour before food delivery. The availability of triazolam and vehicle was examined under single spout conditions. Studies were conducted involving triazolam pretreatment before vehicle drinking in self-administration experienced and naive baboons. Published as abstract: methods similar to Ator and Griffiths (1992). One spout (drug or vehicle alone) conditions and two spout choice (drug and vehicle) conditions were studied. Later, each drink was dependent on completing a lever-press response requirement.

Method

Low concentrations of alprazolam and triazolam were reinforcers under the one spout condition but not under the two spout choice condition. Reinforcement was also shown by the maintainance of higher response requirements by alprazolam and triazolam than by vehicle.

Triazolam was a reinforcer: three of three baboons consumed greater volumes of triazolam solutions than vehicle. Pretreatment with triazolam increased vehicle consumption only in self-administration-experienced baboons, further suggesting that triazolam functioned as a reinforcer.

The authors concluded that diazepam was a reinforcer after ethanol fading, and triazolam and alprazolam were reinforcers when substituted for midazolam. Higher doses of midazolam and diazepam were preferred over lower doses in choice tests.

Midazolam was not a reinforcer when substituted for ethanol. Midazolam reinforcement was demonstrated in three out of four monkeys after ethanol fading. Diazepam was a reinforcer when substituted for midazolam in all three monkeys tested.

Triazolam and diazepam reinforcement was concluded for one of four baboons for each drug under the one spout procedure, and for two of four baboons under the two spout procedure. All baboons showed ethanol reinforcement under the two spout procedure. When the lever press requirement was imposed, higher volumes of drug than vehicle were maintained by ethanol but not by triazolam or diazepam.

Results

26

Midazolam maleate

Chlordiazepoxide hydrochloride Flurazepam dihydrochloride Midazolam maleate Cocaine hydrochloride Ethanol Chlordiazepoxide hydrochloride

Falk and Tang (1985)

Falk and Tang (1989a)

Albino, Holtzman rats (n=4 per group); all were food-restricted (80% of free feed body weight)

Albino, Holtzman rats (n=6–7 per group); all were food-restricted (80% of free feed body weight)

Albino, Holtzman rats (n=6–7 per group); all were food-restricted (80% of free feed body weight)

Hooded rats (n=3–4 per group)

Sprague-Dawley rats (n=30, free choice procedure; n=2–3 per group for other procedures)

The ethanol group consumed more chlordiazepoxide (ml/pellet) in the 5-min probe session than the water or cocaine groups, suggesting that the reinforcing effects of chlordiazepoxide interact with drug consumption history.

Relative to water control groups, midazolam, cocaine and ethanol groups consumed more drug (ml/pellet) during the 3- or 5-min probe sessions. Chlordiazepoxide and flurazepam groups did not show this effect. It was concluded that these differences may reflect differences in reinforcing efficacy.

Under these scheduled-induced drinking conditions, the mean volume consumed of the low dose of chlordiazepoxide group was slightly higher than the mean volume consumed of the water group. When water was substituted for the low dose of of chlordiazepoxide, volume consumed decreased in all three rats, suggesting that chlordiazepoxide was functioning as a reinforcer. Relative to the water control group, the midazolam group consumed more drug (ml/pellet) during the 3- or 5-min probe sessions. Under the two-spout choice condition, both groups preferred midazolam to water only when pellets were delivered all at once (FT 0 min). The magnitude of this preference was greater in the former midazolam group.

Chlordiazepoxide was not a reinforer under two-bottle choice tests either in drug naive rats or in rats exposed to forced drinking conditions. Rats trained to drink chlordiazepoxide with food reinforcement subsequently consumed more drug than water in choice tests (60% of total daily fluid intake). These results can be interpretted either as drug reinforcement or as extinction of a previously reinforced operant.

Amit and Cohen (1974); Yanaura and Tagashira (1975); Wolf et al. (1978); Nelson et al. (1983); Wolfgramm and Heyne (1991) b Portions of triazolam data for two baboons was reported in Griffiths et al. (1985)

Drug solution or water was available from a drink spout during 3-h sessions in which food pellets were delivered according to a fixed-time 1-min schedule. Different groups of rats were exposed to either water, cocaine or ethanol for 68 or more sessions and subsequently switched to chlordiazepoxide. The fixed-time schedule was changed to 3 min and 5 min during single probe sessions.

In one condition drug naive rats were exposed to two-bottle choice tests (drug and water). Some rats were exposed to periods of forced drinking (drug solution only fluid available) preceding twobottle choice tests (drug and quinine solutions). One group was trained to drink drug (FR 50 licks) as an operant, with food delivery as the reinforcer, prior to a 21-day, two-bottle choice test (drug and water). Drug solution or water was available from a drink spout during 1-h sessions in which food pellets were delivered according to a fixed-time 1-min schedule. Different groups of rats were exposed to water, a low dose or a high dose of chlordiazepoxide for 20 sessions. At the end of the study water was substituted for drug in chlordiazepoxide groups. Drug solution or water was available from a drink spout during 3-h sessions in which food pellets were delivered according to a fixed-time 1-min schedule. Different groups of rats were exposed to water or midazolam for 63 or more sessions. The fixed-time schedule was varied (0, 0.5, 3 and 5 min) during single probe sessions. The procedures were repeated with two-spout choice tests (drug and water) for both former water and midazolam groups. Drug solution or water was available from a drink spout during 3-h sessions in which food pellets were delivered according to a fixed-time 1-min schedule. Different groups of rats were exposed to the different drug conditions or water. The fixedtime schedule was varied (0, 0.5, 3 and 5 min) during single probe sessions.

a For brevity, eight additional oral self-administration studies in rats which did not clearly demonstrate benzodiazepine reinforcement have not been summarized in the Table. These studies are: Kamano and Arp (1965); Stolerman et al. (1971); Amit et al. (1973);

Falk and Tang (1989)b

Chlordiazepoxide hydrochloride

Chlordiazepoxide hydrochloride

Sanger (1977)

Rats Harris et al. (1968)

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Table 6 summarizes the results of 18 studies in nonhuman primates and rats which examined oral self-administration of benzodiazepines. In contrast to both the IV and intragastric routes, a much greater proportion of these studies (eight of 18) did not show evidence of benzodiazepine reinforcement. Of those studies which demonstrated reinforcement via the oral route, virtually all involved exposing the animals to special conditions or histories such as food-induced drinking, schedule-induced drinking, or ethanol fading (e.g. Sanger 1977; Falk and Tang 1985; Ator and Griffiths 1992; Stewart et al. 1994a), and the rat studies, in particular, provided only very weak evidence of drug reinforcement. To this extent, establishment of benzodiazepine reinforcement via the oral route appears more difficult than via the IV or intragastric routes, probably due in part to the aversive taste of drug, delayed onset of CNS effects and the small amount of drug consumed per drink (Macenski and Meisch 1994). However, it is also the case that several recent studies in non-human primates provide rather robust demonstrations of benzodiazepine reinforcement via the oral route (Stewart et al. 1994a; Kautz and Ator 1995; Meisch et al. 1995). For example, Stewart et al. (1994a) showed that midazolam functioned as a reinforcer in three of four monkeys after it was gradually substituted for ethanol. In that study midazolam was reliably preferred to water, midazolam maintained a typical fixed-ratio pattern of schedule-controlled behavior, and midazolam intake varied as an orderly function of fixed-ratio response requirement and concentration. This characterization of oral benzodiazepine reinforcement is more thorough and convincing than any of the studies via the intragastric route. Comparison of the self-administration of benzodiazepines to other drugs A generality that emerges across all three routes of administration is that the reinforcing efficacy of benzodiazepines is intermediate relative to other behaviorally active drugs. Benzodiazepines generally maintain lower rates of self-administration or are less likely to function as reinforcers than classic sedative and stimulant drugs of abuse. For example, studies of IV (Findley et al. 1972; Yanigita and Takahashi 1973; Griffiths et al. 1981, 1991; Kubota et al. 1986; Nader et al. 1991) and intragastric (Altshuler and Phillips 1978) self-administration showed that short or intermediate-acting barbiturates such as pentobarbital and secobarbital are more efficacious reinforcers than various benzodiazepines. Likewise, studies of oral self-administration in baboons and monkeys suggest that sedative drugs such as methohexital, pentobarbital and ethanol are more readily established as reinforcers than are benzodiazepines (Ator and Griffiths 1983, 1992; Stewart et al. 1994a). Studies of IV and intragastric self-administration have also shown that benzodiazepines are more efficacious reinforcers than several sedative compounds believed to have low abuse liabil-

ity, such as chlorpromazine, imipramine, buspirone and phenobarbital (Hoffmeister 1977; Altshuler and Phillips 1978; Griffiths et al. 1981, 1991). Figure 7 shows illustrative IV self-injection data in baboons under a fixed-ratio schedule with a 3-h time-out after each injection. Under these conditions, rates of self-injection of two benzodiazepines (triazolam and diazepam) were higher than those with buspirone, which failed to maintain self-injection above vehicle control, but lower than those with pentobarbital which maintained near maximal self-injection rates. These animal drug self-administration data suggesting that benzodiazepines have an intermediate reinforcing efficacy are consistent with human experimental data. The finding that benzodiazepines are less efficacious reinforcers than pentobarbital is consistent with two human drug self-administration studies in drug abusers which showed that pentobarbital was chosen more frequently than diazepam in choice tests (Griffiths et al. 1980b) and that pentobarbital maintained higher and more consistent rates of drug self-administration than diazepam (Griffiths et al. 1979). It is also consistent with several human studies that measured subjective effects in drug abusers and showed that, compared to a benzodiazepine (chlordiazepoxide, diazepam, triazolam), pentobarbital either produced greater ratings of liking or euphoria (Griffiths et al. 1980b; Jasinski et al. 1982, 1983; Roache and Griffiths 1985) or fewer dysphoric changes in mood (Griffiths et al. 1983). Likewise, the animal data indicating that benzodiazepines have a greater reinforcing efficacy than several classic low abuse liability sedatives are consistent with three human drug self-administration studies. One study in drug abusers showed that diazepam maintained self-administration, in contrast to chlorpromazine, which did not (Griffiths et al. 1979). A second study in drug abusers showed that lorazepam was chosen over buspirone in choice tests and produced greater liking and less disliking than buspirone (Troisi et al. 1993). A final study in moderate alcohol consumers showed that diazepam was chosen over buspirone in choice tests (Evans et al. 1996). Differences between benzodiazepines Several IV self-injection studies have shown that the rapidly eliminated benzodiazepines midazolam and triazolam (as well as the rapidly eliminated zolpidem, a nonbenzodiazepine whose actions are mediated at the benzodiazepine receptor), maintain higher rates of self-administration or are more likely to function as reinforcers than a variety of more slowly eliminated benzodiazepines (Griffiths et al. 1981, 1991, 1992; Kubota et al. 1986) (cf. Griffiths et al. 1985 for description of two additional unpublished studies with triazolam). Figure 7 presents illustrative data from baboons showing that triazolam maintained higher rates of IV self-injection than diazepam. A similar relationship between duration of action and rate of IV drug self-injection in monkeys has been

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jects with histories of drug abuse (Mumford et al. 1995a). In contrast to alprazolam which produced increases in a measure of drug reinforcement and ratings of various subjective effects (e.g. liking), abecarnil did not function as a reinforcer and produced elevations in ratings of “bad effects.” Drug history as a determinant of benzodiazepine reinforcing effects

Fig. 5 The self-administration of benzodiazepines in animals is intermediate relative to other behaviorally active drugs. Baboon IV self-injection results with triazolam, pentobarbital, diazepam and buspirone are shown. Injections were dependent on lever pulling under an FR 80 or 160 schedule; a time-out period of 3 h followed each injection for a maximum of eight injections per day. Self-injection of cocaine was established and then drug doses or vehicle were substituted for 12–15 days. C indicates mean of all 3-day periods with cocaine that immediately preceded every substitution of a drug dose or vehicle. V indicates mean of the last 5 days after substitution of the drug vehicle. Drug data points indicate mean of the last 5 days after substitution of a drug dose. Brackets indicate 1 SEM. Data are replotted from Griffiths et al. (1981) (pentobarbital, diazepam), Griffiths et al. (1991) (buspirone), and Griffiths et al. (1992) (triazolam)&ig.c:/f

observed with a series of barbiturates (Winger et al. 1975). A plausible explanation for many of these observations is that drug levels of the more slowly eliminated benzodiazepines and barbiturates cumulate over successive injections within a session, thus decreasing subsequent self-injection rates. These different rates of selfadministration in animals do not predict differences in human reinforcing effects, either as reflected epidemiologically or in experimental studies. As discussed previously, speed of onset of drug effect is one important determinant of differences in reinforcing efficacy and abuse liablity in humans, likely accounting, for example, for the observed difference between diazepam and oxazepam. Clearly, differences in onset of action which are due primarily to absorption differences would not be operational in the IV administration studies. Unfortunately, at present, the intragastric self-administration results are insufficiently reliable to provide meaningful information about differences in reinforcing effects between benzodiazepines, and there have been no attempts to test slow onset benzodiazepines via the oral route in animals. Preclinical self-injection studies with abecarnil, a non-benzodiazepine with actions mediated at the benzodiazepine receptor, suggest a unique status of this compound relative to other benzodiazepine receptor ligands. A series of studies using similar methods to examine IV self-injection of 13 benzodiazepine receptor ligands in baboons showed that only abecarnil did not function as a reinforcer (Griffiths et al. 1981, 1991, 1992; Sannerud et al. 1992). The finding with abecarnil is consistent with the results of a human abuse liability evaluation which compared the effects of abecarnil and alprazolam in sub-

Two studies indicate that a sedative drug self-administration history plays a role in establishing benzodiazepines as reinforcers. One study showed that diazepam was more likely to maintain IV self-injection in monkeys if substituted for pentobarbital than if substituted for cocaine (Bergman and Johanson 1985). A study with rats involving schedule-induced oral self-administration showed that more chlordiazepoxide was consumed in animals with histories of ethanol consumption than in those with histories of cocaine or water consumption (Falk and Tang 1989b). These studies are consistent with the human studies previously reviewed which showed that benzodiazepines are reinforcers in subjects with histories of drug abuse and moderate alcohol drinking but not in normal subjects without anxiety or insomnia. Behavioral contextual determinants of benzodiazepine reinforcing effects Several studies suggest that the behavioral history or current behavioral context are important for establishing benzodiazepines as reinforcers. In a study of IV self-injection, Pilotto et al. (1984) showed that diazepam was self-injected above saline levels in rats concurrently maintained on a FI schedule of food delivery but not in rats without the concurrent schedule. Stewart et al. (1994a) showed that diazepam functioned as a reinforcer orally when gradually substituted for ethanol using an ethanol fading procedure, but not when diazepam was abruptly substituted for ethanol. Furthermore, most of the studies described in Table 6 which demonstrated oral benzodiazepine self-administration used unique behavioral conditions, such as food-induced drinking procedures or schedule-induced drinking procedures (e.g. Sanger 1977; Falk and Tang 1985; Ator and Griffiths 1992). Although different types of contextual manipulations have been conducted, the importance of such contextual conditions for establishing benzodiazepines as reinforcers has also been demonstrated in human research, as previously discussed. The role of physical dependence in benzodiazepine reinforcement Interestingly, although physical dependence and withdrawal are commonly thought to enhance the reinforcing

30

effects of benzodiazepines, the few relevant preclinical studies provide little support for this mechanism. For example, Ator and Griffiths (1992) studied oral diazepam and triazolam self-administration in baboons under a variety of different conditions. Despite the clear development of physical dependence, as manifested by a flumazenil-precipitated withdrawal syndrome and a spontaneous withdrawal syndrome, drug reinforcement was not consistently demonstrated, thus suggesting a dissociation between the reinforcing and physical dependence producing effects of benzodiazepines. Two IV self-injection studies examined the effects of the benzodiazepine receptor antagonist flumazenil on IV benzodiazepine selfinjection. The first of these showed that a single dose of flumazenil suppressed diazepam self-injection in rats (Pilotto et al. 1984). In a more thorough parametric study in rhesus monkeys, Johanson and Schuster (1986) showed that presession injections of flumazenil increased benzodiazepine self-injection at some doses and generally decreased self-injection at higher doses. The authors interpreted the increased self-injection as being functionally equivalent to decreasing the dose of benzodiazepine rather than reflecting a precipitated withdrawal induced increase in the reinforcing efficacy of benzodiazepines. A final preclinical study relevant to the interaction between physical dependence and benzodiazepine reinforcement examined progressive ratio performance maintained by IV injections in monkeys (Yanagita 1987). The study showed that chronic pretreatment with diazepam (1 mg/kg per hour for 4 weeks) did not reliably alter the maximal ratio response requirement maintained by diazepam, suggesting that physical dependence did not alter diazepam reinforcing effects. In contrast, pretreatment with codeine increased the maximal ratio maintained by codeine, a finding consistent with the widely held belief that physical dependence enhance opioid reinforcing effects. As with the preclinical research, little information is available from human research relevant to the commonly held opinion that physical dependence enhances the reinforcing effects of benzodiazepines. A double-blind study by Cappell and coworkers (1987) showed that, compared to a group of therapeutic users of benzodiazepines whose diazepam dose was tapered gradually, a group which was abruptly switched to placebo was more likely to self-administer unauthorized benzodiazepines and was also more likely to show more frequent withdrawal symptoms. In contrast to the preclinical data, these results suggest a causal relationship between deprivation of a benzodiazepine and its self-administration in physically dependent individuals.

Implications and conclusions Drug reinforcement may represent the primary behavioral-pharmacological mechanism underlying two types of problematic use of benzodiazepines – recreational abuse by polydrug abusers and inappropriate chronic use by

patients. High dose polydrug abuse for the purpose of getting high is readily recognized as a significant social problem. In contrast, inappropriate chronic benzodiazepine use is more subtle and may be mistaken for appropriate medical use. At present, the risks of such longterm benzodiazepine use (i.e. memory impairment, risk of accidents, falls and hip fractures in the elderly, a withdrawal syndrome) are much better documented than the benefits (i.e. therapeutic efficacy of long-term use). This unfavorable risk/benefit ratio suggests that, at present, there is little empirical justification for most long-term benzodiazepine use. The elderly represent a particularly vulnerable population in which long-term use is frequent. Given that most of drug sales come from the population of long-term chronic users and that these users represent a large and possibly growing group of benzodiazepine users, it is particularly regrettable that the efficacy of long-term use has not been the focus of more aggressive research efforts. Drug self-administration studies in humans and laboratory animals provide models of both types of problematic benzodiazepine use. Recreational abuse of benzodiazepines has been modeled in human research with polydrug abusers and in animal drug self-administration studies which show that the reinforcing efficacy of benzodiazepines is intermediate relative to other sedative compounds (e.g. Fig. 5). Although both human and animal studies differentiate benzodiazepines from classic sedatives of abuse such as pentobarbital and from non-reinforcing sedatives such as buspirone and chlorpromazine, the present animal models do not differentiate among benzodiazepines in a way that corresponds to the available human data (e.g. diazepam having a greater abuse risk than oxazepam). Because rate of onset after oral administration is probably an important mechanism underlying the human differences in abuse liability among benzodiazepines, further development of intragastric and oral paradigms of preclinical self-administration would be particularly valuable. The problem of inappropriate chronic use of benzodiazepines by patients has been partially modeled both preclinically and clinically. The preclinical demonstration of stable, low-rate benzodiazepine self-injection with concurrent development of physical dependence under conditions of continuous availability appears to capture some of the important features of the clinical syndrome (cf. Weerts et al. 1997). Human studies demonstrating that benzodiazepines function as reinforcers in subjects with anxiety (e.g. Figure 3) and insomnia represent potentially important new approaches for better characterizing the optimal conditions for self-administration, as well as better characterizing the patient subpopulations that are sensitive to such reinforcing effects and thus potentially at risk for developing long-term patterns of inappropriate benzodiazepine use. The implications of recent studies showing that benzodiazepines can function as reinforcers in moderate alcohol consumers (Fig. 2) are unclear. Whether these results suggest that moderate alcohol consumers may be at

31

increased risk of recreational abuse, inappropriate longterm use or both is clearly an important focus for future research. Several other areas are particularly deserving of future research on the reinforcing effects of benzodiazepines. First, both clinical and preclinical studies suggest that the behavioral history or current behavioral context represent important considerations in the establishment of benzodiazepines as reinforcers. The observation in humans that the reinforcing effects of a benzodiazepine can depend on the behavioral requirements following drug ingestion (Fig. 4) would be particularly interesting to extend in human research and to investigate in preclinical studies. Second, although it is commonly believed that physical dependence enhances benzodiazepine reinforcement preclinical data provide no support for such a mechanism and human research is limited to a single study. Future human and animal studies should clarify the role of physical dependence on the reinforcing effects of benzodiazepines. Finally, molecular biological techniques are rapidly advancing understanding of the structure and function of the benzodiazepine (Sanger et al. 1994; Lüddens et al. 1995) and serotonin (Barrett and Vanover 1993; Glennon and Dukat 1995) receptor sites relevant to the development of novel anxiolytic and hypnotic compounds. As previously discussed, abecarnil and buspirone are examples of novel compounds, which were developed as anxiolytics, that both animal and human self-administration research have shown are less efficacious reinforcers than benzodiazepines. It seems likely that continued research into such compounds which can function as partial and/or selective agonists at benzodiazepine and serotonin receptor sites will lead to the discovery of new therapeutically efficacious compounds which will be less likely to be abused recreationally or to engender inappropriate long-term use in patients. &p.2:Acknowledgements This review is based on the Solvay Duphar Award lecture by R. R. G. at the 103rd Annual Convention of the American Psychological Association in Los Angeles, California. Preparation of this paper was supported in part by National Institute on Drug Abuse Grants RO1 DA03889 and RO1 DA01147.

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