Neuroscience & giobehaviora[Reviews. Vol. 9, pp. 133-151. 19_5. e Ankho International Inc. Printed in the U.S.A 0149-7634/85 5300 ÷ 00

Relative Abuse Liability of Triazolam: Experimental Assessment in Animals and Humans

ROLAND R. GRIFFITHS,** RICHARD J. LAMB,* NANCY A. ATOR,* JOHN D. ROACHE* AND JOSEPH V. BRADY**

Departments of *Psychiatry and tNeuroscience. The Johns Hopkins University School of Medicine 720 Rutland Avenue, Baltimore, MD 21205

GRIFFITHS, R. R., R. J. LAMB, N. A. ATOR, J. D. ROACHE AND J. V. BRADY. Relative abuse liability oftriazolam: Experimental assessment in animals and humans. NEUROSCI BIOBEHAV REV 9(1) 133--151. 1985.--The abuse liability of a drug is a positive, interactive function of the reinforcing and adverse effects of the drug. The relative abuse liability of the hypnotic henzodiazepine, triazoiam, has been controversial. This paper reviews animal and human studies beating on its relative abuse liability, including data on pharmacological profile, reinforcing effects, liking, speed of onset, discrimina- tive stimulus effects, subjective effects, physiological dependence, rebound and early morning insomnia, drug produced anxiety, lethality in overdose, psychomotor impairment, interactions with ethanol anterogr_e amnesia, impaired aware- ness of drug effect, and other psychiatric and behavioral disturbances. It is concluded that the abuse liability of triazolam is less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam to other benzodiazepines, there is also substantial speculation among clinical inves- til_tors and some limited data suggesting that the abuse liability of triazolam is greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that it is less. Further research will be necessary to clarify definitively the abuse liability of triazolam relative to other henzodiazepines.

Abuse liability Triazolam Benzudiazepines Barbiturates Reinforcing effects Adverse effects Drtq l self-administration Drug liking Drug discrimination Subjective effects Dependence Lethality Psychomotor impairment Ethanol interactions Amnesia Psychiatric disturbance Animals Baboons Humans

CONTENTS 2. Precipitated withdrawal test ...... 141 I. Introduction ...... 134 3. Spontaneous withdrawal test ...... 141 A. Conceptual Definition of Abuse Liability ...... 134 B. Physiological Dependence in Humans ...... 143 II. Chemical Structure_Pharmacological Profile ...... 134 I. Rebound insomnia ...... 143 II!. Reinforcing Effects ...... 134 2. Early morning insomnia ...... 143 A. Reinforcing Effects in Animals ...... 134 3. Daytime anxiety during hypnotic treatment . 143 I. Intravenous self-administration ...... 134 4. Case reports of physiological dependence ... 143 2. lntragastric self-administration ...... 135 C. Conclusions on Physiological Dependence ..... 143 3. Oral self-administration ...... 135 IX. Adverse Effects ...... 144 4. Conclusions from animal triazolam self- A. Lethality in Overdose ...... 144 administration ...... 136 B. Psychomotor Impairment ...... 144 B. Reinforcing Effects in Humans ...... 137 C. Interactions with Ethanol ...... 144 IV. Ratings of Liking and Monetary Value by Humans 137 D. Anterograde Amnesia ...... 145 V. Speed of Onset of Drug Effects in Humans ...... 138 E. Impaired Awareness of Degree of Drug Effect .. 145 VI. Discriminative Stimulus Effects in Animals ...... 138 F. Other Psychiatric and Behavioral Disturbances . 146 VII. Categorization of Subjective Drug Effects by Humans 139 X. Conclusions About the Relative Abuse Liability of VIII. Physiological Dependence ...... 140 Triazolam ...... 147 A. Physiological Dependence in Animals ...... 140 XI. Acknowledgements ...... 147 1. Substitution tests ...... 141 XII. References ...... 147

133 134 GRIFFITHS ET AL.

BENZODIAZEPINES are among the most widely used of administration behaviors to the exclusion of more socially all prescribed drugs. Concern about the potential for drug desirable behavior. A further illustration of the nonindepen- abuse/dependence has prompted the development of clinical dence of reinforcing properties and adverse effects is that and preclinical methods for assessing various pharmacologi- some adverse effects 1e.g., physiological dependencel can cal effects of these drugs which are relevant to their relative modulate the reinforcing properties of drugs. abuse liability. A series of excellent review papers address- ing various aspects of the relative abuse liability of ben- CHEMICAL STRUCTURE/PHARMACOLOGICAL zodiazepines as a class has been written recently [49, 60, PROFILE 96, 116, 117. 136, 157]. Chemical structure, molecular mechanism of action, and notiOfcs, allthetherelativmarkelyeted newbenzodiazepinehypnotic, triazolamanxiolytics, has andbeenhyp-the simple pharmacological profile sometimes provide crude in- formation for estimating the abuse liability of a new corn- potmoenst tialcontrovandersial.other withadversrespecteffects.to physioloPart ofgicalthis controversydependency pound based on degree of similarity with known drugs of was directly responsible for the removal of triazolam from abuse. Triazolam shares with diazepam and most marketed the drug registry in the Netherlands in 1979 [31, 86, 88]. benzodiazepines a common chemical structure 11.4- Although some of the issues related to this initial con- benzodiazepine), putative molecular site of action /ben- troversy appear to have been resolved, a variety of new zodiazepine receptor), and simple pharmacological profile (sedative/anxiolytic) [130]. Since a variety of preclinical. issues has been raised Icf. [73, 76, 146]). prompting the clinical, and epidemiological data suggests that ben- speculation that triazolam "'will have the highest abuse po- zodiazepines such as diazepam have less abuse liability than tentialThe omajorf all thpure pbenosezodiazof epthiines spaperyetis markto reeviteed"w all[25availabl]. e intermediate-duration barbiturates such as pentobarbital [49, data on the abuse liability of triazolam relative to the inter- 60, 96], the similarities between triazolam and other ben- mediate duration barbiturates, such as pentobarbitai, and to zodiazepines suggest that triazolam may have a modest other marketed benzodiazepines. A secondary purpose is to benzodiazepine-like abuse liability. use triazolam as a case study to illustrate the complexity of REINFORCING EFFECTS the concept of abuse liability by providing an analysis of the Wide range of measures and methodological approaches Reinforcing efficacy of a drug refers to the relative effec- which may be considered relevant, tiveness in maintaining behavior on which the delivery of the drug is dependent [56]. A valid estimate of the relative rein- forcing properties of a drug is central to the assessment of CONCEFTUALDEFINITIONOF ABUSE LIABILITY abuse liability. These properties can be assessed in both Considerable confusion surrounds the meaning of the animals and humans. term abuse liability. Historically, drug abuse liability has been used to refer to: (1) the liability for abuse (i.e., the REINFORCINGEFFECTSIN ANIMALS likelihoodthata drug willbe abused) and/or(2)theliability ofabuse (i.e.,theuntoward effectsofabusingthedrug).For Drug serf-administrationproceduresinlaboratoryanimals purposes of thisreview, the term willbe used in both permitassessmentof therelativeefficacywithwhich differ- senses--theliabilityforand of abuse. These two sensesof eat drugsmaintaindrug serf-administratiThone. validityof abuse liabilitycorrespond directlyto two major charac- thisapproach for providinginformationrelevantto human teristics of drugs of abuse: (1)they have reinforcing proper- drug abuse is supported by the good correspondence be- ties (they have the capacity to maintain drug self- tween those drugs that are serf-administered by laboratory animals and those that are self-administered and abused by administration), and (2) they produce adverse effects (they humans [51] or produce profiles suggesting abuse liability in have the capacity to harm the individual and/or society). The human experiments [50]. presence of both characteristics is necessary to define a drug Self-administration of a variety of benzodiazepines has of abuse (cf. Brady et al. [ 17]). A drug devoid of reinforcing been studied in rats and nonhuman primates [49]. Triazolam effects but producing significant adverse effects should be serf-administration has not been studied in rodents, but five considered a poison, not a drug of abuse (e.g., cyanide). Similarly, a drug having some reinforcing properties but Thsucrhee sthudiaves involvedhave betheen intconductedravenous inroutnone handumanone periacmah tehass. producing no adverse effects is not meaningfully considered involved the intragastric and oral routes. a drug of abuse (e.g., a nontoxic, nonnutritive sweetener). The relative abuse liability of a compound is an interactive Intravenous Self-Administration function of the degree of reinforcing properties and adverse effects. Thus, compounds with high abuse liability could be: The first study [89] used procedures described in detail (1) highly efficacious reinforcers producing highly significant elsewhere [57] to examine serf-injection of diazepam. adverse effects (e.g., phencyclidine), (2) equivocal reinforc- triazolam, pentobarbital, and chlorpromazine in baboons. ers producing highly significant adverse effects (e.g., lyser- Intravenous injections of drug were dependent upon com- gic acid diethylamide), or (3) highly efficacious reinforcers pletion of 160 lever presses (a 160-response fixed-ratio producing modest adverse effects (e.g., moderate cocaine schedule). A 3-hr timeout followed each injection, permitting doses). Compounds with low abuse liability must necessarily a maximum of eight injections per day. Before testing each be those which axe margin al reinforcers and produce mar- dose of drug, serf-injection performance was established ginal adverse effects (e.g., caffeine). It should be recognized with cocaine. Subsequently, a test dose was substituted for that reinforcing properties and adverse effects are not neces- cocaine for a period of either 12 or 15 days. For triazolam, sarily independent dimensions. For example, a highly el'- the dose levels in mg/kg/injection and number of animals ficacious drug reinforcer may produce adverse effects solely studied at each dose level (indicated in parentheses) were: by virtue of maintaining high levels of drug seeking and serf- 0.0001 (2), 0.001 (2), 0.0032 (3), 0.01 (4), 0.032 (2), 0. ! (2), ABUSELIABILITYOFTRIAZOLAM 135

:,- l The third intravenous study [21] compared the self-

Ia1¢ _) T TOIIARalTAL female rhesus monkeys. Drug was available during daily 4-hr <,,, s_e. r_'AZOLAUl ._ T_ I///_PEN I admisessionsnistrationunder ofa fixed-ratiopentobarbital1 scheduleand threeof belevernzodiazepressingpines within cn a 20-see injection duration. High rates of self-injection were z ,- - initially established with cocaine (0.2 mg/kg), and subse-

_-° . • ,_J ,_-'..'zl_r-_,. DIAZEPAI_ quently the test drug was substituted for cc_caine. After 7 O a- O,'_I/..L - _-_ days at an initial dose of the test drug, the dose was in- tu -a_ ,_--._-'_"_._ creased and that dose remained available for the next 7 days. z o CHLORP_OMAZ,NE This doubled dose level of each test drug was selected as a -'_-_ 00'ool ...... 00_ ,0 ,000-- proportion of a dose which produced observable CNS de- pression. Each of the four test drugs was tested in four mort- DOSE (mg/kg/injection) keys with drug order counterbalanced across animals. The FIG. 1. Baboor_ intravenous drug self-injection results with rank ordering of the mean number of injections per session triazolam, pentobarbital, diazepam, and chlorpromazine. Y-axis: in- for the last 3 days was 105.9, 103.3 (pentobarbital 0. I and 0.2 jections per day: X-axis: dose (mi_'kg,'injection). log scale. C indi- mg/kg, respectively), 33.3, 32.2 (triazolam 0.001 and 0.0016 cates mean of all 3-day periods with cocaine that immediately pre- mgskg, respectively), 25.7, 28.7 (flurazepam 0.05 and 0. I ceded every substitution of a drug dose or vehicle. V indicates mean mg/kg, respectively), 15.4 and 13.4 (diazepam 0.12 and 0.25 of the last 5 days after substitution of the drug vehicle. Drug data mg/kg, respectively). Although absolute differences between dopoisen.tsBrackindicaetse indicmeanateofothnee S.E.M.last 5 dayunlsessafteerncomsubpastitutionssed byofthea drudatga compounds were sometimes small, the same rank ordering point. Data with pentobarbital, diazepam, and chlorpromazine are was also apparent with these data on a within subject basis replotted from Griffiths et al. [57]. (i.e., within all four monkeys mean injections for the last 3 days maintained by the four drugs were: pentobarbital > triazolam > flurazepam > diazepam). Except for one mon- and 0.32 (2). These details for diazepam, pentobarbital, and key with diazepam, the mean injections for the last 3 days chlorpromazine have been reported previously [57]. Figure 1 with all four compounds exceeded that for a saline control shows that chlorpromazine failed to maintain self-injection period obtained when the animals were drug naive. performance above vehicle control levels. Diazepam was associated with relatively low levels of self-injection (3. ! in- lntragastric Self-Administration jections/day, maximum) which exceeded vehicle control levels in two of three animals tested. Triazolam maintained Some limited data are available concerning triazolam levels of self-injection (5.6 injections/day, maximum) which self-administration intr'a_a_trically. Using standard proce- were substantially higher than vehicle levels but clearly dures [167] involving a fixed-ratio i schedule of continuous below cocaine control levels in all animals tested. Finally, drug availability in rhesus monkeys, Yanagita and colleagues pentobarbital was associated with dose-dependent increases reported that three out of four animals showed an increased in self-injection performance, with maximal levels (7.7 injec- daily self-administration rate over previous vehicle control tions/day) maintained in the range of cocaine, levels when 0.06 mg/kg/inj triazolam was substituted for re- The second intravenous study was conducted by Romer hicle for a 4-week period. However, these monkeys de- [125] using standard procedures [27] to evaluate the self- creased their self-administration rate when the dose was administration of four benzodiazepines in three or four male subsequently changed to 0.015 or 0.24 mg/kg [165]. In sum- rhesus monkeys. Access to triazolam (0.001, 0.0032 mWkg), marizing these data. Yanagita [ 162] concluded that triazolam temazepam (0.01, 0.032 mg/kg), flurazepam (0.18, 0.56 was intragastrically self-administered by monkeys at daily mg/kg), chlordiazepoxide (0.32 mg/kg), and saline was pro- rates similar to or slightly higher than diazepam vided 23 hr/day under a lever pressing schedule (probably fixed-ratio 1) with a 10-see timeout following each injection. Oral Self-Administration The lowest dose of each drug presumably was selected as a It has been difficult to obtain voluntary oral intake of proportion of a dose which produced CNS depressant effects behaviorally active drug doses in laboratory animals, and in naive monkeys. Drug doses were studied for at least 4 this applies also to the few attempts to study oral ben- weeks. During the f'u'st week of drug availability, there was a zodiazepine self-administration [491. 15-rain period each day during which each lever press The only experiment conducted to date on oral self- produced both a drug injection and a food pellet. Subse- administration of triazolam is one with baboons trained quently, the food condition was eEminated and lever presses under food-induced drinking procedures [3]. Under food- only produced drug injections. The results showed that induced drinking procedures, it has been possible not only to triazolam maintained more consistent and greater numbers establish high levels of oral drug intake with a number of of injections than any of the other drug conditions. For in- different drugs, and to maintain substantial drinking after the stance, during the first week during which drug alone was original inducing procedures were suspended, but also to available, triazolam maintained an average of 112 and 123 demonstrate clearly reinforcing efficacy of these drugs (e.g., inj/23 hr at 0.001 and 0.0032 mWkg respectively, compared to ethanol [62,64]; pentobarbital [28]; methobexital [5]). a saline control and all the other drug conditions which In the study with triazolamo two Called baboons were ranged between 12--63 inj/23 hr. The rank ordering of the studied in 3-hr daily experimental sessions during which 1000 mean number of inj/23 hi" on the fourth week of drug alone ml of fluid were available through an automated drinking availability was: 146 (0.001 triazolam), 118 (0.0032 device [63]. Drink duration was controlled by the baboon triazolam), 103 (0.032 temazepam), 33 (0.18 flurazepam), 25 with a maximum of 30 sec. The baboons had free access to (0.56 flurazepam), 18 (0.01 temaz_pam), 13 (0.32 chlor- water except during this daily session. Ingestion of a large diazepoxide), volume of fluid in a brief period of time was promoted by 136 GRIFFITHS ET AL. delivering the daily ration of dry food all at once 1 hr into the Two BOTTLECHOICE and triazolam concentration was raised gradually across , :: sessions. A substantial proportion of the total volume con- sumed per session (35% or more) soon was taken in the hour before food delivery, and within-session food delivery was i I session. Triazolam was suspended with BIO-SERV Agent K _ _' A : ._.o<_,__ B,.o_ _ i,_<_ then was increased across sessions to 0.04, 0.08.0.16, 0.32, 0.64, and i.28 mg/ml. Drinking at each of these concentra- !i tions was studied for at least 10 sessions and until volume _ I! consumed showed no increasing or decreasing trends for 4 _ : I cdononseiscstantoncutitinuevedacrsoessatssions0.con03. ceVntratimoglume/mlons triaconsumedzoandlam. thugeTshneetrallyheconceamrneotmainedruntation of _ , _ , • , a ,6 _2 ,4 ,0 ,e 32 triazolam received (mg/kg) generally increased monotoni- § ME_XITAL (rag/m4) cally. Peak intake was 10.6 mg/kg for one baboon and 21.3 mg/kg for the other. This relationship between drug concen- _ 0A.oo_ A_, .AeOON _o rI 0aUG j tration and intake (mg/kg) was similar to that obtained in >_ ,ooo Z vE.... Ei previous research with the short-acting barbiturate z that seen earlier with ethanol [62]. With ethanol, volume consumed by these baboons decreased as ethanol concen- tration increased such that ethanol intake (g/kg) remained generallyconstant. At each triazolamconcentratioofn 0.04mg/ml and above, a two-bottlechoiceprocedurewas institutedaiderdrinking methohexital in these same bab°ons [5] but different fr°m _ I _ _ under the single-bottle condition was stable. Positions of .,: .,4 ....0=.,, :s ,4 ,.., 0: ,, ,a ,, 32 ,,, _, J triazolam and vehicle alternated daily. Figure 2 presents the r_t_ZOt.AM(mg/_) results of these two-bottle conditions with triazolam and, for comparison, results of the two-bottle conditions conducted FIG. 2. Oral triazo_un and methohexital self-administration in ba- during the previous study of methohexital with these and two boons. Y-axes: mean volumes consumed in the last 4 sessions in other baboons [5]. Higher mean volumes of methohexital ctwo-boncurreottlentlychowiticehcontheditidrougns. veEachichledru(wgaterconcentrationfor methohewasxital;availablewater than water were consumed at a number of methohexital con- with a suspending agent for triazolam). Each condition was studied centrations by three of the four baboons studied; arrows until volumes consumed of both drug and water showed no increas- indicate conditions in which the ranges of methohexital and ing or decreasing trends across four sessions. Arrows indicate the water volumes did not overlap during the last four sessions, concentrations at which drug volume consumed was higher than the thus indicating clear preference for methohexital over water, vehicle in all four sessions. The methohexital data are replotted from In contrast, when two of these baboons that showed Atorand Griffiths I51. methohexital preference were studied in this same procedure under conditions of triazolam availability, the ranges of triazolam and vehicle volumes overlapped during these ses- (cf. [49]) showing that: (1) benzodiazepines are more ef- sions at all but one concentration for each baboon, ficacious as reinforcers than some drugs, including chlor- In a procedure analogous to that used in some studies of promazine, imipramine, haloperidol or perphenazine; and (2) intravenous drug self-administration, the baboons next were benzodiazepines are less efficacious as reinforcers than a required to press a lever a fixed number of times for each range of other drugs, including pentobarbital, amobarbital, triazolam drink. Response requirements were raised gradu- secobarbital, and cocaine. ally until volume consumed in each session was suppressed It is possible that elimination rate is a determinant of rates to virtually zero. Under these fixed-ratio (FR) schedules of of serf-injection. The finding that triazolam (and possibly reinforcement, triazolam did not maintain greater responding temazepam) maintain higher levels of self-injection than a than vehicle at any response requirement. Responding was variety of other benzodiazepines which are slowly elimi- suppressed for one baboon at FR 8 and for the other baboon hated or have active metabolites which are slowly eliminated at FR 128. in man is consistent with the results of a previous study The results of this initial work with oral triazolam self- which showed that midazolam maintained higher levels of administration are intriguing in that baboons that were not intravenous self-injection than clonazepam, clorazepate, di- water-deprived consumed large quantities of triazolam reli- azepam, flurazepam, and medazepam [57]. These latter five ably over many months and, as will be described below, compounds are also slowly eliminated in humans; triazolam showed signs of physiological dependence. Yet, these same and midazolam, in contrast, are rapidly eliminated. How- baboons did not show strong triazolam preference over drug ever, independent of elimination rate, the possibility also vehicle as had been shown in tests with methohexital [5] and remains that triazolam and midazolam are more efficacious with ethanol [62]. reinforcers than the other benzodiazepines, and thus may have a higher abuse liability. While differences in elimination rate appear to provide an explanation for differences in self- Conclusions From Animal Self-Administration Studies injection between benzodiazepines, they do not account for The results of these five triazolam self-administration the differences in self-injection observed between the barbi- studies with baboons and rhesus monkeys are consistent turates and benzodiazepines. In spite of the fact that both with the results of previous research in nonhuman primates triazolam and midazolam are more quickly eliminated than ABUSE LIABILITY OF TRIAZOLAM 137 pentobarhital, pentobar'oitalm_untamedmore reliable and with historiesof drug abuse. The appropriatenessof using highermean levelsof self-injection, subjectswith historiesof drug abusein suchevaluationsof subjectiveeffects is supportedby its facevalidity and by the REINFORCINGEFFECTSINHUMANS results of experiments showing that there was a closer con'e- The reinforcing properties of drugs in humans can be in- spondence between experimental results and clinical obser- vestigated by adapting procedures developed in the animal ration when studies were conducted with "'postaddict'" drug serf-administration laboratory. The validity and appro- populations rather than with "'normais'" or "'patient popula- priateness of such an approach is demonstrated in studies tions'" [12]. With this approach, the reinforcing properties with subjects with histories of drug abuse which have shown are assumed to be a function of the degree to which a drug that the reinforcing efficacy ofdiazepam is greater than that produces pleasant subjective effects (sometimes called of chiorpromazine and oxazepam, but less than that of pen- euphoria or liking) or estimates of "street" monetary value. Such effects can be assessed by using various scale- or tobTharbiertael ar[53e ,tw55o, e59].xperimental studies and one case report item-based questionnaires. Although it is sometimes ex- which provide some limited information about reinforcing plicitly or implicitly assumed that the reinforcing effect of a properties of triazolam. Fleming [40] described a patient with drug is causally dependent on the pleasant subjective effects a history of multiple drug abuse (including psychomotor it produces [70] such assumptions can be reasonably ques- stimulants, opioids, marijuana, alcohol, and diazepam) who tioned [137]. Furthermore, although there appears to be a preferred triazolam to all other medications he had used or generally good correspondence between pleasant subjective abused. While the limitations of such case reports are sub- effects and reinforcing effects, there have been reports of stantial, it is noteworthy that analogous case reports of pref- dissociations between these effects [55,72]. Thus, assess- erence for a benzodiazepine over all other drugs in patients ment of such subjective effects is useful as a measure of with histories of multiple drug abuse are nonexistent, abuse liability only to the extent it actually predicts reinforc- In the two experimental studies, Bechelli et al. [11] and ing properties. Boissl et al. [16] used similar double-blind crossover designs The experimental literature demonstrating that ben- to investigate in humans the reinforcing properties of zodiazepines and barbiturates produce pleasant subjective triazolam in comparison to zopiclone, a nonbenzodiazepine effects in subjects with histories of drug abuse has been re- hypnotic with a putative site of activity at the ben- viewed recently [60]. There is only one study to date assess- zodlazepine receptor. Chronic alcoholics who hadjust corn- ing pleasant subjective effects of triazolam in such subjects. pleted withdrawal treatment were told that the study in- Using a double-blind Latin Square design, Roache and Grif- volved testing drugs that may give the same Rind of feelings fiths [123] compared oral doses of placebo, triazolam (0.5, they get from alcohol, and that they should tare the test 1.0, 2.0, and 3.0 nag) and pentobarbital (100, 200, 400, and capsules whenever they felt like talcing an alcoholic drink. 600 rag). At 1, 2, 3.4, 6, 8, 12, and 24 hr after drug adminis- Subjects were permitted to tare up to eight capsules per day tration various questionnaire and performance measures of either 0.25 mg triazolam or 3.75 mg zopictone. On days 1 were taken. The two drugs produced similar dose-related and 2 subjects received one color-coded treatment and on effects with area under the time-action curve (AUC) data days 3 and 4 the other color-coded treatment. They were from a variety of performance measures (psychomotor per- then permitted to choose which color-coded treatment they formance, digit-symbol substitution task performance, staff would receive on days 5 and 6. Although significantly more ratings of magnitude of drug effect); statistically valid rela- subjects choose triazolam than zopiclone (25 vs. 15subjects) tive potency estimates were obtained indicating triazolam in the Bechelli study [IlL this effect was not replicated (72 was approximately 200 times more potent than pentobarbi- vs. 18 subjects) in the Boissi study [16]. tad. With subject ratings of magnitude of drug liking (AUC), The implications of these experimental results for however, statistically valid relative potency estimates could triazolam are rather limited. Other studies have shown ben- not be obtained because, even though triazolam produced zodiazepine and sedative reinforcement effects to be dose elevations in liking, pentobarbital produced substantially dependent [52, 53, 99]. Thus, the lack of dose manipulations greater increases than did triazolam. Figure 3 shows the es- substantially limit the possible conclusion from the Bechelli timated "street" monetary value of placebo, triazolam, and study that triazolam is a more efficacious reinforcer than pentobarbital. Subjects estimated monetary value of a given zopiclone. Furthermore, in the absence of a placebo control, dose of drug on the morning following the day on which drug one cannot conclude with certainty that triazolam per se was administered. Analysis of variance and post hoc corn- served as a positive reinforcer. Finally the failure to replicate parisons showed that only 2 mg of triazolam, and 400 and 600 this finding in a similarly designed experiment only further mg of pentobarbital were significantly different from reduces confidence in the finding. At best, these limited re- placebo. Pentobarbital produced significant dose-related in- sults in humans are not incompatible with the animal drug creases in estimated street value (600 mg was significantly self-administration results which suggest that triazolam is a different from either the 100 or 200 mg doses). In contrast, the effect of trlazolam was not a monotonically increasing more efficacious reinforcer than other pharmacologically re- function of dose and there were no significant differences luted anxiolytics and sedatives, among doses. Overall, these data with liking and estimated monetary RATINGS OF LIKING AND MONETARY VALUE value suggest that triazolam has somewhat less abuse liabil- BY HUMANS ity than pentobarbital. This conclusion is consistent with a series of human studies reviewed elsewhere [60] which One indirect approach to providing information about the showed that the pleasant subjective effects and/or reinforc- reinforcing properties of drugs is to utilize placebo con- ing properties of pentobarbital were greater than those of the trolled, double-blind methodologies to characterize the benzodiazepinesdiazepamand chlordiazepoxide. Ratings of pleasant subjective effects produced by drugs in subjects pleasant subjective effects and monetary value have also 138 GRIFFITHS ET AL.

travenous abuse, and reports of abuse via inhalation or snort- ing are virtually nonexistent. Given that speed of onset of _ y drug effect is a determinant of reinforcing efficacy, it follows

m - turates may be importantly determined by speed of onset

B- PENTOSARBITA after oral administration. Support for this within the ben- • zodiazepine class comes from a recent sei of studies which > _' - involved a variety of subjective, behavioral, and lo._ i that the relative abuse liability of benzodiazepine and barbi- = " TRIAZOLAM bility as well as the actual incidence of abuse of diazepam :E "_ 4- ,; was greater than that of oxazepam [58.59]. Inspection of . ,, time-action functions showed that onset of effect was more cn 2- _ j_, rapid and time to maximal effect was shorter with diazepam ua - than oxazepam (time to maximal effect was 1-2 hr with _ = e"" t"__rT diazepidemioepamlogicalvs. 4-12meahrsureswithandoxazepamconcluded). Interestingly.that the abusewhenlia- o- • subjects were asked to write comments about what they -np, 110 lo'.o loo0' mooo' liked about the drugs which had been administered double- blind, subjects often cited the rapid onset of effects as being DOSE (mg) a desirable feature of the diazepam effect. FIG. 3. Estimated "'street" monetary value of triazolam and pen- Triazolam absorption after oral administration is rapid tobarbital in nine subjects with histories of sedative drug abuse, with maximum serum concentrations generally occurring at Y-_tis: estimated value in dollars; X-axis: dose (rag). log scale. P 1-2 hr [8, 32/45]. Time-course studies of the effects of 0.25 indicatesplacebo. Points showmeans;bracketsshow -.-S.E.M. Oral dosesof triazolam (0.5, 1.0, 2.0 and3.0 rag) and pentobarbital (100, mg triazolam on performance on a psychomotor task and 200, 400, and 600 nag)producedsimilar dose-relatedsuppressionin digit-symbol-substitution task (DSST) in normal subjects psychomotorperformance. Monetary street valueof eachdosewas show peak effects at 1-2 hr [8,108]. In the study by Roache estimated in the morningfollowing the day on which drug was ad- and Griffiths [123] comparing triazolam and pentobarbitai in ministered. Data are replotted from Roaocheand Griffiths [ 123]. drug abusers, analysis of time-course of psychomotor and DSST performance showed that the drugs were associated with similar rapid onset of effects with the mean peak-effect of triazolam ( 1-2 hr) occurring somewhat sooner than that of been used as a basis for comparing different ben- pentobarbital (2-3 he). zodiazepines. Although conclusions from some studies have To the extent that speed of onset of effects is a determi- been limited because only a narrow range of doses was in- nant of drug reinforcing efficacy, the relatively rapid onset of vestigated, the results to date suggest that there are differ- effects with triazolam suggests that triazolam may have ences among benzodiazepines; lorazepam has been greater abuse liability than pharmacologically similar corn- suggested to have reinforcing/subjective effects similar to pounds (i.e., benzodiazepine hypnotics and anxiolytics) diazepam, while oxazepam, halazepam, and chior- which have slower onset profiles, such as oxazepam [58], diazepoxide may have reinforcingsubjective effects less and halazepam ([69] and Roache and Griffiths, unpublished than diazepam [60]. Unfortunately no study to date has corn- observations). Although thorough onset time-course com- pared triazolam with another bcnzodiazepine with respect to parisons apparently have not been done, the possibility also such ratings of pleasant subjective effects and/or monetary remains that triazolam may have less abuse liability than value, pharmacologically similar compounds which have excep- tionally fast onset latencies, such as diazepam [36]. SPEED OF ONSET OF DRUG EFFECTS IN HUMANS DISCRIMINATIVE STIMULUS EFFECTS IN ANIMALS It is widely believed that the efficacy of drug reinforcers is partly determined by speed of onset of drug effects. Drug discrimination procedures provide information AnecdotaUy, drug abusers appear to prefer routes of admin- about the interoceptive stimulus properties of drugs. Degree istration resulting in rapid absorption (e.g., intravenous, in- of discriminability with such procedures is not necessarily halation) over those resulting in slower absorption (e.g., related to abuse liability [115]. However, under appropriate oral). Consistent with this, drugs are much more readily training and testing conditions, drug discrimination proce- shown to be reinforcing in animal serf-administration when dures permit the categorization of the interoceptive stimulus delivered intravenously as opposed to orally or properties of a test drug as being similar or dissimilar to intrag,astrically. Some limited experimental data also support standard compounds. If the test drug occasions responding the proposition that speed of onset is a partial determinant of similar to a standard training drug, the test drug and standard reinforcing effects. When the dose and duration of intrave- are sometimes assumed to have similar abuse liability. This nous cocaine infusions were manipulated in rhesus monkeys assumption, however, is valid only to the extent that the [9] and drug abuser subjects [39], the speed of infusion was discriminative stimulus properties covary with the reinforc- directly related to measures of reinforcing efficacy in mon- ing and adverse effects of the standard and test compound. keys and euphoria in humans. While under appropriate training conditions the correlation Many abused drugs (e.g., cocaine, amphetamine, heroin, between discriminative stimulus and reinforcing properties is phencyclidine) can be readily taken via routes resulting in remarkably high within some dru B classes [159], there are rapid onset of effect (e.g., intravenous, inhalation, snorting), notable exceptions. For instance, although racemic With benzodiazepines and barbiturates, in contrast, solubil- N-allylnormetazocine (SKF 10,047) produces discriminative ity limitations and injection-related toxicity discourage in- stimulus properties similar to phencyclidine [ 18], phencyc- ABUSE LIABILITY OF TRIAZOLAM 139 lidine maintains drug self-administration (i.e., is a reinforcer) co in contrast to racemic N-allylnormetazocine which does not cotu,oo- aol ,_..... a_ T j_--o' [1411. Thus, appropriate caution must be exercised in inter- z - TPUAZOLAM // g'''" preting drug discrimination results in terms of abuse liability, o.° so- :,' SO+AZE"AU In drug discrimination procedures, animals are trained to co - Idd / respond differentially depending on the nature of the drug n- 80- pretreatment. The most frequently used procedures have in- ¢ . ," / volved either a T-maze _e.g., go left if drugged: go right if not uJ)' 40 - / / drugged) or a two-lever choice situation (e.g., left lever re- . -J'" _ ,' /,' sponses produce food if drugged; right lever responses _ 20 • _// i PENTOBARBITAL coprodnductceed foodin ifwhichnot druggednovel). druAgfterconditionstraining, tesaret sepresented.ssions are ,-m,_" 0- _m _';"" I" _----_-----_/ ' r._, When different doses of the training drug are tested, re- _ T-'r" , , , , , • -- sponding generally is similar to that with the training drug L v o._, oi_ ,o ,c;o dose except at low doses. When other drugs are compared. DOSE (m0/kg) drugs from the same or similar pharmacological classes also tend to produce responding like that under the drug training FIG. 4. Baboon drug discrimination results with triazolam. conditions at some doses, while drugs from different classes diazepam, and pentobarbital in animals tr',uned to discriminate Iorazepam (I.0 mWkg, IM or PO) from the no-drug condition. do not. Y-axis: druglever responsesexpressedas a percentageof total ses- The discriminability of benzodiazepines has been sion responding; X-axis: dose(mWkg), log scale. L and V indicate demonstrated in studies in which animals were trained to test sessionresultsafter administration of 1.0 mg/kgIorazepam or discriminate a benzodiazepine from saline (e.g., chlor- vehicle, respectively. Points indicate means; brackets show diazepoxide, diazepam, flurazepam, or oxazepam [i 14]). --S.E.M. unlessencompassedby the data point. Numerals indicate When other drugs were substituted in benzodiazepine- number of baboonstested at eachdose.Administration oftriazolam trained animals, drug-appropriate responding has occurred was oral, pentobarbital was intramuscular, and diazepam was both consistently for all other benzodiazepines, inconsistently for: oforalpe(ntwotobabrbabooitalns(1) 7.and8 mgint/rkag)muscumarlkaredl(oney supprebaboon)ssed. resA hpoigherndingdosein other sedative-hypnotics, and not at all for antipsychotics; four of the six baboons tested• thus indicating some specificity of effect (e.g., [ 10,231). To date, three studies have investigated the discrimina- tive stimulus properties of triazolam. In two studies with rats [81,140], triazolam was similar to other benzodiazepines The findings in Iorazepam-trained animals suggest that (including diazepam, chlordiazepoxide, flurazepam, flunit- triazolam produces interoceptive stimuli similar to razepam, nitrazepam, bromazepam, and midazolam) in that Iorazepam and diazepam, but dissimilar to pentobarbital. To triazolam occasioned drug-lever responding in both the extent that such interoceptive stimuli covary with rein- diazepam- and pentobarbital-trained animals, forcing properties, these data suggest that the abuse liability In the third study, which used drug discrimination proce- of triazolam may be more like diazepam and Iorazepam than dures described in detail elsewhere [4,6], baboons and rats pentobarbital. That the benzodiazepines occasion drug lever were trained to discriminate either iorazepam (1.0 mg/kg) vs. responding in pentobarbitai-trained animals may be relevant no drug or pentobarbital (5.6 or 10.0 mWkg in baboons; 10.0 to the drug abuse phenomenon of illicit "'look-alike" or mg/kg in rats) vs. no drug in a two-lever drug discrimination "counterfeit" drugs. In recent years, diazepam has appeared procedure. Food delivery depended on 20 (baboons) or I0 in the illicit drug abuse market in preparations designed to (rats) consecutive responses on one lever in sessions pre- resemble hypnotic compounds such as methaqualone which ceded by intraperitoneal (rats) or intramuscular or oral (ba- are believed to have substantial abuse liability. The fact that boons) administration of drug, and on the same number of triazolam produces pentobarbital-like interoceptive stimuli consecutive responses on the other lever following no drug. in pentobarbital-trained animals suggests the possibility that Drug pretreatment time was 60-min in baboons and 15 (pen- triazolam could be similarly misused as a "'look-alike'" hyp- tobarbitai) or 60 (Iorazepam) rain in rats. All animals reliably notic. completed 100% of the response runs on the appropriate lever in training sessions. Test sessions were conducted in CATEGORIZATION OF SUBJECTIVE DRUG EFFECTS which a drug dose different from the training dose was ad- BY HUMANS ministered, and the appropriate number of consecutive re- sponses on either lever produced food. In the lorazepam- Despite the demonstrated utility of the drug discrimina- trained baboons and rats, diazepam, triazolam, and tion procedure in the animal laboratory, there have been Iorazepam but not pentobarbital occasioned drug-lever re- relatively few attempts to adapt this methodology for use in sponding. Figure 4 shows these results with diazepam, human studies and no attempts to evaluate anxiolytic or triazolam, and pentobarbital in baboons. Interestingly, al- sedative-hypnotic drugs with such techniques. However, though pentobarbital failed to occasion drug lever respond- data which may be analogous to animal drug discrimination ing in lorazepam-trained animals, diazepam, triazolam, can be provided in the context of double-blind evaluation of Iorazepam, as well as pentobarbital produced drug-lever re- drugs in subjects with histories of drug abuse. Subjects can spondiog in pentobarbital-trained baboons and rats. This as- be asked to categorize the subjective effects of a test com- ymmetrical generalization with Iorazepam and pentobarbital pound as being similar or dissimilar to standard compounds training conditions suggests a specificity of discriminative with which they presumably have had experience. The abuse stimulus effects which has not been clearly documented in liability of the test compound is assumed to be similar to that previous drug discrimination experiments with ben- of the standard compound(s) with which it is categorized. zodiazepines and barbiturates. Such a procedure has been used to distinguish between mor- 140 GRIFFITHS ET AL.

phine and pentobarbital, morphine and nalorphine, and mor- TABLE I

phine and d-amphetamine [70]. Such a procedure has also CATEGORIZATION OF DRUG EFFECT BY NINE SUBJECTS WITH been used to differentiate between two benzodiazepine HISTORIES OFSEDATIVE DRUG ABUSE anxiolytics. Although diazepam and oxazepam were equally often categorized as "benzodiazepine." diazepam was more Percent SubJects frequently categorized as "'barbiturate" than oxazepam Selecting Category [58,59]. Dose/Drug One study has evaluated triazolam using categorization Administered (N) Placebo Barb Benzo Other procedures in subjects with histories of drug abuse [123]. This study (described in more detail in Ratings of Liking and Placebo (9) 100 0 0 0 Monetary. Value by Humans section) involved the double- blind evaluation of placebo, triazolam, and pentobarbital. 0.5 mg TZ (9) 22.2 0 77.8 0 Subjects were informed that various drugs would be adminis- 10 mg TZ t9) 11.1 0 77.8 I I. 1 tered and that these could include neuroleptics, minor tran- 2.0mgTZ (9) 0 222 778 0 3.0mgTZ _9) 0 I1.1 88.9 0 quilizers, sedatives, stimulants, and placebo. Other than re- ceiving this general information, subjects were blind to the Total TZ _36_ 8.3 8.3 80.6 2.8 type of drug administered. At !, 2, 3, 4, 6, 8, 12, and 24 hr after drug administration subjects completed a questionnaire 100 mg PB (9) 44.4 II. I 22.2 22.2 which involved categorizing the drug effects as being most 200 mg PB (9) 22.2 55.6 0 22.2 similar to one of 13 categories of psychoactive drugs. The 400 mg PB (9) 0 77.8 22.2 0 questionnaire provided descriptive titles for, and examples 600 mg PB (9) 0 77.8 11.1 1I. I of, drugs in each of the following drug categories: placebo, opioids, phenothiazines, barbiturates and sleeping medica- Total PB (36) 16.7 55.6 13.9 13.9 tions (examples included pentobarbital, phenobarbital, Tui- nal, Nembutal, reds, yellows, methaqualone, quaaludes, After receiving oral doses of triazolam (TZ). pentobarbital (PB). Placidyl), antidepressants, hallucinogens, benzodiazepines and placebo, subjects were required to identify the drug effect as being most similar to one of several categories of psychoactive (Examples included Valium, Librium, Tranxene), stimulants, drugs, including "'Blank or placebo" (PLACEBO), "'Barbiturates alcohol, cocaine, marihuana, phencyclidine, and other, and sleeping medication" (BARB), and Benzodiazepines (BENZOL Except for potency differences, both drugs produced Data show the percentage of subjects selecting a given category; row similar dose-related effects on various performance meas- totals do not always equal 100 percent because of rounding errors. ures. Table 1 shows the results of subject categorization of With a given dose of drug, if a subject selected more than one drug drug effects. Placebo was reliably categorized as ""placebo or category during the multiple daily ratings, the most frequently cho- blank." 'While the lowest doses of triazolam and pentobarbi- sen category was used. Data are derived from Roache and Griffiths tal were rated as pla,_ebo by some subjects, higher doses of [123]. both drugs were consistently rated as similar to a psychoac- tive drug category. Interestingly, as reflected by this proce-. dure, triazolam and pentobarbital produced clearly different effects: triazolam was categorized predominately as a "ben- ical dependence, but do produce substantial drug seeking zodiazepine'" while pentobarbital was categorized predomi- behavior (e.g., cocaine, amphetamine [38,481); and finally, nately as a "barbiturate or sleeping medication." there are situations in which the drug doses and/or schedules The present results are consistent with the animal drug of drug availability preclude the development of physiolog- discrimination results presented in Discriminative Stimulus ical dependence yet are associated with drug-seeking behav- Effects in Animals section. As with the results obtained with ior [42, 120, 158]. benzodiazepine-trained baboons and rats, the human data Physiological dependence may contribute to the abuse suggest that the interoceptive stimulus properties of liabilityofadrugintwoways:(l)asanadverseeffectofdrug triazolam may be more diazepam-like than pentobarbital- use that is revealed upon discontinuation of drug use; and (2) like. To the extent that such interoceptive stimulus proper- as a potential mechanism by which the reinforcing effects of ties covary with reinforcing and adverse effects, the animal a drug may be enhanced. While this latter point seems rea- and human data suggest that the abuse liabiEty of triazolam sonable and is consistent with some clinical descriptions of is more diazepam-like than pentobarbitad-like. As discussed benzodiazepine abuse, a clear experimental demonstration previously, categorization of drug effect by humans has also of this mechanism is not available. In fact, there are some been used as a basis for differentiating between ben- animal drug self-administration data which suggest that, zodiazepines. Regretably such procedures have not been while physiological dependence increases the reinforcing used to compare triazolam with other benzodiazepines, properties of morphine, such is not the case with diazepam [160,163]. In any event, physiological dependence certainly represents a significant adverse effect of drug use and thus PHYSIOLOGICAL DEPENDENCE should be considered in a balanced analysis of the abuse Although at times people appear to believe that the ability liability of benzodiazepines. of a drug to produce physiological dependence is the sine PHYSIOLOGICALDEPENDENCEIN ANIMALS qua non of an abused drug, this has long been realized not to be the case, and is constantly being rediscovered not to be Three general methods have been used to assess the abil- the case [68, 85, 106]. For instance, there are drugs that ity ofbenzodiazepine-like compounds to produce physiolog- produce physiological dependence without eliciting drug ical dependence in laboratory animals: (1) substitution tests seeking behavior (e.g., cyclazocine, nalorphine [97]); there in which the ability of the test drug to suppress withdrawal are also drugs which are thought not to produce physioiog- signs of animals physiologically dependent on another drug ABUSE LIABILITY OF TRIAZOLAM lal

is assessed; (2) precipitated withdrawal tests in which the pentobarbital withdrawal signs in rats. However, these re- test drug is given chronically and the presence or absence of suits contrast with those of Yanagita [ 161] showing triazolam precipitated withdrawal signs is noted when a ben- and other benzodiazepines were effective in suppressing zodiazepine antagonist is given: and, (3) spontaneous with- barbital withdrawal in rhesus monkeys. Clearly, this topic of drawal tests in which the test drug is given chronically and cross-dependence between benzodiazepines and barbitu- animals are assessed for withdrawal signs when drug admin- rates needs further study. At present, however, there is little istration is abruptly terminated, that distinguishes triazolam from other benzodiazepines in this regard, except potency.

Substitution Tests Prec'ipitLtted Withdra, ul Test Two groups have assessed the ability of triazolam to sub- stitute for a barbiturate in barbiturate dependent animals. Administration of Ro 15-1788. a benzodiazepine Yanagita [161.165] reported that triazolam 10.25 and 1.0 antagonist, to animals treated chronically with a ben- mg/kg, PO) suppressed withdrawal signs in rhesus monkeys zodiazepine precipitates signs suggesting a benzodiazepine normally maintained on barbital (75 mg/kg; PC): b.i.d.), withdrawal syndrome (e.g., [26. 87. 90, 91, 1130. 126]). Other benzodiazepines were also effective at suppressing Whether this withdrawal syndrome differs from the spon- barbital withdrawal signs [161]. However, not all sedative taneous withdrawal syndrome only in the kinetics of drugs studied with this procedure were able to suppress agonist-receptor dissociation or along some other dimension barbital withdrawal signs (e.g., benzoctamine and methaqua- as well is presently undecided [90,100]. However, most in- lone [ IIM, 167]), Therefore, these effects cannot be accounted vestigators do agree that the Ro 15-1788 precipitated with- drawal syndrome is relevant in assessing the degree of phys- for solely in terms of the sedative effects of benzodiazepines, iological dependence produced by benzodiazepine adminis- Investigators at the Upjohn Company conducted two tration. studies to assess the ability of triazolam to substitute for With respect to triazolam, Cumin and co-workers [26] barbiturates in barbiturate-dependent rats. In the first study reported that administration of Ro 15-1788 ( 100 mg/kg) to [201 female Sprague-Dawley rats were maintained on a diet cats that had received triazolam (I mg/kg/day x 16 days) (0.14%of powdered) for at Pleaurinast 3 mratonthschowpriocontainingr to beginningphenobarbitalof a test produced rigidity, vocalization, and hypersalivation. They phase in which they were tested repeatedly with an interval also reported that administration of Ro 15-1788 to squirrel of at least three weeks between tests. Tests consisted of first monkeys that had received triazolam (3 mg/kg/day x 15 depriving the rats of food (and drug) for one day. On the next days) produced rigidity, loss of reactivity and refusal of food. day the rats were allowed access to powdered rat chow In our laboratory, we conducted precipitated withdrawal without phenobarbital and were given either drug or placebo studies in three baboons receiving triazolam and three re- (orally in a suspension) at approximately 8:30 a.m. and 3:30 ceiving diazepam. Observations were conducted on four of these baboons while they were subjects in triazolam (two p.m. On the morning of the third day amount eaten and baboons) or diazepam (two baboons)oral self-administration change in body weight were recorded. On the first day, rats that were exposed to the phenobarbital diet lost amounts of experiments (cf. Reinforcing Effects section) in which they weight (approximately 24 g) that were similar to those lost by consumed drug during daily 3-hr sessions. The two other baboons received triazolam (one baboon) or diazepam (one identically treated control rats never exposed to phenobarbi- tal. However, rats on the phenobarbital diet regained only baboonl via continuous intragastric infusion. Mean drug ex- about 7 g when given placebo on day 2, while the control rats posure at the time of testing was 3.0, 5.0, and 8.9 mg/kg/day regained essentially all the weight lost. When triazolam (3, 6, for the three triazolam-exposed animals, and 2.6, 16.3, and and 12 mg/kg) was administered, only the 6 mg/kg dose in- 20 mg/kg/day for the three diazepam-exposed animals. creased weight gain above placebo levels, but this dose did Animals received intramuscular injections of Ro 15-1788 (5.0 not produce weight gains as great as those produced by mg/kg) or vehicle and were observed for withdrawal signs phenobarbital (15--40 mg/kg). Like triazolam, diazepam using methods similar to those previously described {901. (15--60 mg/kg), flurazepam (30.-120 mg/kg), and barbital (25- Figure 5 shows that baboons displayed more precipitated withdrawal signs following Ro 15-1788 administration than 100 mg/kg) also showed weak effects. In another study [22], after vehicle administration. the ability of triazolam to suppress intravenous self- administration (continuous reinforcement) of pentobarbital- These results and those of Cumin er al. {26] indicate that sodium (3.2 mg/kg/inj; mean intake approximately 250 triazolam, like other benzodiazepine agonists such as di- mg/kg/day) by female Sprague-Dawley rats was examined, azepam, flurazepam, and Iorazepam, produces physiological Test drugs were administered by mixing with the rats" pow- dependence as revealed by Ro 15-1788 precipitated with- dered diet. Triazolam (at concentrations of 0.01 and 0.03%) drawal. Data presently available do not provide a basis for and diazepam (at 0.1 and 0.3%) were tested for two days. distinguishing triazolam from these other benzodiazepine Except for potency differences the effects of the two drugs agonists. were similar. The highest concentrations of triazolam and diazepnm resulted in an average intake of 16 and 109 Spontaneous Withdrawal Test mg/k_day, respectively; these levels of intake reduced pen- Yanagita and co-workers [165] conducted a study in six tobarbital self-administration by approximately 3 !% for both rhesus monkeys which involved administration of: triazolam drugs. (2--.4 mg/k_day) during weeks 1--4. no drug during week 5, The latter two studies suggest that triazolam and other triazolam (4.--6 mg/kg/day) during weeks 6-9. and no drug benzodiazepines show weak or incomplete cross- during week 10. Using standard withdrawal criteria [167], dependence with phenobarbital and pentobarbital, a result during the first withdrawal period three monkeys showed compatible with a report of Martin and co-workers [981 intermediate grade withdrawal signs while the other three which showed that diazepam did not completely suppress showed mild grade signs. During the second withdrawal 142 GRIFFITHS ET AL.

PRECIPITATED WITHDRAWAL IN TRIAZOLAM-AND spontaneous withdrawal signs as severe as those described DIAZEPAM-MAINTAINED BABOONS by Yanagita after diazepam and Iorazepam treatment in rhesus monkeys [167,168) have not been observed following RO is- 1r88 Ro 15-1788 abrupt termination of these same drugs in baboons [87,901, VEHICLE (S.O r.o/kO ) Investigators at the Upjohn Company have examined MINUTIrSAFTERINJECTION UlNUTESAF"rtn INJltC'rloN triazolam spontaneous withdrawal in two studies with ro- D-t0 o-=o 40-6o dents. In the first study [133], separate groups of female NOtE MUllS • I • • • •ram=I Sprague-Dawley rats were fed a diet of powdered Purina rat , []/X, 0 r"IAOi[]/N chow containing either 0.0017% or 0.005% tnazolam, 0.017% i'D •• • 1A• • •• or 0.05% diazep'am. 0.017% chlorpromazine, or no drug. The YAWNS [] i-']/N D/NO /NO [] drug concentrations were increased at weekly intervals by VOMITING • • units of 0.15 Iog_., and by the fourth week the a_erage #, []A O /'_(_ amount of drug consumed per day was 3.6 and 9.6 mg/kg of • •0 • triazolam, 31.7 and 94.8 mg/kg of diazepam, and 27.8 mg/kg RFTCHING ["]/_O D/kO of chlorpromazine. When drug was eliminated from the food ABNORMAL • • • • 11 • on weeks 5 and 6, body weights and food intake were not pos'runts (3 /NC) (3 affected in the chlorpromazine or no drug groups but were • mmm••• ram- decreased in a dose-dependent fashion in the triazolam and rMtMOR [] I"I/NC A.C ) []/kO diazepam groups. For both triazolam and diazepam, weight loss peaked on day 2 of withdrawal and recovered to pre- withdrawal levels by days 6--7 with the low dose groups and liD •" TRIAZOLAM'MAINTAINEDBAllOONS by days 9-10 with the high dose groups. A key-rattle

•/_ 00|AZEPAM'MAiNTA|NED IIABOONS stimulus on day 2 of withdrawal elicited seizures in 15%, 37%, 0%, and 0% of the triazolam, diazepam, chlor- FIG. 5. Benzodiazepine antagonist precipitated withdrawal in ba- promazine, and control (rio drug) animals, respectively. boons. Three triazolam-malntained animals (figed symbols) =rod In a second study at the Upjohn Company [132], separate three diazepam-maintained animals (open symbols) were observed groups of female mice were fed a Purina chow diet contain- for withdrawal signs after receiving intramuscular injections of Ro ing either triazolam (three concentrations), flurazepam (four 15-1788 vehicle and Ro 15-1788 (5.0 mg/kg). Presence of symbols concentrations), diazepam (three concentrations), pheno- indicates withdrawal sign occurred one or more times during the barbital (three concentrations), or no drug for 15 days. time block. Thirty hours after drug was eliminated from the diet. elec- troshock seizure thresholds were obtained using an up-and- down titration method [82] (0. I sec, 60 Hz starting at 7. l mA period, severe, intermediate and mild grade withdrawal signs and changed by mA units of 0.05 logan). Following this, mice were observed in two monkeys each. These results with were returned to the drug diet for a further 15days. Drugwas triazolam are generally similar to those reported by Yanagita then eliminated and seizure thresholds determined daily for 4 with diazepam and a variety of other benzodiazepine days. Drug intake was an increasing function of concentra- agonists (e.g., [166. 167, 168]). tion for all drugs, with average daily consumption for the The only other study of spontaneous withdrawal from three triazolam groups being 0.41, 1.1. and 3.3 mg/kg before triazolam in non-human primates consists of observations drug withdrawal. Reliable dose-dependent decreases in sei- made in our laboratory in two baboons which had histories of zure threshold were not obtained after 15 days but were oral triazolam self-administration and Ro 15-1788 precipitated obtained after 30 days with all four drugs. Peak withdrawal, withdrawal tests, as previously described in this section and as indicated by lowered thresholds, occurred on day 1 under Reinforcing Effects section. At the time of the spontaneous all drug conditions except for high dose flurazepam which withdrawal test, baboons AP and KU had been self- occurred on day 2. administering various amounts of triazolam orally in daily 3-hr A final study on triazolam spontaneous withdrawal was sessions for 210 and 48 days, respectively, with average daily conducted by Tanabe and colleagues [144] in rats and mice. doses during the last 10 days being 21.8 and 2.7 mg/kg, respec- During the 2-month course of oral administration of gradu- tively. Neither animal had received Ro 15-1788 during the ally increasing doses of triazolam, spontaneous withdrawal preceding 3-months. The spontaneouswithdrawal test in- was assessed during 1 to 2 day drug abstinence periods. volved replacing triazolam with vehicle alone for a period of I I Measures of pentylenetetrazole-induced convulsion, body (AP) or 16 (KU) days, and then reinstating the triazolam. The weight, and wet weight of brain, heart, kidney and testicles baboons were observed for withdrawal signs [90] during l5-min provided no evidence of physiological dependence on observation periods twice daily, once in the morning and once triazolam. This finding is at variance with the four previously in the afternoon. After terminating triazolam, abnormal cited studies on triazolam spontaneous withdrawal. Unfor- posturing and sct'atching/nose-rubbing increased over previ- tunately, for purposes of this review the Tanabe study was ous baseline levels and returned to those baseline levels available in abstract form only. Thus, insufficient detail of when triazolam was reinstated. These withdrawal signs were the Tanabe results preclude reconciliation of the discrepant relatively mild compared to some of the observations made findings. by Yanqita in rhesus monkeys undergoing spontaneous Overall, the animal studies on spontaneous withdrawal triazolam withdrawal [165]. Whether the withdrawal signs are show that triazolam produces dose-dependent physiological any milder than would be observed after comparable treat- dependence, but provide no basis for distinguishing qualita- ment of baboons with other benzodiazepines is unknown. It tively or quantitatively between the withdrawal signs ob- may be that the baboon is generally less sensitive to hen- served after abrupt termination of triazolam and that ob- zodiazepine withdrawal than the rhesus monkey because served after termination of other benzodiazepines. ABUSE LIABILITY OF TRIAZOLAM 143

PHYSIOLOGICALDEPENDENCEIN HUMANS inated benzodiazepines, triazolam and midazolam, but not The signs and symptoms associated with termination of during treatment with the slowly eliminated ben- treatment with benzodiazepines has been extensively de- zodiazepines, flurazepam and quazepam. As with rebound insomnia, early morning insomnia can be interpreted as a andscribedsymandptomsrevieincludwed etchf.eadach[96. 1e1, 6an, 11xie7ty. ,13h6y]).peThesersensitivsignsity manifestation of physiological dependence. to sensory stimuli and other perceptual disturbances, deper- Further research will be necessary to determine the con- sonalization, tremor, insomnia, anorexia, hallucinations, de- ditions under which triazolam-induced early morning in- lirium, diaphoresis, and convulsions. The more severe of somnia reliably occurs, as well as to clarify the interpretation these signs and symptoms, e.g.. delirium and convulsions, of the phenomenon. In the one study demonstrating early have been seen only infrequently. Several studies report morning insomnia [79} the mean early morning increase in triazolam-related insomnia and anxiety which may represent wake time for the condition during triazolam was small (5.2 manifestations of physiological dependence, mini: however, when three individual nights at the end of the condition were analyzed, wake time was consistently greater than baseline, reaching statistical significance on one night Rebound Insomnia (18.1 minutes vs. 8.3 minutes, respectively). Two recent Kales and co-workers [78] coined the term rebound in- studies which may have used data averaged across nights somnia to describe the significant worsening of sleep which failed to find evidence of early morning insomnia [ 1.951. Fi- occurred following abrupt termination of several of the ben- nally, while early morning insomnia was proposed to be a zodiazepine hypnotics which had been administered in single drug withdrawal sign, an alternate interpretation is that pa- doses nightly for relatively short periods. These inves- tients tend to wake earlier because they have slept soundly, tigators first noted the phenomenon with relatively rapidly and that flurazepam and quazepam prevent this awakening eliminated benzodiazepines, and hypothesized that the in- by their prolonged hypnotic action. tensity of these withdrawal related effects should be in- versely related to the elimination rate. Rebound insomnia Daytime Anxiety Daring Hypnotic Treatment has been reported following termination of treatment with a Another phenomenon hypothesized to be related to the wide range of benzodiazepines having short to intermediate development of benzodiazepine physiological dependence is half-lives, including triazolam, flunitrazepam, nitrazepam, daytime anxiety during treatment with the rapidly eliminated Iorazepam, lormetazepam, and midazolam (cf. [80]). With hypnotics, triazolam and midazolam. Morgan and Oswald flurazepam or quazepam which have slowly eliminated [1041 briefly reported that nightly use oftriazolam was ass,o- active metabolites, evidence for rebound insomnia has either elated with a progressive increase in patient-rated daytime not been found [80,95], or the sleep disturbance noted has anxiety, and Kales and co-workers [79] came to similar con- been rather modest [46, 80, 102,103]. It is possible that a bias clusions in analyzing data from previous studies with toward demonstrating rebound insomnia with quickly elimi- triazolam and midazolam. hated compounds but not with slowly eliminated compounds Clarification of the generality and interpretation of may result from a statistical artifact produced by variable triazolam-associated daytime anxiety will require more data rates of drug elimination across subjects in combination with and less debate [105, 107, 109, 112, 113]. Neither study de- withdrawal periods of insufficient duration [103]. However, scribing the phenomenon [79,104] reported the absolute Bixler and associates [14] in reanalyzing individual data from magnitude of increased anxiety, and one study has failed to a 15-withdrawal night study [75] with flurazepam and obtain the effect [95]. It is possible that the increased anxiety quazepam found no such statistical bias. Although furth.cr represents increased wakefulness in insomniac patients research is needed, individuals who have been treated for rather than the development of physiological dependence longer periods of time and with higher doses would appear to [ 15,19]. be at greatest risk for rebound insomnia as well as other withdrawal signs following termination of benzodiazepine Case Reports of Physiological Dependence treatment. With respect to triazolam, it is clear that transient deteri- Compared with the numerous case reports of physiolog- oration of sleep can occur following termination of treatment ical dependence with diazepam and some of the other widely [1,74, 77, 95, 103, 128, 153, 1541. When triazolam-associated used benzodiazepines (cf. [96,116]), there have been rela- insomnia does occur, its onset is rapid (maximal effects may tively few case reports of withdrawal reactions with occur in one day [1, 95, 103, 154]), andsleep loss may be triazolam [40,1511. This low rate has no meaningful implica- substantial (maximal sleep loss may be 1-3 hr or more per tion for relative risk of dependence because triazolam is a night [1,77, 95, 103]). The rapid speed of onset of withdrawal relatively new compound and the rate of such reports is un- effects distinguishes triazolam from some of the more slowly doubtably a function of drug usage. One case report of acute eliminated benzodiazepines such as flurazepam, chior- triazolam overdose suggests the interesting possibiEty of an diazepoxide, and diazepam which are associated with slower acute physiological dependence syndrome [145]. After tak- onset of withdrawal signs (cf. [67, 102, 103, 118, 156]). ing more than 5 mg triazolam the patient presented as anx- ious, sweating profusely, confused, beUigerant, suffering visual and auditory hallucinations, and tremulous. The au- Early Morning Insomnia thors state that the clinical picture 8 to 12 hr after ingestion Kales and co-workers [79] were first to describe the phe- resembled that of hypnotic withdrawal delirium. nomenon of benzodiazepine-related early morning insomnia which is characterized by an increase in time awake during the last few hours of sleep (i.e.. the early morning) during CONCLUSIONS ON PHYSIOLOGICALDEPENDENCE hypnotic drug treatment. These investigators reported the Triazolam, like other benzodiazepine anxiolytics and effect during 1or 2 weeks administration of the rapidly elim- hypnotics, can produce physiological dependence in animals 14,1 GRIFFITHS ET AL. and humans. The frequenc-y and severity of withdrawal re- pound. The diversity of possible adverse effects is clearly actions are probably an increasing function of dose and du- enormous (cf. [33,138]) and spans the range of physiological ration of drug administration, although there is surprisingly systems in which benzodiazepines are active ¢e.g., central little evidence of this from the animal and human studies nervous system, metabolic/endocrine, immunologic, gas- reviewed. The available animal studies provide insufficient trointestinal, hepatic, etc.). For purposes of this review, dis- information to distinguish triazolam from other ben- cussion will be limited to five categories of central nervous zodiazepines with respect to probability and severity of system adverse effects which may have particular relevance withdrawal signs, as well as time of onset of spontaneous to evaluation of the relative abuse liability of tnazolam: A. withdrawal signs. Human studies, however, show that onset Lethality in overdose; B. Psychomotor impairment; C. In- of peak withdrawal effects may occur more rapidly with teractions wi.th ethanol; D. Anterograde amnesia: E. lm- triazolam than with some of the more slowly eliminated ben- paired awareness of degree of drug effect: F. Other psychi- zodiazepines, such as flurazepam, chlordiazepoxide, and attic and behavioral disturbances. diazepam. Studies of rebound insomnia indicate that the consistency' and magnitude of this withdrawal sign are LETHALITYINOVERDOSE greater with triazolam than with flurazepam and quazepam. With central nervous system depressant compounds, the The triazolam-associated phenomena of early morning in- lethality of the drug in overdose is perhaps the single most somnia and daytime anxiety during hypnotic treatment re- important adverse effect relevant to drug abuse/misuse. The quire further study to determine the conditions under which relatively high mortality associated with barbiturate over- they reliably occur as well as their status as withdrawal- dose is an important determinant of the high abuse liability of related events, this class of compounds and contrasts with the relatively low As a whole, these data on physiological dependence do mortality associated with benzodiazepine overdose [24]. not provide a strong basis for making predictions about the With regard to triazolam, animal laboratory studies suggest relative abuse liability of triazolam. Although Tyrer [146] has that triazolam is similar to other marketed benzodiazepines said that the rapidly eliminated compounds triazolam and in having a remarkably favorable therapeutic ratio in con- lorazepam are associated with more severe withdrawal trast to barbiturates. For instance, the therapeutic ratio symptoms than slowly eliminated ones, evidence for this (LD_ED_) for anticonvulsant effects in mice exceeds •viewpoint is not strong, especially with triazolam. One study 11,000 for triazolam [131] in contrast to a therapeutic ratio of showed that in self-referred patient groups participating in a 9.3 for phenobarbital [121]. The absence of mortality in clini- benzodiazepine detoxification study, the severity of early cal case reports of substantial overdose with triazolam withdrawal symptoms and the dropout rate with Iorzaepam [88,145] is consistent with overdose reports with other ben- was higher than with diazepam after abrupt drug withdrawal zodiazepines [37,441, and attests to the remarkable safety of [148,149]. Other investigators have implied that there is an these compounds. unusually high frequency of case reports of severe with- drawal signs after abrupt termination of drugs like Iorazepam PSYCHOMOTOIMPR AIRMENT [66,116]. Part of the belief that triazolam and Iorazepam should be associated with severe withdrawal signs is based Next to lethality the most important adverse effect rele- on the pharmacokinetic hypothesis that withdrawal severity rant to the abuse/misuse of central nervous system de- should be a function of the rate at which drug leaves the pressant compounds is probably impairment of psychomotor brain. Although a relationship between plasma level and or gross behavioral performances, which increases the risk withdrawal intensity or probability of withdrawal symptoms of automobile and other accidents. As with other ben- was shown in one study [148], other studies failed to confirm zodiazepine and nonbenzodiazepine hypnotics and this effect [2, 103, 147]. Finally, and with specific reference anxiolytics, a variety of studies has shown that triazolam to triazolam, Hollister [66] expanded the pharmacokinetic produces such impairments in a dose-related fashion in nor- hypothesis by suggesting that withdrawal severity should be real, insomniac, and drug abuser subjects (cf. [108, 123, 129, an inverted U-shaped function of elimination rate. Thus, 142]). Although there are clear differences between com- under ordinary divided dose schedules of administration, ex- pounds with respect to time-course of impairments, the lim- tremely rapidly eliminated compounds such as tybamate, ited comparative studies to date provide no basis for drawing produce less dependence than rapidly eliminated compounds meaningful qualitative distinctions between triazolam and such as lorazepam, presumably because it is difficult to other hypnotics and anxiolytics with respect to such drug- maintain continually high levels of drug. From this perspec- induced psychomotor impairments. tire, the extremely rapidly eliminated triazolam (mean half- INTERACTIONWITHS ETHANOL life 2-3 hr [45,71]) would be predicted to produce relatively less intense withdrawal than rapidly eliminated compounds Given the frequency of ethanol ingestion in western soci- such as lorazepam (mean half-life 14 hr [43]). Overall. al- ety, the interaction of a drug with ethanol may represent a though triazolam indisputably produces physiological de- potentially serious adverse effect. Concurrent ingestion of pendence, neither scientific data nor pharmacokinetic benzodiazepines and ethanol generally produce greater ira- hypotheses provide a basis for making a strong prediction pairment than either agent alone [30], and most deaths asso- about the relative physiological dependence potential of ciated with benzodiazepine overdoses also involve concur- trlazolam compared to that of other benzodiazepines, rent ethanol ingestion [37]. Three studies of triazolam-ethanol interactions showed that, as with other benzodiazepines, triazolam and ethanol ADVERSE EFFECTS together produce greater impairments on some measures, An understanding of the extent of adverse effects that but not all measures, than either drug alone [29, 30, 65]. This might emerge with misuse/abuse of a drug is important to a effect is not due to pharmacokinetic interactions [29, 30, meaningful assessment of relative abuse liability of a corn- 110]. There is some indication that, compared to other ben- ABUSE LIABILITY OF TRIAZOLAM 145

zodiazepines, triazolam may produce greater impairments in combination with ethanol. On the basis of a study (published 7- as an abstract) involving triazolam (0.125 rag) and ethanol >" _ e PENTOSARBITAL (breath concentrations of 800-950 mWI), Dorian and co- O u workers[29]concludedthat"'thetriazolam-ethancoolmbi- • =_ 7- nation results in marked impairment of psychomotor rune- u_ tion which is greater than that produced by other ben- _[ o ( _. zodiazepines when combined with ethanol." In a similar ¢n studyusinga higherdoseoftriazolam(0.25mg),thesesame uJ investigatorsconcludedthatthemagnitudeof impairment reza [ produced by triazolam-ethanol combinations was similar to D E 2 TRIAZOLAM thatmatedprodto bucee 20-30d by%othergreaterbenzthanodiazepineither eds,rug whichalone [3they0]. Theseti-ir gO- ",--" _h, T ± graphically presented data, however, showed peak "_,, triazolam-ethanoi impairment to be 50-80%. Only two

studies have directly compared triazolam and another ben- o "-'I" 1 _j zodiazepine with respect to ethanol interactions. Hill et al. P 1_0 10.0' 100.0 1000.0 [65] showed a higher frequency of ataxia, slurred speech, hiccups, nausea and vomiting, dipiopia and blurred vision, DOSE (rag) and amnesia after a combination of triazolam (0.5 mg) and FIG. 6. Effectsof triazolamand pentobarbital on recognition mem- ethanol (0.8 g/kg) than after ethanol combined with or5'in eight subjects with histories of sedative drug abuse. Y-axis: flurazepam (30 rag)or a lower dose of triazolam (0.25 mg). A numberof picturescorrectlyidentified;X-axis:dose(mg),log scale. related study [101] showed that the interactions of triazolam P indicates placebo. Points show means; brackets show _-S.E.M. and ethanol may be of a shorter duration than the interac- Oral doses of triazolam (0.5, 1.0, 2.0, and 3.0 rag)and pentobarbital tions of flurazepam and ethanol. (100, 200. 400, and 600 rag) producedsimilardose-related suppres- Conclusions based on these data must be tentative given sion in psychomotor performance. Pictures were presented 2-hr after drug administration,and the recogmtion task was conducted the few rigorous cross-drug comparisons and lack of sub- 23-hraRerdrugadministration. Data arerepiotted fromRoache and stantial dose manipulations. However, from the limited Griffiths [123]. ethanol interaction studies conducted to date, it would ap- pear that triazolam could be relatively more toxic than other benzodiazepines, nizable items (i.e., ball, fork, dog, etc.). At 8:30 a.m. the following day subjects were given a booklet containing 165 ANTEROGRADEAMNESIA pictures from which they attempted to identify the 10 pic- tures presented previously. Figure 6 shows that triazolam A well documented effect of some benzodiazepines is that produced markedly greater amnestic effects than pentobarbi- they produce short-term anterograde amnesia, i.e., memory tal; post hoc comparisons showed that all four doses of loss for events occurring after drug administration. Although triazolam were associated with significantly fewer correctly this effect is used to clinical advantage when ben- identified pictures than placebo and 100, 200, and 400 mg zodiazepines are administered as a premedication for some pentobarbital. This effect cannot be attributed to administer- types of surgical procedures, anterograde amnesia repre- ing non-equivalent doses because both drugs produced simi- sents a potentially serious adverse consequence of drug lar dose-related effects on other performance measures. use/abuse outside of closely monitored medical settings. Further, the difference cannot be explained as a failure of Studies suggest that there may be meaningful differences in memory consolidation due to sleep onset (cf. [124,127]) be- thedegreeofanterogradeamnesiaeffectsproducedby oral causeno subjecstlepftoratleast2hrafterthememorization dosesofseveralbenzodiazepines(Iorazepam,diazepam,and session. clorazepatewh)ichareusedprimarilyas anxiolyti[6cs1,94, The preciseimplicationsof thesedataon anterograde 135,155]. amnesiafortherelativeabuseliabilityof triazolamarenot Withrespecttotriazolam,therehavebeenbothanecdotal clear.Unquestionablysuch, amnesticeffectsrepresenta po- reports[77,I19,122,139]and experimentalstudie[s124, tentiaIlyserioussideeffecoft triazolamW.hileamnesticef- 127,142]ofanterogradeamnesiaafteroraladministratiason fectsmightrepresenta desirablaspecte of drugactionfor a hypnoticTwo. studiescomparingtheamnesticeffectofs some individuals,itisalsoplausiblthae tsuchan effectcould triazolawim ththoseof Iorazepam,flurazepam,and seeD- substantialllimyithet appealoftriazolaasm a drugofabuse. barbitaconcl ludedthattheseeffectswere neitherdrugspe- Infact,aftereceivingdosesoftriazolamseveralsubjectsin cificnordrug-classspecific,butweresimplyrelatedto the theRoacheandGriffithsstudyspontaneouslyand independ- hypnoticpropertiesof thecompounds [124,127]Unfort. u- entlycommented thattheywishedto avoidtakingthatun- nately,lack of dose effectsand possibleuse of non- known drug"'onthestreet"becauseof theremarkablyand equivalentdoseslimitsthegeneralioftythisconclusion, unusuallyhighdegreeof memory impairmentA.lso,no ex- Data from thepreviouslydiscussedstudywhich com- perimentalstudyhas comparedtriazolawithm otherben- pared oral triazolam and pentobarbital in drug abusers have zodiazepines with respect to anterograde amnestic effects. demonstrated the dissociability of sedative and anterograde anmestic effects [ 123]. In this study a picture memorization session was scheduled approximately 1.75 hours aRer drug IMPAIREDAWARENESOFS DEGREEOFDRUGEFFECT administration which had occurred at 10:00 a.m. During a An interesting but apparently not widely recognized ad- l-min session subjects studied a piece of paper on which was verse effect of some benzodiazepines is that individuals re- printed a set of 10 black and white pictures of easily recog- ceiving high doses may have an impaired awareness of the 146 GRIFFITHS ET AL.

magnitude of drug effect/impa,rment. Two studies with sub- TRIAZOLAM PENTO§AR§ITAL jects with histories of drug abuse showed that. compared _ so,

chlorpromazine, subjects were relatively less aware of the it_t. degree of impairment/effect produced by high doses of a. diazepam [53,541. An analogous effect with triazolam was t_ shown in the previously cited study by Roache and Griffiths ¢a 4o with other CNS depressant drugs such as pentobarbital and 0 ,_,_ [ 1231in which the effects of triazolam and pentobarbital were n- ,., / compared in drug abuser subjects. In this study, subjects ca O

participated in psychomotor performance and digit-symbol _ <_ / substitution tasks, and staffand subjects rated the magnitude _ "" %, of drug effect at 1, 2, 3, 4. 6, 8, 12, and 24 hr after drug < 3o. administration. Statistically valid relative potencies were ob- n- tained with area under the time-action curve data from u. psychomotor performance, digit-symbol substitution task < • performance, and staff ratings of magnitude of drug effect, tvo- but not with subjects' ratings of magnitude of drug effect. 2o Figure 7 shows these effects for staff and subject ratings. "-r- , , , , - Analysis of variance and post hoc comparisons showed that i.- 5o, although subject ratings with both triazolam and pentobarbi- o tal were higher than placebo, subject ratings with 400 and Igt_ 600 mg pentobarbital were significantly greater than all doses a. of tr/azolam. During the study subjects were given no objec- tu tire feedback (i.e., their scores) on the psychomotor and O 4o digit-symbol substitution tasks. After each performance n-

performed relative to their "normal" performance by using a ca 100 mm visual analog rating scale going from "much worse" I--tu '_<' to "normal" tO "much better." A comparison of those < ratinsessigosn withsubjectsactualwere performancerequired to estoinmatethe htaowsks wepllrothevideyd hada rees _ 3o _/ /_,, T,_ ± measure of the extentto which subjectsunderratedthede- o_- gree of performance impairment. Analysis of variance and tu • post hoc comparisons showed that triazolam produced m dose-relatedunderratingof impairment in contrast to pen- :_ tobarbital which did not. u_ 2o Clearly, additional studies are needed to determine the -_- 1_o ld.o 10o.o lo60.0- extent and pharmacological specificity of the impaired FIG. 7. Staff- and subject-rated magnitude of drug effect in nine awareness of degree of drug effect. As with anterograde am- subjects with histories of sedative drug abuse. Y-axis: staff- and nesia, because of the very nature of this potentially serious subject-rated drug effect expressed as area under the time-action side effect, it is likely to be underreported by patients and curve (AUC); X-axis: dose (rag), log scale. P indicates placebo. thus may escape detection in clinical trials not specifically Points show means; brackets show "-S.E.M. unless encompassed designed to assess the effect. Since studies to date indicate by the data points. Oral doses of triazolam (0.5. 1.0, 2.0. and 3.0 rag) that this adverse effect is associated with the administra- and pentobarbital (100, 200, 400, and 600 mg) produced similar tion of diazepam and triazolam, but not pentobarbital or dose-related increases in staff ratings, however, triazolam produced chlorpromazine, it may represent a general property of ben- smaller increases than pentobarbital in subject ratings. Data are re- zodiazepines having anxiolytic and hypnotic activity, plotted from Roache and Griffiths [123].

hypnotics and anxiolytics are relatively safe and free from OTHERPSYCHIATRICAND BEHAVIORALDISTURBANCES adverse effect. There has been, at a fairly low frequency, a variety of With respect to triazolam, there have been case reports behavioral and mood disturbances associated with use of attributing a wide variety of adverse effects, including all benzodiazepine hypnotics and anxiolytics in clinical situa- those adverse effects cited above which were attributed to tions, including increased hostility, depression, paranoid other benzodiazepines [34, 35, 119, 143, 150, 151, 152]. tendencies, suicidal tendencies, confusion, sleepwalking, Noteworthy among these reports are those from a Dutch and hallucinations (cf. [54,88]). Because such observations psychiatrist [150,15 i] which resulted in substantial media at- have been relatively rare, it has often been assumed that tention and ultimately suspension oftriazolam from the drug such effects represent idiosyncratic reactions to ben- registry in the Netherlands [31, 86, 881. Subsequent position zodiazepines. A series of controlled studies using normal papers, in combination with a more extensive and systematic doses in healthy subjects [41, 83, 84, 134] and higher than analysis of data from clinical trials have provided conflicting normal doses in drug abusers [54,55] suggests that some of results and interpretations regarding the suggestion that these adverse effects may represent common rather than triazolam is associated with a high frequency or unusual idiosyncratic effects of benzodiazepines insofar as they profde of such adverse effects [7, 13, 47, 76, 86, 88, 92, 93, occur reliably under experimental conditions. Despite these 111,152]. At present, there is no strong basis for differentiat- experimental findings, by"normal" standards f or evaluating ing triazolam from other benzodiazepine hypnotics and adverse effects of psychomotor drugs, the benzodiazepine anxiolytics with respect to these adverse effects. ABUSE LIABILITY OF TRIAZOLAM t47

CONCLUSIONS ABOUT RELATIVE ABUSE fects in animals; (2) speed of onset in humans: and (3) in- LIABILITY OF TRIAZOLAM teraction with ethanol. Finally, there are seven areas about The data reviewed indicate that the abuse liability of which insufficient data exist to draw firm conclusions about triazolam is clearly less than that of the intermediate dura- the abuse liability of triazolam relative to other ben- tion barbiturates such as pentobarbital. Support for this zodiazepines: (I) reinforcing effects in humans; (2) ratings of conclusion comes from data on: (1) chemical struc- liking and monetary value in humans; (3) categorization of ture/pharmacological profile; (2) reinforcing properties in subjective drug effects by humans; (4) physiological depend- animals; (3) human liking and ratings of monetary value; (4) ence in humans; (5) anterograde amnesia; (6) impaired discriminative stimulus effects in animals; (5) human awareness of drug effect; and (7) psychiatric/behavioral dis- categorization of drug effect; and (6) lethality in overdose, turbances. It is noteworthy, however, that in three of these Although there are data indicating that triazolam has a more areas, concerned clinical investigators have speculated and rapid onset of ac.tivity than pentobarbital, this difference is cautioned that triazolam may have relatively greater toxicity apparently unimportant because it is not reflected in the than other benzodiazepines: physiological dependence in other measures assumed to reflect reinforcing properties, humans including rebound insomnia, early morning insom- There are also data suggesting that triazolam has greater nia, and daytime anxiety [25, 80, 104, 143, 146]; anterograde amnestic effects than pentobarbital, and that triazolam is amnesia [73, 119, 122, 139]; psychiatric/behavioral disturb- associated with a greater impairment of awareness of degree ances [13, 35.76, 119, 150. 15I, 152]. There has been little or of drug effect than pentobarbital. Although these represent no speculation on part of clinicians that triazolam may have potentially serious adverse effects, their importance is cer- relatively less abuse liability than other benzodiazepines. tainly less than that of lethality in overdose for which pen- In conclusion, triazolam has less abuse liability than the tobarbital indisputably has the greater risk. Although impor- intermediate duration barbiturates. Although there are con- tant pieces of comparative data are not available, such as siderable data indicating similarities of triazolam to other studies comparing reinforcing properties in humans, the benzodiazepines, there is substantial speculation among clin- presently available data are compelling, and it would seem ical investigators and some limited data suggesting the abuse unlikely that additional studies will alter the conclusion that liability of triazolam to be greater than that of a variety of triazolam has relatively less abuse liability than the inter- other benzodiazepine anxiolytics and hypnotics, and virtu- mediate barbiturates such as pentobarbital, ally no credible data or clinical speculation that it is less. Conclusions about the abuse liability of triazolam relative Further animal and human laboratory research along with careful epidemiological monitoring will be necessary to to other benzodiazepine anxiolytic/hypnotics axe less clear, clarify definitively the status of the abuse liability of dThrueg discriminationdata on chemicinalanimalstructures, ph/pysiologicalharmacologicdealpendenceprofile,in triazolam relative to other benzodiazepine anixolytic/ animals, lethality in overdose, and psychomotor impairment hypnotics. are derived from reasonable studies and provide no strong ACKNOWLEDGEMENTS basis for distinguishing triazolam from other marketed ben- Preparation of this paper was supported in part 15yNational lnsti- zodiazepines. However, there are at least three types of data tute on Drug Abuse grants DA-03889, DA-01147 and contract suggesting that triazolam may have greater abuse liability 271-83-4023. The authors thank D. Sabotka for typing the manu- than at least some other benzodiazepines: (!) reinforcing ef- scripr.

REFERENCES

I. Adam, K., I. Oswald and C. Shapiro. Effects of Ioprazolam 9. Balster, R. L. and C. R. Schuster. Fixed-interval schedule of and of triazolam on sleep and overnight urinary cortisol. Psy- cocaine reinforcement: Effects of dose and infusion duration. J chopharmacology (Berlin) 82: 389-394, 1984. Exp Anal Behav 20: 119-129, 1973. 2. Ashton. H. Benzodiazepine withdrawal: An unfinished story. 10. Barry, H. and E. C. Krimmer. Similarities and differences in Br Med J 288:1135--I 140. 1984. discriminative stimulus effects of chlordiazepoxide, pentoba.r- 3. Ator, N. A. and R. R. Griffiths. Oral serf-administration of bital,, ethanol and other sedatives. In: Stimulus Properties of triazolam and diazepam in the baboon: Effects of a ben- Drugs: Ten Years of Progress. edited by F. C. Colpacrt and J. zodiazepine antagonist. Paper presented at the meetings of the A. Rosecrans. Amsterdam: Elsevier. 1978, pp. 31-51. International Study Group Investigating Drugs as Reinforcers, 11. Bechelli. L. P. C.. F. Navas and S. A. Pierangelo. Comparison Toronto, 1982. of the reinforcing properties of zopiclone and triazolam in 4. Ator, N. A. and R. R. Griffiths. Lorazepatn and pentobarbital former alcoholics. Pharmacology 27: 235-241, 1983. drug discrimination in baboons: Cross-drug generalization and 12. Beecher, H. K. Measurement of Subjective Responses: Quan- interaction with Ro 15-1788. J Pharmacol Exp Ther 226: 776- titative Effects of Drugs. New York: Oxford University Press, 782, 1983. 1959. 5, Ator, N. A. and R. R. Griffiths. Oral self-administration of 13. Bixler, E. O. and A. Kales. Clinical and laboratory evaluation methohexital in baboons. Psychopharmacology (Berlin) 79: of hypnotics Ipersonal communication.) 120--125, 1983. 14. Bixler. E. O.. J. D. Kales, A. Kales, J. Jacoby and C, R. 6. Ator, N, A. and R. R. Griffiths. Lorazepom and pentobarbital Soldatoz. Rebound insomnia and elimination half-life: Assess- discrimination: Interactions with CGS 8216 and caffeine. Ear J ment of individual subjects responses (personal communication.) Pharmacol, in press, 1984. 15. Bliwise, D., W. Seidelo I. Karacan, M. Miller, T. Roth, F. 7. Ayd. F. J., W. R. Barclay. J. P. CaUan, W. J. Curran. E.A. Zorick and W. Dement. Daytime sleepiness as a criterion in Gardner, D. J. Greenblatt. I. Ladimer, Y. Lapierre. H.E. hypnotic medication trials: Comparison of triazolam and Lehmann, J. T. O'Donnell, H. M. van lh-aag and R. I. Shader. flurazepam. Sleep 6: 156-163, 1983. Behavioural rcartions to triazolam. Lancet il: 1018, 1979. 16. Boissl, K., J. F. Dreyfus and M. Delmotte. Studies on the 8. Baktir. M. S., H. U. Fisch, P. Huguenin and J. Bircher. dependence-inducing potential of zopiclone and triazolam. Triazolam concentration-effect relationships in healthy sub- Pharmacology 27: 242-247, 1983. jects. Clin Pharmacol Ther 34: 195-200, 1983. 148 GRIFFITHS ET AL.

17. Brady, J. V., S. E, Lukas and R. D. Hienz. Relationship be- 37. Finkle, B. S., K. L. McCIoskey and L. S. Goodman. Diazepam tween reinforcing properties and sensory/motor toxicity of and drug-associated deaths. JA._IA 24Z: 429--434. 1979, CNS depressants: Implications for the assessment of abuse 38. Fischman, M. W. and C. R. Schuster. Cocaine _elf- liability. In: Prob/em_ of Drug Dependence, edited by L.S. administration in humans. F_,d Pr¢_ 44: 241-246, 1982. Hams. National 4nstitute on Drug Abuse Monograph No. 43, 39. Fischman. M, W. and C. R. Schuster. Injection duration of DHHS Publication No. (ADM)g3-1264. Washington. DC: U.S, cocaine in humans. Fed Pro," 43: 570. 1984. Government Printing Office. 1983, pp. 196-202. 40. Fleming, J. A. E. Triazolam abuse, f,_. _l_,d ,4_,,_ J 129: 18. Brady. K, T., R. L. Balster and E. L. May. Stereoisomers of 324--325. 1983. N-allylnormetazocme: Phencyclidine-like behavioral effects in 41. Gardos, G., A. DiMascio. C. Salzman and R. 4. Shader Differ- squirrel monkeys and rats. S('ience 21J: 178-180. 1982. ential actions of chlordiazepoxide and oxazepam on hostility 19. Carskadon. M. A., W. F. Seidel. D. J. Greenblatt and W. C, Ar¢h Gvn Pxy('hiatry 18: 757-760. 1968. Dement. Daytime carryover of triazolam and flurazepam in 42. Goldberg, S. R.. W. H. Morse and D. M. Goldberg Behavior elderly insomniacs. Sleep 5: 361-371, 1982. maintained under a second-order schedule by intramuscular 20. Collins, R. J. Cross-dependence to phenobarbital: Effect of injection of morphine or cocaine in rhesus monkeys. J Pit,r- three benzodiazepines and barbital. Paper submitted by the ma_ol Exp Ther 199: 278--286. 1976. Upjohn Company to the World Health Organization for the 43. Greenblatt. D. J. Clinical pharmacokinetics of oxazepam and Fifth Review of Psychoactive Substances for International Iorazepam. Clin Pharma_okinet 6: 89-105, 1981. Control, November. 1981. 44. Greenblatt. D. J.. M. D. Allen. B. J. Noel and R. I. Shader. 24.Collins, R. J. Reinforcing properties of intravenous triazolam Acute overdosage with benzodiazepine derivatives. C/in in the rhesus monkey: Comparison to flurazepam, diazepam, Pharma_ol Ther 21: 497-514, 1977. and pentobarbital. Paper submitted by the Upjohn Company to 45. Greenblatt, D. J., M. Divoll, D. R. Abernethy, H. R. Ochs and the World Health Organization for the Fifth Review of Psycho- R.I. Shader. Clinical pharmacokinetics of the newer ben- active Substances for International Control, November, 1981. zodiazepines. C/in Pharmacokinet 8: 233--252. 1983. 22. Collins, R. J., R. R. Russell and J. R. Weeks. Suppression of 46. Greenblatt, D. J., M. Divoll0 J. S. Harmatz, D. S. MacLaughlin self-administration of pentobarbital in addict rats by triazolam and R. 1. Shader. Kinetics and clinical effects of flurazepam tn and diazepam. Paper submitted by the Upjohn Company to the young and elderly noninsomniacs. Clin Pharmaco/ Ther 30:. World Health Organization for the Fifth Review of Psychoac- 475-486, 1981. tire Substances for International Control, November, 1981. 47. Greenblatt, D. J.. R. I. Shader, M Divoll and J. S. Harmatz. 23. Coiimert, F. C., L. K. C. Desmedt and P. A. J. Janssen. 13is- Adverse reactions to triazolam, flurazepam and placebo in con- criminative stimulus properties of benzodiazepines, barbitu- trolled clinical trials. J Clin Psychiatry. 45: 192-195. 1984. rates, and pharmacologically related drugs: Relation to some 48. Griffith, J. A study of illicit amphetamine drug traffic in Okla- intrinsic and anticonvulsant effects. Eur J Pharmacol 3/: 113-- homa City. Am J Psychiatry 123: 560--569. 19(_S. 123, 1976. 49. Griffiths, R. R. and N. A. Ator. Benzodiazepine self- 24. Cooper, J. E. (editor). Sedative-Hypnotic Drugs: Risks and administrm.ion in animals and humans: A comprehensive litera- Benefits. DHEW Publication No. (ADM) 78-592. Washington, ture review, In: Benzodiazepines. edited by J. Ludford and S. IX;: U.S. Government Printing Office, 1977. Szara. National Institute on Drug Abuse Monograph No. 33, 25. Crawford, R. J. M. Benzodiazepine dependency and abuse. DHHS Publication No. (ADM)81-1052. Washington, DC: U.S. New Zealand Med J 94: 195, 1981. Government Printing Office, 1984, pp. 22-36. 26. Cumin, R., E. P. Bonetti, R. Scherschlicht and W. E, Haefely. 50. Griffiths. R. R. and R. L. Balster. Opioids: Similarity between Use of the specific benzodiazepine antagonist. Ro 45-1788, in evaluations of subjective effects and animal self-administration studies of physiological dependence on benzodiazepines. Ex- results. Clin Pharmacol Ther 25:641-617. 4979. perientia 38: 833-834, 4982. 51. Griffiths, R. R., G. E. Bigelow and J. E. Henningfield, 27. Deneau. G. A., T. Yanagita and M. H. Secrets. Self- Similarities in animal and human drug taking behavior. In: Ad- administration of psychoactive substances by the monkey_A vances in Substance Abuse: Behavioral and Biological Re- measure of psychologJcal dependence. Psychopharmacologia search, edited by N. K. Mello. Greenwich. CT: JAI Press, 16: 30--48, 1969. 1980, pp. 1-90. 28. DeNoble, V. J., D. S. Srikis and R. A. Meisch. Orally deliv- 52. Griffiths. R. R., G. E, Bigelow and I. Liebson. Human sedative ered pentobarbital as a reinforcer for rhesus monkeys with self-administration: Effects ofinteringestion interval and dose. concurrent access to water: Effects of concentration, fixed- J Pharmacol Exp 1-her 197: 488--494, 1976. ratio size, and liquid positions. Pharmacol 8iochem Behav 16: 53. Griffiths. R. R., G. Bigelow and [. Liebson. Human drug self- 413--417, 4982. administration: Double-blind comparison of pentobarbital, di- 29. Dorian, P., E. M. Sellers, H. Kaplan. D. J. Greenblatt and D. azepam, chlorpromazine and placebo. J Pharmacol Exp Ther Abernethy. Triazolam-ethanol interaction. Clin Pharmacol 215: 649-661. 1979. Ther 33: 238, 1983. 54. Griffiths, R. R.. G. E, Bigelow and I. Liebson. Differential 30. Dorian, P., E. M. Sellers, H. L, Kaplan, C. Hamilton. D.J. effects of diazepam and pentobarbital on mood and behavior, Greenblatt and D. Abernethy. Triazolam and ethanol interac- Arch Gen Psychiato, 40:. 865--873, 1983. tion: Pharmacokinetic and pharmacodynamic consequences. 55. Griffiths, R. R., G. E. Bigelow. I. Liebson and J. E, Kaliszak. Clin Pharmacol Ther, in press, 4984. Drug preference in humans: Double-blind choice comparison 31. Dukes, M. N. G. The van der Kroef syndrome. In: Side Effects of pentobarbital, diazepam and placebo, J Pharmacol Exp Ther of Drugs Annual 4. edited by M. N. G. Dukes. Amsterdam, 215: 649--661. 1980. Excerpta Medica, 1980, pp. v-ix. 56. Griffiths, R. R.. J. V, Brady and L. D. Bradford. Predicting the 32. Eberts0 F. S.. Y. Philopoulos, L. M. Reineke and R. W. Vliek. abuse liability of drugs with animal drug self-administration Tria.zolam disposition. Clin Pharmacol Ther 2_ 81-93, 1981. procedures: Psychomotor stimulants and hallucinogens. In: 33. Edwards. J. G. Adverse effects of antianxiety drugs. Drugs 22: Advances in Behavioral Pharmacology. vol 2, edited by T, 495.-544, 1981. Thompson and P, B. Dews. New York: Academic Press, 1979. 34. Einarson, T. R. Hallucinations from triazolam. Drug Intell Clin pp. 163-208. Pharm 14: 744-715. 1980. 57. Griffiths, R. R.. S, E. Lukas, L. D. Bradford, J. V. Brady and 35. Einarson, T. R. and E. S. Yoder. Triazolam psychosis--A J.D. Snell. Self-injection of barbiturates and benzodiazepines syndrome? Drug Intell Clin Pharm 16: 330, 4982. in baboons. Psychopharmacology (Berlin1 75: 101-109, 1981. 36. Ellinwood, E. H., M. Linnoila, M. E. Easier and D. W. Molter. 58. Griffiths. R. R.. D. R. McLeod, G. E. Bigelow, I. A. Liebson Onset of peak impairment after diazepam and after alcohol, and J. D. Roache. Relative abuse liability of diazepam and Clin Pharmacol Ther 30:. 534--538, 1981. oxazepam: Behavioral and subjective dose effects. Psycho- pharmacology (Berlin) 84: 147-154. 4984. ABUSE LIABILITY OF TRIAZOLAM 149

59. Gnffiths. R. R., D. R. McLeod. G. E. I_ligelow. 1. A. Liebson, 81. Katzman. N. J.. S. Herling and H. E. Shannon. Discriminative J. D. RoacheandP. Nowowieski. Compansonofdiazepamand properties of pentobarbital (Pb): Comparisons with ben- oxazepam: Preference. liking, and extent of abuse. J Phar- zodiazepines (BZ) and other sedative-hypnotics in rats. F_,d ma_ol Exp Ther 229: _01-._08, 1984. Pr,_ 42: 344. 1983. 60. Griffiths. R. R. and JL D. Roache. Abuse liability of ben- 82. Kimball. A. W., W. T. Burnett. Jr. and D. G. Doherty. Chemt- zodiazepines: A review of human studies evaluating subjective cal protection against ionizing radiation. 1, Sampling me_ht_d,, and/or reinforcing effects. In: Benzodiazepines' Standard._ _Jt for screening compounds in radiation protection studies with Use in Clinical Practi(e, edited by D. E. Smith and D.R. mice. Radiat R_'s 7: 1-12, 1957. Wesson. Lancaster. England: MTP Press Limited. 1984, in 83. Kochansky, G. E.. C. Salzman, R. I. Shader. J. S. Harmatz press, and A. M. Ogettree. The differential effects of chlor- 61. Healey. M., R. Pickens. R. Meisch and T. McKenna. Effects diazepoxide a,',d oxazepam on hostility in a small group setting. of clorazepate, diazepam. Iorazepam. and placebo on human Am J Psy( hiatry 132: 861-863, 1975. memory. J Clin Psy(hiatry 44: 12. 1983. 84. Kochansky, G. Er. C. Salzman. R. I. Shader. J. S. Harmatz 62. Henningfield. J. E., N. A, Ator and R. R. Griffiths. Establish- and A. M, Ogeltree. Effects ofchlordiazepoxide and oxazepam ment and maintenance of oral self-administration in the ba- administration on verbal hostility. Ar_ h G_'n P_3_ hi_ttr3 34: boon, Dru_, Ahohol Depend 7: 113-124. 1981. 1457-1459, 1977. 63. Henningfield, J. E. and R. A. Meisch. Drinking device for 85. Kolb. L. Clinical contribution to drug addiction: The struggle rhesus monkeys. Pharrnacol Bio('hern Behav 4: 609-610. 1976, for cure and the conscious reasons for relapse. J ,V_,rv ,_4elrt D/,_ 64. Henningfield. J. E. and R. A. Meisch. Ethanol drinking by 66: 22-43. 1927. rhesus monkeys with concurrent access to water. Pharrnac ol 86. Ladimer, I. Trials and tribulations of triazolam. J Clin Pfi_r- Biochern Behav 10: 777-782. 1979. rnacol 20: 159-161, 1980. 65. Hill. S. Y.. D. W. Goodwin. J. B. Reichman. W. B. Mendelson 87. Lamb. R. J. and R, R. Griffiths. Precipitated and spontaneous and S. Hopper. A comparison of two benzodiazepine hypnotics withdrawal in baboons after chronic dosing with Iorazepam and administered with alcohol. J Clin Psychiatry 43: 408.-410. 1982. CGS 9896. Drug Alcohol Depend 14:11-17, 1984. 66. Hollister. L. E. Pharmacology and pharmacokinetics of the 88. Lasagna. L. The halcion story: Trial by media. Lancet i: 815- minor tranquilizers. Psychiatr Ann I1: 26--31. 1981. 816, 1980. 67. Hollister, L. E., F. P. Motzenbecker and R. O. Degan. With- 89. Lukas. S. E. and R. R. Griffiths. Comparison of triazolam and drawal reactions from chlordiazepoxide ("Librium"). Psy(h_- diazepam self-administration by the baboon. Pharrna_logtst pharrnacologia 2: 63---68, 1961. ,14: 133, 1982. 68. Isbeli, H.. A. Wilker, A. J. Eisenman. M, Daingerfield and K. 90. Lukas. S. E. and R. R. Griffiths. Precipitated withdrawal by a Frank. Liability of addiction to 6-dimethylamino-4-4-xliphenyl- benzodiazepine receptor antagonist (Ro 15-1788) after 7 days of 3-heptanone (methadon, "'amidone" or ""10820") in man. Arch diaZel_Un. Science 117: 1161-I 163. 1982. Intern Med 112: 362-392, 1948. 91. Lukas, S. E. and R. R. Griffiths. Precipitated diazepam with- 69. Jaffe. J. H., D. A. Ciraoio. A. Nies, R. B. Dixon and L.L. drawal in baboons: Effects of dose and duration of diazepam Monroe. Abuse potential of halazepam and of diazepam in pa- exposure. Fur J Pharrnacol IKI:. 163-171, 1984. tients recently treated for acute alcohol withdrawal. Clin 92. MacLeod, N. Triazolam: Monitor'_l release in the United Pharrnacol Ther 34: 623--630, 1983. Kingdom. Br J C/in Pharrnacol 11: 51S..-53S. 1981. 70. Jasinski. D. R. Assessment of the abuse potentiality of 93. MacLeod, N. and C. H. Kratochvil. Behavioural reactions of morphine-like drugs (methods used in man). In: Handbook of triazolam. Lancet ii: 638.--639. 1979. Experimental Pharmacology. vol 45. edited by W. R. Martin. 94. Magballbeola, J. A. O. A comparison of Iorazepam and New York: Sprinller-Vedag. 1977. pp. 197-258. diazepam as oral premedicants for surgery under regional an- 71. Jochemsen, R.. C. J. Van Boxtel, J. Hermans and D.D. aesthesia. BrJAnaesth 46: 449-451, 1974. Breimer. Kinetics of five benzodiazepine hypnotics in healthy 95. Mamelak. M., A, Csima and V. Price. A comparative 25-night subjects. Clin Pharmacol Ther 34: 42-.-47. 1983. sleep laboratory study on the effects of quazepam and 72. Johanson, C. E. and E. H. Uhlenhuth. Drug preference and,. triazolam on chronic insomniacs. J Clin Pharrnacol 24: 65--75. mood in humans: Repeated assessment of d-amphetamine. 1984. Pharrnac'ol Bh_chern Behav 14: 159-163. 1981. 96. Marks. J. The Benzodiazepines--Use. Overuse. Misuse. 73. Kales, A. Commentary to pharmacology and hypnotic efficacy Abuse. Baltimore: University Park Press, 1978. oftriazolam. Pharrnacotherapy 3: 147-148, 1983. 97. Martin, W. R. and C. W. Gorodetzky. Demonstration of 74. Kales, A., E. O. Bixler, J. D. Kales and M. B. Scharf. Corn- tolerance to and physical dependence on N-allylnormorphine parative effectiveness of nine hypnotic drugs: Sleep laboratory (nalorphine). J Pharrnacol Exp Ther 150: 437-442. 1965. studies. J C/in Pharrnacol 17: 207-213, 1977. 98. Martin, W. R., L. F. McNicholas and S. Cherian. Diazepam 75. Kales. A., E. O. Bixler. C. R. Soldatos. A. Vela-Bueno, J. and pentobarbital dependence in the rat. Life Sci 31: 721-730. Jacoby and J. D. Kales. Quazepam and flurazepam: Long-term 1982. use and extended withdrawal. Clin Pharrn Ther 32: 782-788, 99. McLeod. D. R. and R. R. Griffiths. Human progressive-ratio 1982. " performance: Maintenance by pentobarbital. Psychopharrna- 76. Kales, A. and J. D. Kales. Evaluation and Treatment of In- cology (Berlin) 79: 4-9. 1983. ,gornnia. New York: Oxford University Press. 1984. 100. McNicholas. L. F. and W. R. Martin. The effect of a ben- 77. Kales, A., J. D. Kales. E. O. Bixler, M, B. Scharf and E. zodiazepine antagonist. Ro 15-1788. in diazepam dependent Russek. Hypnotic efficacy of triazolam: Sleep laboratory rats. Life Sci 31: 731-738, 1982. evaluation of intermediate-term effectiveness. J Clin Phar- 101. Mendelson, W. B., D. W. Goodwin, S. Y. Hill and J. D. macol 16: 399--406. 1976. Reichman. The morning al_er: Residual EEG effects of 78. Kales. A., M. B. Scharf and J. D. Kales. Rebound insomnia: A triazolam and flurazepam, alone and in combination with alco- new clinical syndrome. Science 201: 1039-1041, 1978. hol. Curt Ther Res 19. 155-163, 1976. 79. Kales, A., C. R. Soldatos. E. O. Bixler and J. D. Kales. Early 102. Mendelson, W. B., H. Weinlllu'tner, D. J. Greenblatt. D. Gar- morning insomnia with rapidly eliminated benzodiazepines, nett and J. C. GiUin. A clinical study of flurazepam. Sleep 5: Science 220:. 95-97, 1983. 350-360. 1982. 80. Kales, A.. C. R. Soldatos. E. O. Bixler and J. D. Kales. Re- 103. Mitler. M. M., W. F. Seidel, J. Van Den Hoed. D. J. bound insomnia and rebound anxiety: A review. Pharrnacol- Greenblatt and W. C. Dement. Comparmive hypnotic effects of ogy ,?,6: 121-137, 1983. flurazepama, triazolam, and pl_ebo: A Ionli-term simultaneous nighttime and daytime study. J Clin Psyc'hopharrnacol 4: 2-13. 1984. 150 GRIFEITHS ET AL.

104. Morgan, K. and 1. Oswald. Anxiety caused by a short-life hyp- 30. Roth, T., T. A. Roehrs and F. J. Zorick. Pharmacology and notic. Br ,Wed J 284: 942, 1982. hypnotic efficacy of triazolam. Ph,rma<'other,py 3: 137-14_;. 105. Morgan, K. and 1. Oswald. Anxiety caused by a short-life hyp- 1983. notic. Br Med J 284: 1785, 1982. 3 I. Rudzik. A. D., J. B. Hester, A. H. Tang. R. N Straw and W [06. Newman. R. G. The need to redefine "'addiction.'" New En_l J Friis. Triazolobenzodiazepines. a new class of central nervous Med ,_16: 1096--1098. t983. ',ystem-depressant compounds. In: Tht, Be,I:,dm:epmc_. 107. Nicholson. A. N., A. J. Belyavin. B. M. Stone and M.B. edited by S. Garattini. E. Mussini and L. O Randall New Spencer. Anxiety caused by a short-life hypnotic. Br Med J York: Raven Press, 1973. pp. 285-297. 285: 215. 1982. 32. Russell. R. R. and R. J. Collins. Lowered electroshock seizure log. Nicholson, A. N.'and B. M. Stone. Activity of the hypnotics, thresholds on withdrawal of drug treatment: Compartson of flunitrazepam and triazolam, in man. Br J Cfin Pharmat_l 9: triazolam" to standards. Paper submitted by the Upjohn Com- 187-194,1980. pany to the World Health Organizationfor the Fifth Reviev,of 109, Nicholson. A, N.. B, M, Stone and M, B. Spencer, Anxiety Psychoactive Substances for International Control November, caused by a short-life hypnotic. Br Med J 284: 1785. 1982. 1981. II0. Ochs. H. R., D. J. Greenblatt, R. M. Arendt, W. Hubbel and 133. Russell. R. R. R. N. Straw and R. J. Collins. Bod_, _,eight R. I. Shader. Pharmacokinetic noninteraction of triazolam and changes on withdrawal of drug treatment: Comparison of ethanol. J Clin Psychopharmacol 4: 106--107, 1984. triazolam to diazepam and chlorpromazine. Paper submitted by I 1I. Offerhaus, L. Trials and tribulations of triazolam. J Clin Phar- the Upjohn Company to the World Health Organization for the macol 20:. 700--701, 1980. Fifth Review of Psychoactive Substances for International 112. Oswald, I. Anxiety caused by a short-life hypnotic. Br Med J Control, November. 1981. 285: 511, 1982. 134. Salzman. C., G. E. Kochansky, R. 1. Shader. L. D. Porrino, J. 113. Oswald, I. Hypnotics and anxiolytics. Br Med J 2157: 28%290. S. Harmatz and C. P. Swett. Chlordiazepoxide-induced hostit. 1983. ity in a small group setting. Arch Gen Psychiatry 31: 401-405, 114. Overton, D. A. Comparison of the degree of discriminability of 1974. various drugs using the T-maze drug discrimination paradigm. 135. Scharf, M. B.. N. Khosla, N. Brocker and P. Goff. Differential Psychopharmacology (Berlin) 76: 385-395, 1982. amnestic properties of short- and long-acting benzodiazepines. 115. Overton, D. A. and S. K. Batta. Relationship between abuse J Clin Psychiatry 45: 51-53, 1984. liability of drugs and their degree of discriminability in the rat. 136. Schopf, J. Withdrawal phenomena after long-term administra- In: Predicting Dependence Liability of Stimulant and "De- tion of benzodiazepines: A review of recent investigations. pressant Drugs. edited by T. Thompson and K. R. Unna. Bal- Pharmacopsychiatria 16: I-8, 1983. timbre: University Park Press, 1977, pp. 125-135. 137. Schuster, C. R.. M. W. Fischman and C. E. Johanson. Internal 116. Owen, R. T, and P. Tyrer. Benzodiazepine dependence: A stimulus control and subjective effects of drugs. In: Behavioral review of the evidence. Drugs 25: 385-398, 1983. Pharmacology of Human Drug Dependence. edited by T. 117, Petursson, H. and M. H. Lader. Withdrawal from long'term Thompson and C, E. Johanson. National Institute on Drug benzodiazepine treatment. Br Med J 2.83: 643.-.64.5, 1981. Abuse Research Monograph No. 37, DHHS Publication No. !!8. Pevnick, J. S., D. R. Jasinski and C. A. Haertzen. Abrupt (ADM) 81-1137. Washington, DC: U.S. Government Printing withdrawal from therapeutically administered diazepam. Arch Office, 1981, pp. 116--129. Gen Psychiatry 35: 995-998, 1978, 138. Shader, R. 1. and A. Dimascio. Psychotropic Dru_ Side Ef- !19. Poitras, R. A propos d'episodes d'amnesies anterogrades as- fects: Clim(al and Theoretical Perspectives. Baltimore: socies a l'utilisation du triazolam. Union Med Can 109:. 427- Williams and Wilkins. 1970. 429, 1980. 139. Shader. R. 1. and D. J, Greenblatt. Triazolam and anterograde 120. PoweR, D. H. A pilot study of occasional heroin users. Arch amnesia: All is not well in the Z-zone. J Clin Psychopharmacol Gen Psychiatry 28: 586-594, 1973. 3: 273, 1983. 121. Randall. L, O. and B. Kappell. Pharmacological activity of 140. Shannon, H. E. and S. Herling Discriminative stimulus effects some benzodiazepines and their metaholites. In: The Ben- of diazepam in rats: Evidence for a maximal effect. J Phar- zodiazepines, edited by S. Garattini, E. Mussini and L.O. macol Exp Ther 227: 160-166, 1983. Randall. New York: Raven Press, 1973, pp. 27-51. 141. Slifer, B. L. and R. L. Balster. Reinforcing properties of 122. Regestein, Q. R. Commentary. Pharmacotherapy 3: 146, 1983. stereoisomers of the putative sigma agonists 123. Roach¢, J. D. and R. R. Griffiths. Comparison oftriazolam and N-allylnormetazocine and cyclazocine in rhesus monkeys. J pentobarbital: Performance impairment and subjective effects Pharmacol Exp Ther 225: 522-528, 1983, in human drug abusers. 1984, unpublished manuscript. 142. Spinweber, C. L. and L. C. Johnson. Effects of triazolam _0.5 124. Roehrs, T., F. J. Zorick, J. M. Sicldesteel, R. M. Wittig, K.M. rag) on sleep, performance, memory, and arousal threshold. Hartse and T. Roth. Effects of hypnotics on memory. J Clin Psychopharmacoloey tBerlin) 76: 5-12, 1982. Psychopharmacol 3: 310-313, 1983. 143. Tan. T.. E. O. Bixler. A. Kales, R. Cadieux and A. Goodman. 125. Romer, D. Dependence liability studies in the rhesus monkey, Early morning insomnia, daytime anxiety, and organic mental Basel, October 25, 1978. Paper submitted by Sandoz Ltd. to disorder associated with triazolam. J Faro Pruc. in press. the World Health Organization for the Fifth Review of Psycho- 144. Tanabe. K., H. Kurihara, M. Kawamura, H. Yogz and K. active Substances for International Control, November, 1981. Kimishima. A pharmacological study on dependence--and 126. Rosenberg, H. C. and T. H. Chiu. An antagonist-induced ben- tolerance_producing liability of triazolam, a new ben- zodiazepine abstinence syndrome. Eur J Pharmacol $1: 153- zodiazepin¢ derivative. Yonago Igaku Zasshi 26: 324--331, 157, 1982. 1976. 127. Roth. T.. K. M. Harts¢, P. G. Snub. P. M. Piccione and M. 145. Trappler, B. and T. Bezeredi. Triazolam intoxication. Can Kramer. The effects of flurazepam, Iorazepam, and triazolam Med Assoc J 126: 893--894, 1982. on sleep and memory. Psychopharmacology (Berlin) 70: 231- 146. Tyrer, P. J. Benzodiazepines on trial. Br MedJ 288:1101-1102. 237. 1980. 1984. 128. Roth. T., M. Kramer and T. Lutz. Intermediate use of 147. Tyler, P., R. Owens and S. Dawling. Gradual withdrawal of triazolam: A sleep laboratory study. J Int Med Res 4: 59..-63, diazepam after long-term therapy. Lancet i: 1402-1406, 1983. 1976. 148. Tyrer. P., D. Rutherford and T. Haggett. Benzodiazepine 129. Roth, T.0 M. Kramer and T. Lutz. The effects of hypnotics on withdrawal symptoms and propranolol. Lancet i: 520--522. sleep, performance, and subjective state. Drugs Exp Clin Res 1981. 1: 27%286, 1977. ABUSE LIABILITY OF TRIAZOLAM 151

149. Tyrer. P. J. and N. Seivewright. Identification and manage- 160. Yanagita. T. An experimental framework for evaluation of de- ment of benzodiazepine dependence. Po._terud .%fed J 60: pendence liability of vanous types of drug in monkeys. Butl Suppl 2, 41--46, 1984. .Varc 25: 1-17, 1973. 150. van der Kroef, C. Halcion. een onschuldig slaapmiddel? Ned T 161. Yanagita. T. Dependence-producing effects of anxiolytic,, In: Gcnee_t, 12.3: 1160, 1979. Psyclhotroptc A eents Part I1: .4n.r,_Ivtt( _. G¢,r, Jnto- 151. van der Krocf. C. Reactions to triazolam. Lancet ii: 526, 1979. p,Lvc'hopharma('oloei('al Agent,_. and P_y(homotor Sttmtdant_ 152. van der Krocf. C. Antwoord op de ingezonden brief van Van edited by F. Hoffmeister and G. Stille. New York: Spnnger- der Laan en Van Limbeek op de Halcion-artikelen. Tijdschr Verlag. 1981. pp. 395-406. Alcohol. Drugs Andere Psychotrope Stojfen 9: 132-133, 1983. 162. Yanagita. T. Dependence-related pharmacological charac- 153. Vogel, G. W., K. Barker. P. Gibbons and A. Thurmond. A teristics of benzodiazepines. Paper submitted to the World comparison of the effects of flurazepam 30 mg and triazolam Health Organization for the Eighth Review of Psychoacti',e 0.5 mg on the sleep of insomniacs. Psychopharmacoloey 47: Substances for International Control. September, 1983. 81-86, 1976. 163. Yanagita. T. Prediction of drug abuse liability from animal 154. Vogel, G., A. Thurmond. P. Gibbons. K. Edwards, K.B. studies. In: 3,tethodsoJA._._e_,_ine the Rei,jiJr(ine Pr_,per/w_ _,/ Sloan and K. Sexton. The effect of triazolam on the sleep of Ahtl._ed Dr, es. edited by M. A. Bozarth. Brunswick. ME: insomniacs. P_ychopharm,cololei, 41: 65-.--69, 1975. Haer Institute. 1984. in press. 155. Wilson. J. and F. R. Ellis. Oral premedication with Iorazepam 164. Yanagita, T. and K. Miyasato. Dependence po(ential of meth- (Ativan): A comparison with heptabarbiton (Medomin) and aqualone tested in rhesus monkeys. CIEA Preclin Rpt 2: 63-68, diazepam (Valium). Br J Anaesth 45: 738-744, 1973. 1976. 156. Winokur. A.. K. Rickels, D. J, Greenblatt. P. J. Snyder and N. 165. Yanagita. T.. K. Miyasato and H. Kiyohara. Drug dependence J. Schatz. Withdrawal reaction from long-term, low-dosage potential of triazolam tested in rhesus monkeys. CIEA Prec'lin administration of diazepam. Arch Gen Psychiatry 35: 101-105. Rpt 3: I-7, 1977. 1980. 166. Yanagita. T., N. Oinuma and H. Nakanishi. Drug dependence 157. Woods. J. H.. J. L. Katz and G. Winger. Abuse and depend- potential of clonazepam tested in the rhesus monkeys. CIEA ence liabilities of benzodiazepines. Paper submitted by the F. Preclin Rpt 7: 29-35, 1981. Hoffmann-La Roche Co. to the World Health Organization for 167. Yanagita, T. and S. Takahashi. Dependence liability of several the Eighth Review of Psychoactive Substances for lnterna- sedative-hypnotic agents evaluated in monkeys. J Pharmucol tional Control. September, 1983. E.rp Ther lg$: 307-316, 1973. 158. Woods. J. H. and C. R. Schuster. Reinforcement properties of 168. Yanaglta. T., S. Takahashi and N. Oinuma. Drug dependence morphine, cocaine, and SPA as a function of unit dose. Int J potential of Iorazepam (WY 4036) evaluated in the rhesus mon- Addict 3: 231-236. 1968. key. CIEA Preclin Rpt !: I---4, 1975. 159. Woods, J. H., A. M. Young and S. Herling. Classification of narcotics on the basis of their reinforcing, discriminative, and antagonist effects in rhesus monkeys. Fed Proc 41: 221-227, 1982.