Abuse liability of alprazolam relative to other commonly used benzodiazepines: A review

Neurosctenceand BiobehavioralReviews.Vol. 17, pp. 277-285, 1993

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Abuse Liability of Alprazolam Relative to Other Commonly Used Benzodiazepines: A Review C R A I G R. R U S H , l S T E P H E N T. H I G G I N S , W A R R E N K. B I C K E L A N D J O H N R. H U G H E S

Departments o f Psychiatry and Psychology, University o f Vermont, Vermont (Received 19 O c t o b e r 1992) RUSH, C. R., S. T. HIGGINS, W. K. BICKEL, AND J. R. HUGHES. Abuse hability of alprazolam relative to other commonly used benzodiazepines: A review. NEUROSCI BIOBEHAV REV 17(3) 277-285, 1993-Nonhuman and human studies comparing the abuse liability of aiprazolam to other commonly used benzodiazepines are reviewed. These studies are reviewed to determine to what extent prospective, controlled, experimental studies support opinions that aiprazolam's abuse liability is greater than that of other commonly used benzodiazepines. Studies comparing the self-administration of alprazolam, the discriminative stimulus effects of aiprazolam, self-reported effects of aiprazolam, physiological dependence on aiprazolam, and adverse effects of alprazolam relative to other benzodiazepines are reviewed. Overall, the experimental literature does not support the widely held belief that aiprazolam's abuse liability is greater than that of other benzodiazepines, but much more research is needed. Such research should focus explicitly on alprazolam's reinforcing effects, and the nature and severity of the chscontinuation syndrome associated with its long-term use. Important issues such as selection of an appropriate comparison drug, selection of an appropriate population, dosing regimen and test doses need to be considered in future studies. Alprazolarn Abuse liability Benzodiazepines Drug discrimination Self-reports

Drug reinforcement

ALPRAZOLAM (XANAX TM) is the most commonly prescribed benzodiazepine in the United States (75). Some evidence suggests alprazolam is distinguishable from other benzodiazepines in terms of its abuse potential. First, individuals with a history of alcohol and opiate abuse prefer alprazolam to other benzodiazepines (e.g., chlordiazepoxide and oxazepam), and report alprazolam produces a greater "high" (44, 80). Second, 75070 of drug-abuser-experienced physicians reported alprazolam as having a greater potential for abuse than other benzodiazepines (40). Third, emergency room admissions involving alprazolam increased 50070 between 1985-1988 (16-19). Finally, admissions to substance abuse treatment clinics for alprazolam dependence increased during this same period, with three-fold increases reported in some clinics (24). The present paper reviewed the existing experimental literature to determine to what extent these concerns are supported by prospective, controlled, experimental studies. Retrospective studies, case reports, and published abstracts are not discussed. Both nonhuman and human studies assessing alprazolam's liability for abuse (i.e, maintenance of self-administration), as well as its liability of abuse (i.e., adverse effects)

Adverseeffects

relative to other benzodiazepines are reviewed (12,13). The abuse potential of alprazolam and diazepam was recently reviewed (46), but the present paper differs from this report in that studies comparing alprazolam and other commonly used benzodiazepines (e.g., lorazepam and triazolam) are also included. STUDIES CONDUCTEDWITH LABORATORYANIMALS Preclinical trials are critical in determining the abuse liability of a drug. First, these trials determine whether a drug maintains self-administration, which is thought to be central to its abuse liability (12,13,37). Second, drug discrimination studies determine a drug's interoceptive effects, which may be analogous to categorizing the self-reported drug effects in humans (57,58). Finally, studies of a drug's lethality in overdose and ability to produce physiological dependence characterize its adverse effects.

Self-Administration One study compared the number of dally self-administrations of alprazolam (0.01-3.2 mg/kg/injection), bromazeparn

' Requests for reprints should be addressed to Craig R. Rush, Ph.D. Behavioral Pharmacology Research Unit, FSKMC, 5510 Nathan Shock Drive, Suite 3000, Francis Scott Key Medical Center, Baltimore, MD, 21224. 277

278 (0.032-3.2 mg/kg/injection), chlordiazepoxide (0.032-3.2 mg/kg/injection), lorazepam (0.001-3.0 mg/kg/injection), and triazolam (0.0001-0.32 mg/kg/injection) in separate groups of baboons (N = 3-4) (38). All benzodiazepines maintained greater self administrations at some dose than placebo, but between-benzodiazepine differences were small. The average number of injections/day across the last 5 days for the dose maintaining the greatest number of self-administrations was 5.6 for triazolam (range = 4.5-6.6), 4.8 for lorazepam (range = 2.0-7.0), 4.3 for chlordiazepoxide (range = 3.25.1), 4.1 for alprazolam (range = 2.0-6.5), 3.1 for bromazepam (range = 2.2-4.9), and 1.5 for vehicle (range = 0.33.3). Statistical analyses were not offered in support of between-drug differences, but reanalysis of the data based on the graphic presentation found no between-drug differences at the dose that maintained the highest rate of self-administration (p = 0.3170). While these data suggest the abuse liability of alprazolam is not different from that of other commonly used benzodiazepines, it is important to note that studies of this type may not accurately predict the relative extent of abuse of various drugs (47).

lnteroceptive Stimulus Effects Interoceptive stimulus (i.e., discriminative stimulus) effects of a drug are typically assessed in laboratory animals using drug discrimination procedures (57,58). In these procedures, one response (e.g., press lever A) is reinforced following the injection of drug and a different response (e.g., press lever B) following the injection of saline. Following training, novel compounds can be substituted to determine if subjects respond as if the novel drug is the training drug. The abuse liability of the novel drug can be inferred if it substitutes for a drug with a known abuse liability. Three studies assessed the discriminative stimulus effects of alprazolam relative to other benzodiazepines (22,28,79). In the first study, four rhesus monkeys were trained to discriminate pentobarbital (10 mg/kg) from saline (27). Alprazolam, bromazepam, diazepam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, temazepam, or triazolam occasioned at least 80°7o pentobarbital-appropriate responding in all monkeys. In the second study, separate groups of rats were trained to discriminate a low (1 mg/kg) or high (10 mg/kg) dose of diazepam from saline (79). Alprazolam, adinzolam, triazolam, and pentobarbital occasioned 80°70 diazepam-appropriate responding in both groups. In the third study, five pigeons were trained to discriminate midazolam (1.0 - 3.0 mg/kg) from saline (28). Alprazolam, diazepam, flurazepam, Iorazepam, nitrazepam, nordiazepam, and triazolam occasioned at least 80% midazolam-appropnate responding in all pigeons. Overall, these studies suggest alprazolam produces a pharmacological profile similar to that of other benzodiazepines and sedative/hypnotic compounds.

Adverse Effects Lethality in overdose. Alprazolam, like other benzodiazepines, has a large margin of safety, and death due to overdose is rare (30,33). In the rat, for example, the lethal dose (i.e., LD 5° alprazolam is 331-2,171 mg/kg (63), while the effective anxiolytic dose (ED 5°) is 0.5 mg/kg (77). Thus, the therapeutic ratio (LDS°/EDS°) of alprazolam is 662/4,342. Physzological dependence. Benzodiazepine physiological dependence and withdrawal is often assessed in nonhuman laboratory animals by administering the drug chronically,

RUSH ET AL. abruptly discontinuing it, and assessing withdrawal with a standardized scale. Benzodiazepine withdrawal can also be precipitated with a benzodiazepine antagonist (e.g., flumazenil) in subjects chronically maintained on drug. In an abrupt discontinuation experiment, 0.025°7o (percent by body weight) alprazolam was added to the daily food ration of mice, and subjects ingested approximately 40-65 m g / k g / day of alprazolam for 28 days (32). These data were compared to those from a similar experiment in which 0.10% (percent by body weight) diazepam was added to the daily food ration of mice, and subjects ingested approximately 1000 m g / k g / day of diazepam for 52 days (31). Removal of drug from the diet resulted in a physiological withdrawal that was qualitatively similar in both alprazolam- and diazepam-treated mice (31,32). The peak withdrawal scores associated with alprazolam dependence ranged from 19-25 vs. 26-36 with diazepam. Alprazolam withdrawal was discernible 8 h after drug discontinuation, peaked at 32 h, and abated by 2-3 days (32). Diazepam withdrawal onset approximately 24 h after drug discontinuation, peaked at 72 h, and lasted up to 17 days (31). These findings must be viewed tentatively because dose and duration of exposure were not equivalent across the two experiments (alprazolam < diazepam), and these variables are important determinants of the severity of withdrawal (49). One study explicitly examined the precipitated withdrawal syndrome in dogs (N = 6) chronically treated with alprazolam (48 mg/kg/day) (76). Following at least 1 week of exposure to alprazolam, dogs were challenged with oral administrations of flumazenil (6, 18, or 36 mg/kg). Scores on a modified version of the Nordiazepam-Precipitated-Abstinence Scale and the frequency of seizures were generally an increasing function of flumazenil dose. These data were compared to those from a similar experiment in which dogs were chronically maintained on diazepam (24 or 36 mg/kg/day) and challenged with oral administrations of flumazenil (2, 6, or 18 mg/kg) (54). Nordiazepam-Precipitated-Abstinence-Scale scores for the alprazolam-treated dogs were significantly less than for the diazepam treated dogs following the 6 and 18 mg/kg doses of flumazenil. Seizure activity did not differ significantly across drugs (76). Another report summarized several experiments from the same laboratory in which dogs were chronically treated with alprazolam, diazepam, flunitrazepam, halazepam, lorazepam, oxazepam, and nordiazepam and then challenged with flumazenil (52). Drugs were administered 4-5 times a day for 210 weeks followed by oral administrations of flumazenil (2-72 mg/kg). Scores on the Benzodiazepine Precipitated-Abstinence Scale and the frequency of seizures generally were an increasing function of flumazenil dose in all benzodiazepinetreated dogs, while benzodiazepine-naive dogs showed no effect. Following flumazenil (18 mg/kg), the benzodiazepines appeared to differ in terms of Benzodiazepine-Precipitated-Abstinence Scale scores (diazepam > flunitrazepam = halazepam > alprazolam = nordiazepam > oxazepam > lorazepam) and the frequency of seizures (flunitrazepam > alprazolam > diazepam > nordiazepam > lorazepam > halazepam = oxazepam), but the report did not mention whether between-drug differences were statistically significant.

Summary of Studies With Nonhumans The available preclinical data suggest alprazolam's abuse liability does not differ from that of other benzodiazepines. Alprazolam maintains rates of self-administration similar to

A L P R A Z O L A M ABUSE LIABILITY those of other benzodiazepines (38). The interoceptive stimulus effects of alprazolam are similar to those of other benzodiazepines as determined in drug discrimination procedures (22, 28,79). The adverse effects of alprazolam are not significantly different from those of other benzodiazepines. As with other benzodiazepines, alprazolam has a high therapeutic-lethality ratio. The withdrawal syndrome associated with chronic alprazolam treatment onsets, peaks and abates more rapidly, but may be somewhat less severe at peak than that of diazepam (31,32). STUDIES CONDUCTED WITH HUMANS Human abuse liability assessment trials should determine whether a drug maintains self-administration and its adverse effects. Self-administration procedures adapted for use with human subjects, unfortunately, are under utilized in such trials (8,36). Instead, self-report instruments are commonly used to assess the abuse liability of drugs in humans (45). Commonly studied adverse effects of benzodiazepines include physiological dependence, impairment of recall, learning and performance, and interactions with alcohol (81-83).

Self-Reported Effects One study examined self-reported preference for alprazolam over diazepam in patients (N = 7) undergoing benzodiazepine-withdrawal therapy (2). Patients were stabilized on 5 mg/day of diazepam (t.i.d.). Alprazolam (0.5 mg) was then substituted for the morning or noon medication and patients reported their preference 1 h prior to the evening medication. Subjects preferred alprazolam over diazepam on 13 of 14 test occasions. A second experiment was conducted in these same patients with a lower dose of alprazolam (0.37 rag), but alprazolam was not preferred to diazepam. Another experiment compared the self-reported effects of alprazolam (2 mg), diazepam (20 mg), lorazepam (4 mg), methaqualone (300 mg), and placebo in recreational sedative users (N = 30) using a within-subject, randomized, doubleblind design (56). Each benzodiazepine increased subject ratings of sedation and scores on the Morphine-Benzedrine Group (MBG) scale of the Addiction Research Center Inventory, a putative measure of euphoria. Diazepam and lorazepam, but not alprazolam, differed significantly from placebo 1 h after drug on the MBG scale. Alprazolam, diazepam and lorazepam did not differ from each other in terms of MBG scores. Alprazolam, diazepam and lorazepam did not differ in terms of estimated street value or subject ratings of "high."

Adverse Effects Physiological dependence. Terminating benzodiazepine therapy results in a recognizable discontinuation syndrome, and this syndrome is purportedly more common and severe when treatment involved a short half-life benzodiazepine (e.g., alprazolam or lorazepam) (59,64,67). Despite these reports and several case studies of severe withdrawal syndrome following the discontinuation of alprazolam (14,24), only three controlled discontinuation studies with humans included alprazolam and other benzodiazepines (65,68,74). In one study, the discontinuation syndromes of short halflife (SHL) (alprazolam and lorazepam) and long half-life (LHL) (clorazepate and diazepam) benzodiazepines were compared following abrupt termination in outpatients currently undergoing treatment with these drugs (65). The groups differed in terms of amount of daily medications and length of

279 treatment (SHL < LHL), but not clinical features. Patients treated with SHL benzodiazepines exhibited higher rates of attrition and relapse, and higher scores on the Hamilton Anxiety Scale for Anxiety and the Physician-Withdrawal Checklist. Peak severity of the discontinuation syndrome occurred 2-3 and 4-8 days after the termination of medication for most patients treated with SHL and LHL compounds, respectively. Specific between-drug comparisons (i.e., alprazolam vs. diazepam or alprazolam vs. clorazepate) were not reported. Alprazolam-treated patients experienced slightly lower peak scores on the Physician-Withdrawal Checklist than lorazepamtreated patients even though the pharmacokinetics of these two drugs are similar (20,35), but this may be attributable to differences in amount of daily medications and length of treatment (alprazolam < lorazepam). A second study examined the effects of a gradual taper (i.e., 25%/week) in outpatients currently undergoing treatment with SHL (alprazolam and lorazepam) and LHL (clorazepate and diazepam) benzodiazepines (74). Again, the groups differed in terms of the amount of daily medication and length of treatment (SHL < LHL), but not clinical features. Patients treated with SHL benzodiazepines exhibited higher rates of attrition and relapse. Patients treated with SHL benzodiazepines experienced lower peak scores on the Hamilton Anxiety Scale for Anxiety and Physician-Withdrawal Checklist scales. Specific between-drug comparisons were not reported. The authors of this study combined their data with that from the Rickels et al. (1990) study (65) and found a statistically significant interaction of half-life and mode of discontinuation across most measures. Patients treated with SHL benzodiazepines experienced a more severe discontinuation syndrome than patients treated with LHL benzodiazepines when the drugs were abruptly terminated, but not when they were gradually tapered as is medically recommended. A final study assessed the effects of a partial taper and abrupt discontinuation of alprazolam, diazepam, and placebo in panic patients (68). Alprazolam- and diazepam-treated patients were ingesting a comparable number of tablets, while placebo patients were taking significantly more tablets. The number of tablets were gradually tapered to approximately half over 2 weeks. The remaining medications were then abruptly discontinued. Following the 2-week taper, scores on the Hamilton Anxiety Scale for Anxiety did not differ significantly across the three groups. Following abrupt discontinuation, however, scores on the Hamilton Anxiety Scale for Anxiety were significantly higher for the alprazolam group than the diazepam and placebo groups. There was not a significant increase in panic attacks following the partial or abrupt discontinuation of drug. Impatrment of recall (anterograde amnesia). Benzodiazepines impair recall of information presented after drug administration (i.e., anterograde amnesia) (66,69). Significances between benzodiazepine differences have been reported (4, 9,60,61,71-73). Five studies examined the effects of aiprazolam relative to other benzodiazepines including diazepam (11,51), lorazepam (10,34,48), prazepam (34), and quazepam (11) on recall. These studies were similar in terms of subjects, procedures and measures (see Table 1). One study found alprazolam (2 mg) was more disruptive than diazepam (10 mg), but theses doses are not clinically equivalent, and the results must be viewed tentatively (1,20,51). In another study, alprazolam was more disruptive than prazepam (34). Alprazolam did not differ from lorazepam or quazepam (10, I 1,34,48). Impairment of learning. Benzodiazepines impair human learning (5-7,21,41,42,70). The only available study that

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A L P R A Z O L A M ABUSE LIABILITY tested the effects of alprazolam and another benzodiazepine on learning (i.e., acquisition of new information) found alprazolam to be more disruptive than diazepam (6). Alprazolam (0, 1, 2, 3 mg/70 kg), diazepam (0, 10, 20, 30 mg/70 kg), and triazolam (0, 0.25, 0.5, and 0.75 mg/70) dose-dependently increased the overall percentage of errors in learning new material on a modified version of the repeated acquisition of behavioral sequences procedure, but the highest doses of alprazolam and triazolam were more disruptive than the highest dose of diazepam. These results must be viewed tentatively because this study was not designed to explicitly compare the effects of alprazolam and diazepam, and subjects were entered sequentially in to a drug condition. Impairment of performance. Benzodiazepines impair varied aspects of human performance (25,53,81-83). Nine studies with humans included alprazolam and at least one other benzodiazepine (3,10,11,26,27,29,34,55,78). These studies were similar in terms of subjects, procedures, and measures (see Table 2). Alprazolam did not produce significantly greater impairment than the other benzodiazepines tested in any of the studies. Definitive conclusions are difficult because most of these studies compared only a single dose of each compound, and often the doses studied were not clinically equivalent (1,20). Interactions with alcohol. Combined use of alcohol and benzodiazepines pose a substantial risk because benzodiazepine-induced impairment is greater when alcohol is also ingested (15,50). One study examined the effects of alprazolam (0.5 and 2.0 mg) and diazepam (10 mg) alone and in combination with alcohol (0.8 g/kg) in 10 healthy volunteers on a battery of performance tasks (51). Alcohol exacerbated the effects of both drugs, but combining alprazolam (2 mg) and alcohol was more deleterious than combining diazepam (10 mg) and alcohol. The authors did not report whether these differences were statistically significant. Another study examined the effects of alprazolam (0.25 or 0.5 mg), diazepam (5 or 10 mg) and placebo alone and in combination with alcohol (0.5 and 0.8 ml/kg) in 10 healthy volunteers using similar performance tasks (43). Diazepam (10 mg) combined with alcohol impaired performance relative to placebo, but neither dose of alprazolam combined with alcohol did. Meaningful conclusions are difficult based on these studies because the doses of alprazolam and diazepam were not clinically equivalent (1,20). Discerning differential interactions of benzodiazepines with alcohol require the doses or the range of doses to be clinically/functionally equivalent.

Summary of Studies With Humans The human experimental literature, like the nonhuman experimental literature, does not provide a basis for distinguishing alprazolam from other benzodiazepines in terms of abuse liability. In patients with a history of long-term benzodiazepine use, differences in alprazolam's abuse potential relative to diazepam were not consistently demonstrated across a range of doses (2). The adverse effects of alprazolam are the same as other commonly used benzodiazepines. The discontinuation syndrome associated with chronic alprazolam use is more intense than that of LHL compounds when alprazolam is abruptly terminated, but not when gradually tapered. Finally, most studies found the effects of alprazolam on measures of recall, learning, and performance to be qualitatively and quantitatively similar to those of other commonly used benzodiazepines.

281 CONCLUSIONS AND DIRECTION OF FUTURE RESEARCH Many clinicians believe the abuse liability of alprazolam is greater than that of other commonly used benzodiazepines, but this opinion is not supported by the available scientific information (40). While pointing out that the available experimental literature does not suggest the abuse liability of alprazolam is greater than that of other benzodiazepines, it is important to note a lack of prospective, experimental studies that explicitly address this question. Moreover, only limited conclusions can be drawn from the existing studies because most tested only a single dose of each compound, and in many instances these doses were not clinically equivalent. Well controlled studies that explicitly compare the effects of alprazolam to those of other commonly used benzodiazepines are clearly needed. Studies conducted with nonhumans suggest the abuse liability of alprazolam is qualitatively and quantitatively similar to that of other commonly used benzodiazepines, as determined by its ability to maintain self-administration, discriminative stimulus effects, and adverse effects including physiological dependence. Studies with humans also suggest alprazolam's abuse liability is similar to that of commonly used benzodiazepines. The only difference is that the discontinuation syndrome associated with aiprazolam may onset more rapidly and be more severe if drug is abruptly terminated. Thus, clinicians should clearly instruct patients who are prescribed alprazolam to avoid situations in which they are unable to take their medications and not to spontaneously stop taking them. Perhaps future studies that explicitly address alprazolam's abuse liability relative to other commonly used benzodiazepines will find differences, but this awaits confirmation. Future research with nonhumans should focus on aiprazolam's relative reinforcing effects and the severity of the discontinuation syndrome associated with its long-term use. With regard to the relative reinforcing effects of alprazolam, before such studies can be conducted the procedures used to compare the reinforcing effects of drugs need to be refined (47). The lack of adequate procedures to compare the relative reinforcing effects of drugs may explain the failure to detect significant differences between commonly used benzodiazepines (38). With regard to the discontinuation syndrome, studies that carefully control the dose and duration of drug exposure are needed because these variables affect the severity of the discontinuation syndrome (49). Similar studies with humans explicitly addressing alprazolam's reinforcing effects and the severity of the discontinuation syndrome are needed, but must consider important issues such as selection of a appropriate comparison drug, population selection, dosing regimen, and dose. For example, comparison studies of alprazolam and other benzodiazepines typically used diazepam or lorazepam as the comparison drug, and these compounds may also have greater abuse liabilities than other benzodiazepines (e.g., oxazepam) (40,44,80). Studying alprazolam's relative abuse liability in chronically anxious patients using a chronic dosing regimen would seem most clinically relevant. However, patients in general practice often use benzodiazepines intermittently to treat temporary anxiety related to environmental demands (e.g., college entrance exams or job interviews). Thus, studies of intermittent dosing are also relevant. Human benzodiazepine-comparison studies must test a wide range of doses of both compounds to determine whether there are differences in maximal effects or

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only in dose equivalencies (23). The inclusion o f supratherapeutic doses is also necessary because higher doses are often involved in abuse and overdose (23,39). Finally, with regard to the discontinuation syndrome associated with alprazolam, human studies that carefully match the groups on the basis of daily dose and duration of drug exposure are needed. In conclusion, the c o m m o n l y held belief that the abuse liability o f alprazolam is greater than that of other c o m m o n l y used benzodiazepines is not supported by the available scientific literature. Rigorous experimental studies are needed that explicitly compare alprazolam and other c o m m o n l y used ben-

zodiazepines to determine if differences exist. Until such research is available, definitive conclusions concerning the relative abuse liability of alprazolam are not possible. ACKNOWLEDGEMENTS This research was supported in part by a US Public Health Service First Independent Research Support and Transition Award (STH) DA-04545, Predoctoral Fellowship Award (CRR) DA-05382, Research Grant (WKB) DA-05538, Research Grant (JRH) DA-04843, and Research Scientist Development Award (JRH) DA-00109 from the National Institute on Drug Abuse.

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