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A SUPPLEMENT TO Clinical Psychiatry News® CLINICAL UPDATE Abuse Potential of Sleeping Agents: Liability Varies Among Agents

TOPIC Introduction HIGHLIGHTS Roland R. Griffiths, PhD he treatment of is a challenging undertaking, and all individuals and not all / carry the same liability for •Abuse Potential many physicians hesitate to prescribe pharmacologic therapy abuse or toxicity. For patients judged to be vulnerable to abuse or of Sleeping Agents: T for this condition, preferring to avoid the risk of exposing toxicity, these possible problems can be minimized by administering Liability Varies patients to the abuse and dependence potential of sedative/ low-risk . Among Agents drugs. The result is that patients with insomnia may be untreated or A study analyzing the currently available /hypnotics is undertreated. However, the risk of abuse or dependence is not great in reviewed on page 3. Insomnia: A Brief Review ly showed that 27% of American by for diazepine receptor to increase Effects of Insomnia respondents reported having insom- the treatment of anxiety and sleep GABAergic inhibitory transmision. Pharmacologic Treatment nia.4 In France and Italy,the rate was disorders. Compared with barbi- For individuals who experience of Insomnia 37%; in Japan, 7% of respondents turates, benzodiazepines caused fewer daytime sleepiness and impaired per- reported insomnia. In the entire unwanted side effects, were relatively formance related to transient insom- Patterns of Sedative/ safer in overdose, were less likely to Hypnotic Abuse sample of respondents, the mean nia, the use of sleeping agents usually number of symptoms reported was produce severe withdrawal symptoms, provides rapid relief of symptoms and •Abuse Potential of two. The three most commonly and were less likely to be abused. may improve sleep and next-day Hypnotic Agents: reported symptoms were difficulty Currently, 14 drugs alertness. maintaining sleep (73%), difficulty are marketed in the United States and Benzodiazepine receptor agonists Study Evaluates initiating sleep (61%), and poor sleep all possess sedative-hypnotic properties are safe and effective, but risks associ- Relative Abuse Liability quality (48%). to varying degrees; these properties ated with their use include memory Defining Relative Abuse are extensively exploited impairment, withdrawal syndrome, Liability and Toxicity Roland R. Griffiths, PhD clinically, especially to and increased frequency of accidents, Effects of Insomnia For individuals who facilitate sleep.10 falls, and hip fractures in the elderly. Relative Abuse Professor of Behavioral Biology Chronic insomnia experience daytime By binding to spe- Concern about overuse and abuse Liability Table Departments of Psychiatry may be associated with sleepiness and impaired cific receptor sites, ben- has also dampened prescribing. Re- Results of Analysis and Neuroscience a variety of adverse ef- zodiazepines potentiate cently the less efficacious and possi- Johns Hopkins University fects on quality of life, performance related to the effects of gam- bly less safe School of Medicine including impaired so- transient insomnia, the use ma-aminobutyric acid has became the most commonly pre- Baltimore, Md. (GABA) and facilitate cial functioning and of sleeping agents usually scribed medication for insomnia in work problems (for inhibitory GABA neu- the United States.11,12 FACULTY AND UNAPPROVED Insomnia: A Brief Review example, time missed provides rapid relief of rotransmission. The USE DISCLOSURES Primary insomnia is the com- from work and im- symptoms and may improve discovery of selective Patterns of Sedative/ Faculty must disclose any significant plaint of sleeplessness that is not paired job performance). binding sites led to the Hypnotic Abuse sleep and next-day alertness. financial interest or relationship with attributable to a medical, psychiatric, In addition, chronic discovery and develop- Dating to the introduction of proprietary entities that may have a or environmental cause. Its diagnosis sleep loss may result in ment of other drugs barbiturates and benzodiazepines, direct relationship to the subject mat- is based on a patient’s subjective subjective reports of memory with sedative/hypnotic properties physicians and patients have been ter. The faculty must also disclose any report of sleep patterns, including impairment and next day functional that differ structurally from ben- concerned about abuse potential of discussion of investigational or unlabeled complaints of nonrestful sleep and impairment.5,6 Insomnia is also asso- zodiazepines but that also interact drugs used to treat insomnia. Two uses of products. difficulty with sleep onset or mainte- ciated with an increased risk for with the benzodiazepine receptor patterns of nonmedical use are recog- nance. The Diagnostic and Statistical comorbid psychiatric and medical (eg, , , ). nized. One is described as chronic UNAPPROVED/OFF-LABEL USE DISCLOSURE Manual of Mental Disorders, Fourth illness and is a strong predictor of Thus, the term “benzodiazepine quasitherapeutic abuse (ie, long-term Edition (DSM-IVR®)1 criteria for pri- future development of depression.7,8 receptor agonist” is useful for denot- taking by patients for a duration Opinions expressed with regard to mary insomnia is shown in the Table. 9 ing any drug, regardless of chemical unapproved uses of products are solely Stoller calculated that the cost those of the faculty and do not necessar- A detailed discussion of insomnia of lost productivity and accidents structure, that acts on a benzo- Continued on page 4 ily reflect the views of the supporter or and other sleep disorders is available related to insomnia is approximately the Publisher. in the International Classification of $80 billion each year.These estimat- Sleep Disorders Revised, Diagnostic and ed expenses likely result from insom- Table. Primary Insomnia DSM-IV Diagnostic Criteria Dr Griffiths has disclosed that he is Coding Manual.2 nia-related effects on daytime alert- Principal Investigator of two grants Individuals with insomnia typi- ness and behavior. 6 A. The predominant complaint is difficulty initiating or maintaining from the National Institute on Drug cally have one or more common sleep, or having nonrestorative sleep, for at least 1 month. Abuse (NIDA) (R01 DA03889 and R01 complaints: difficulty initiating sleep, Pharmacologic Treatment B. The sleep disturbance (or associated daytime fatigue) causes DA03890) and co-investigator on a con- waking up often during the night of Insomnia tract and several other grants from clinically significant distress or impairment in social, occupational, and having trouble going back to Until the late 1960s, barbiturates NIDA. During the past 5 years, on issues or other important areas of functioning. about drug abuse liability, he has been sleep, waking up too early in the such as and secobarbi- a consultant to or received grants from morning, or unrefreshing sleep. tal were widely used in the treatment C. The sleep disturbance does not occur exclusively during the course the following pharmaceutical companies: Unsatisfactory sleep quality is per- of insomnia. However, the use of of narcolepsy, a breathing-related sleep disorder, a circadian Abbott Laboratories, Forest Laboratories ceived by the patient as inadequate these drugs declined with the recog- rhythm sleep disorder, or a parasomnia. Inc., Merck & Co., Inc., Neurocrine or nonrestorative, despite ample nition that barbiturates were associ- Biosciences, Inc., Novartis Pharmaceu- opportunity to sleep. ated with abuse and could produce D. The disturbance does not occur exclusively during the course ticals Corporation, Orphan Medical, In a 1998 survey of patients clinical dependence, including severe of another mental disorder (eg, major depressive disorder, Pharmacia Corporation, Pfizer Inc., enrolled in five managed care organ- withdrawal symptoms with abrupt generalized anxiety disorder, a ). Takeda Pharmaceuticals, TransOral izations, Hatoum and colleagues3 cessation of use. Pharmaceuticals, Inc., Somaxon Pharma- E. The disturbance is not due to the direct physiological effects of a ceuticals Inc., and Wyeth Pharmaceu- found that, of the 3,447 patients who The discovery of the benzodiaze- substance (eg, a drug of abuse, a medication) or a general medical ticals. He has disclosed that he will responded (46% of the enrollees), pine anxiolytic and be discussing non-medical use (ie, abuse) 33% endorsed insomnia with day- subsequent development of numerous condition. time dysfunction. An international analogs with similar pharmacologic of various hypnotic drugs. Source: American Psychiatric Association.1 survey of insomnia published recent- profiles rapidly led to replacement of

SUPPORTED BY TAKEDA PHARMACEUTICALS NORTH AMERICA, INC. Takeda-ClinPsych 3/8/06 3:54 PM Page 2

2 CLINICAL UPDATE Summary of a Key Study Abuse Potential of Hypnotic Agents: Study Evaluates Relative Abuse Liability

President, Elsevier/IMNG ossible recreational abuse, in- of abuse, the authors present infor- Conclusion 2.Ator NA, Griffiths RR. Principles of drug Alan J. Imhoff appropriate chronic use, and mation that was used in estimating Concern about recreational abuse liability assessment in laboratory withdrawal symptoms may dis- the likelihood of abuse of each agent. abuse, the development of inappro- animals. Drug Depend. 2003;70(3 Vice President, P suppl):S55–S72. Medical Education & courage the appropriate use of seda- In the first two columns under this priate long-term use, or adverse tive/hypnotic agents. However, it effects should not deter physicians 3. Griffiths RR, Bigelow GE, Henningfield Business Development heading, the results of studies of drug JE. Similarities in animal and human drug- Sylvia H. Reitman, MBA should be recognized that the risk of self-administration conducted in from prescribing hypnotics when taking behavior. In: Advances in or problematic use of hypnotics nonhuman primates and humans clinically indicated. After clinical Abuse, Behavioral and Biological Research, Program Manager, varies with the characteristics of the form the basis of ratings of the degree evaluation, physicians may choose vol 1. Greenwich, Conn: JAI Press, Inc; Medical Education patient (it is increased in patients to which the various drugs function from a range of compounds that dif- 1980:1–90. Malika Wicks with histories of drug or alcohol as reinforcers. The third column fer in their potential for problematic 4. Griffiths RR, Bigelow GE, Ator NA. abuse, as well as with elderly patients Principles of initial experimental drug Clinical Editor (actual abuse) uses epidemiologic use and toxicity. Choice among spe- abuse liability assessment in humans. Drug Joanne M. Still and individuals with chronic pain) data to estimate the amount of non- cific compounds should depend on Alcohol Depend. 2003;70(3 suppl):S41–S54. and with the characteristics of the medical use and recreational abuse. the clinician’s assessment of the vul- 5. Griffiths RR, Wolf B. Relative abuse National Account Managers hypnotic drug (hypnotic drugs vary The ratings in each of these columns nerability of the patient for nonmed- potential of different benzodiazepines Cathy McGill widely in their abuse liability). range from 0 to 4 (designated as 0 or ical use, as well as other drug charac- in drug abusers. J Clin Psychopharmacol. Susan Fagan Recently, Griffiths and Johnson with one to four “plus” signs). A teristics that may be important for 1990;10:237–243. Graphic Design [J Clin Psychiatry. 2005;66 (suppl “likelihood of abuse” score was optimal treatment of the individual 6. Iguchi MY, Handelsman L, Bickel WK, 9):31-41] conducted an analysis of Griffiths RR. Benzodiazepine and seda- Lehner & Whyte, Inc. derived from these three types of data patient (eg, speed of onset, duration tive use/abuse by methadone mainte- hypnotic drugs and concluded that and is expressed as a mean percentage of action). Available hypnotic agents Production Specialist nance clients. Drug Alcohol Depend. differences exist among these agents, across the three columns. range from compounds with virtual- 1993;32:257–266. Rebecca Slebodnik in terms of both the likelihood of Four columns contain informa- ly no likelihood of abuse (eg, 7. Jaffe JH, Bloor R, Crome I, et al. A post- abuse and toxicity. They note that tion used to estimate the other toxic , trazodone) to those with marketing study of relative abuse liability This CLINICAL UPDATE was pro- wide variations are found among consequences of use of each of the varying degrees of both likelihood of of hypnotic sedative drugs. Addiction. 2004;99:165–173. duced by the medical education these drugs and range from high to compounds: the relative severity of abuse and other toxicity. The Table department of International Medical 8. Johnson MW,Suess PE, Griffiths RR. Dose no abuse potential and/or toxicity. withdrawal symptoms after cessation reprinted on page 3 provides evi- News Group. Neither the Editor of effect comparison of ramelteon and triazo- the parent publication, the Editorial of chronic supratherapeutic doses; dence-based information about the lam: Abuse potential and behavioral effects. th Advisory Board, nor the reporting Defining Relative Abuse the degree of behavioral or cognitive potential for recreational abuse, the Presented at the 67 annual meeting of the staff reviewed or contributed to its Liability and Toxicity impairment after acute suprathera- development of inappropriate long- College on Problems of Drug Dependence; 18–23 June 2005; Orlando, Fla. contents. The opinions expressed in The authors use Balster and peutic doses; and the likelihood that term use, or adverse effects of seda- this supplement are those of the fac- Bigelow’s definition of abuse liability tive/hypnotic agents. an overdose would be fatal.The mean Based on Griffiths RR, Johnson ulty and do not necessarily reflect as the likelihood that a drug with percentage across the four columns in MW. Relative abuse liability of the views of the supporter or the central nervous system effects will this category represents an overall References hypnotic drugs: A conceptual Publisher. sustain patterns of nonmedical self- toxicity score for each compound. 1. Balster RL, Bigelow GE. Guidelines and framework and algorithm for dif- administration that result in dis- methodological reviews concerning drug ferentiating among compounds. J Clin Psychiatry. 2005;66(suppl 9): ruptive or undesirable effects.1 Results of Analysis abuse liability assessment. Drug Alcohol Depend. 2003;70:S13–S40. 31–41. The likelihood that a drug will be Based on this analysis, the likeli- abused is primarily influenced by its hood of abuse scores of 19 hypnotic reinforcing effects, which can be drugs (Figure) range from 100% Figure. Relative Abuse Liability of Hypnotic Drugs.a examined using drug self-administra- (pentobarbital) to 0% (trazodone and tion methods in both animal and ramelteon). The benzodiazepines human studies.2,3 In clinical trials, the (, , , Pentobarbital gold standard for determining the , , , Methaqualone potential for abuse of a novel hypnot- , , and ) ic compound is to compare three or and with activi- Diazepam more dose levels of the test drug with ty at the benzodiazephine receptor Flunitrazepam those of a known drug of abuse in a binding site (zaleplon, eszopiclone, double-blind manner among subjects , and zolipdem) vary wide- Lorazepam 4 with histories of sedative drug abuse. ly in likelihood of abuse scores, GHB Outcome measures that reflect degree despite the fact that all of these com- of behavioral reinforcement include pounds are active at the same recep- Temazepam subjective ratings of liking/disliking, tor sites.The scores range from highs Zaleplon positive/negative drug effects, and of 67% for diazepam and fluni- disposition to take the drug again.5-7 trazepam to 13% for quazepam. Eszopiclone A defining characteristic of drugs The three drugs that do not have Triazolam of abuse is their ability to reinforce GABA-mediated activity (diphenhy- behavior (ie, sustain nonmedical self- dramine, trazodone, and ramelteon) Zopiclone administration). In addition to rein- had low abuse liability scores and Flurazepam forcing effects, drugs of abuse pro- produce atypical profiles of subjective Zolpidem Copyright © 2006 Elsevier Inc. All duce adverse effects that also con- effects. and tra- rights reserved. No part of this pub- tribute to the overall liability or toxic zodone were associated with some Estazolam lication may be reproduced or trans- consequences of nonmedical use. unpleasant subjective side effects mitted in any form, by any means, These two factors—the reinforcing greater than those of classical hyp- Oxazepam without prior written permission of effects and the toxic effects—served notics, whereas ramelteon produced Diphenhydramine the Publisher. Elsevier Inc. will not as the authors’ basis for characterizing no detectable subjective effects at assume responsibility for damages, the relative abuse liability of a variety supratherapeutic doses of up to 20 Quazepam loss, or claims of any kind arising of compounds used in the treatment times the recommended therapeutic from or related to the information Trazodone of insomnia (Table, page 3). 8 contained in this publication, dose. Ramelteon including any claims related to the The relative toxicity scores products, drugs, or services men- Relative Abuse Liability Table ranged from 94% (pentobarbital) to 0% 0 20 40 60 80 100 tioned herein. The comprehensive Table is di- (ramelteon).The analysis also showed vided into three main categories: that, at supratherapeutic doses, pento- Likelihood of Abuse Toxicity pharmacology, likelihood of abuse, , methaqualone, and gamma- aAs discussed in text, relative abuse liability comprises an assessment of both the and other toxic consequences. The hydroxybutyrate are more likely to be likelihood of abuse (dark bars) and the toxicity (light bars). Scores show the mean three columns under the category lethal than are the other hypnotics. percentage of maximum possible score (see text and Table [on page 3] footnotes for details). heading of pharmacology provide infor- Ramelteon is the exception: at 20 ␥ mation about each drug’s molecular times the recommended therapeutic GHB = -hydroxybutyrate (also known as ) site of action, half-life, and peak time. dose, it produced no detectable Source: Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: A conceptual framework and algorithm for differentiating among compounds. Under the heading of likelihood motor or cognitive impairment.8 Takeda-ClinPsych 3/8/06 4:01 PM Page 3

CLINICAL UPDATE 3

TableTable. 2.Relative Relative Abuse Abuse LiabilityLiability ofof Hypnotic Drugs (a)(a) Pharmacology (b) Likelihood of Abuse (b) Other Toxic Consequences (b) Acute Likelihood Animal Sedation/ of Abuse Toxicity Half- Peak Drug Self- Human Liking/ Animal Human Memory Lethality in Score, % of Score, % of Receptor Site Life, h Time, h Administration Reinforcement Actual Abuse Withdrawal Withdrawal Impairment Overdose Maximum Maximum Drug (d) (e) (f) (g) (h) (i) (j) (j) (k) (l) (c) (c)

Pentobarbital Barb/GABAA 33 2–3 ++++ ++++ ++++ ++++ ++++ +++ ++++ 100 94 Nembutal (1) (2) (3,4) (5–7) (8–10) (11) (12,13) (2) (14,15)

Methaqualone* GABAA 30 2 ++ ++++ ++++ ++ ++++ +++ ++++ 83 81 Quaalude (presumed) (14) (14) (17) (18–20) (18,21) (22,23) (14) (14) (14) (aa) (16) (o)

Diazepam BZ/GABAA 43 1.3 ++ +++ +++ ++ ++ +++ ++ 67 56 Valium and others (1) (1) (3) (6,7,24) (24–27) (m) (m) (27) (y) (bb)

Flunitrazepam* BZ/GABAA 14 2 ++ +++ +++ ++ ++ +++ ++ 67 56 Rohypnol (28) (28) (3) (29,30) (30,31) (31) (31) (30) (y) (m) (m)

Lorazepam BZ/GABAA 14 2 ++ +++ ++ ++ ++ +++ ++ 58 56 Ativan and others (1) (28) (3) (24,32–37) (24,26,32,37,38) (m) (m) (35) (y) GHB (␥-hydroxybutyrate, GHB and 0.75 0.9 + ++ +++ ++ ++++ ++++ ++++ 50 88

also known as sodium GABAB (39) (39) (40,41) (42) (43,44) (45) (46) (42) (43,47) oxybate) Xyrem (u) (cc)

Temazepam BZ/GABAA 11 1.2 ++ ++ ++ ++ ++ +++ ++ 50 56 Restoril and others (1) (48) (49) (25) (25,50,51) (m) (m) (52) (y) Zaleplon BZ/GABA 11 ++ ++ … ++ … +++ ++ 50 58 ␣ A Sonata 1 selective (53) (53) (54) (55) (v) (56) (39) (y)

Eszopiclone BZ/GABAA 61 ++ ++ … ++ ++ +++ ++ 50 56 Lunesta (57) (57) (x) (57) (v) (x) (x) (58) (x) (x) (x)

Triazolam BZ/GABAA 2.9 1.3 ++ ++ + ++ ++ +++ ++ 42 56 Halcion and others (1) (1) (3) (55,59) (24,60–62) (m) (m) (2) (y) (q)

Zopiclone* BZ/GABAA 51 ++ ++ + ++ ++ +++ ++ 42 56 Imovane (63) (63) (64) (65,66) (25,67) (64) (67) (63) (68)

Flurazepam BZ/GABAA 74 1 ++ … + ++ ++ +++ ++ 38 56 Dalmane and others (1) (28) (3) (24,37,38,62) (m) (m) (69) (y) Zolpidem BZ/GABA 2.5 1.6 ++ + + ++ ++ +++ ++ 33 56 ␣ A Ambien 1 selective (53) (53) (3,70) (25,59,71,72) (25,67,73) (70,74) (73) (59,71,72) (y) (r)

Estazolam BZ/GABAA 17 3 ++ …o ++ ++ +++ ++ 25 56 ProSom and others (48) (48) (3) (w) (75) (m) (z) (y)

Oxazepam BZ/GABAA 8.0 2–4 … + + ++ ++ +++ ++ 25 56 (1) (28) (24,27,32,76,77) (24,27,78) (m) (m) (76) (y) (p)

Diphenhydramine H1 8.5 2.3 ++ + o…+++++ 25 42 Benadryl and others (1) (1) (79) (25,33,34) (25,33,80) (81) (33) (82–84) (s) Quazepam BZ/GABA 39 2.5 + …o ++ ++ +++ ++ 13 56 ␣ A Doral 1 selective (1) (48) (85) (w) (m) (m) (86) (y) Trazodone 5-HT and 6 2.0 …oo …++ + ++ 042 ␣ Desyrel and others adrenergic 1 (1) (1) (72) (25,87) (88,89) (72) (87,90) (n)

Ramelteon MT1 and MT2 1–5 0.8 oo…oooo00 Rozerem (91) (91) (92) (93) (v) (94) (95,96) (93) (t)

*Methaqualone, flunitrazepam, and zopiclone are not approved by the US Food and Drug Administration for use in the United States. Source: Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: A conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry. 2005;66(suppl 9):31–41. Reprinted with permission.

a. Throughout the table, the number of “+” symbols indicates the degree to which i. Provides an estimate of relative recreational abuse and nonmedical use based on s. Although, like lorazepam, diphenhydramine produced liking and reinforcement,33,34 the rated dimension was positive; “…” indicates no information available for that drug abuse epidemiology data as well as from the frequency of case reports of recre- it did so less reliably33 and also produced a profile of unpleasant somatic symp- drug. Within a column, scores can vary from “o” (none) to “++++.” A score of ational abuse in the medical literature. A ranking of “o” does not necessarily indi- toms.33,34 In retrospective questionnaires, it produced less liking than zolpidem and “++++” is assigned to the drug(s) that is judged, on the basis of available evidence, cate a total absence of reports of abuse but indicates that the rate, relative to drug temazepam.25 to be greatest on that dimension within a column. References and footnotes pro- availability and to abuse of other drugs, is very low. t. In an oral escalating-dose acute toxicity study in monkeys, the lethal oral dose of vide the rationale for the relative ratings of the dimensions as well as key citations j. An estimate of the relative severity of withdrawal signs after abrupt termination of ramelteon was greater than 2000 mg/kg (Takeda Chemical Industries, personal to other relevant literature. chronic dosing at supratherapeutic doses. communication, July 2005). b. Pharmacologic and behavioral dimensions relevant to the relative abuse and toxic- k. Indicates the relative behavioral or cognitive impairment after acute drug adminis- u. The dose-effect function with GHB appears steeper than that for other hypnotics, ity of hypnotic drugs. tration at supratherapeutic doses. including pentobarbital, thus increasing the risk of inadvertent overdose.42 c. Likelihood of Abuse Score: For each drug in each of the 3 columns summarizing l. Indicates the relative likelihood of death after overdose with the drug alone or in v. Although there are apparently no reports of recreational abuse of this compound, a likelihood of abuse (columns 4–6), a numerical value of +1 for each “+” symbol combination with other sedatives. meaningful estimate of relative abuse is not possible because of the relatively short was assigned; the percentage of the maximum score (ie, 4) was then calculated for m. Animal and human withdrawal from benzodiazepines is rated as intermediate based duration of clinical availability of this compound. each drug in each column.The overall Likelihood of Abuse Score is the mean score on numerous studies evaluating withdrawal from different benzodiazepines and the w. To our knowledge, there are no published reports of abuse of quazepam or estazolam. across the 3 columns for that drug, excluding columns for which no information well-documented pharmacologic similarities among benzodiazepines. Reviews of x. This rating for eszopiclone [which is the (S)-isomer of zopiclone] is estimated to was available for that drug. The Toxicity Score is calculated similarly for the 4 this literature generally do not differentiate among benzodiazepines69,99;however, be identical to that for zopiclone on the basis of strikingly similar behavioral columns summarizing toxicity information. some reviews of human research have concluded that withdrawal severity and fre- profiles of eszopiclone and zopiclone.103,104 ␥ d. Barb/GABAA = site on the -aminobutyric acid-A (GABAA) receptor quency and rebound insomnia are greater with rapidly eliminated benzodiazepines y. Animal and human studies of benzodiazepine receptor agonists indicate a remark- 100,101 complex; BZ/GABAA = benzodiazepine site on the GABAA receptor complex; than with slowly eliminated benzodiazepines. able safety profile when administered alone, with the lethal dose being hundreds or ␣ 102 99,105–107 BZ/GABAA 1-selective = preferential binding at the benzodiazepine site of n. Trazodone appears to have low efficacy as a hypnotic. thousands of times the therapeutic dose. ␣ -containing subtypes of the GABA receptor complex; H = histamine-1 recep- 1 A 1 o. Methaqualone produced severe , although species and sex dif- z. The acute sedative and memory impairing effects of estazolam are assumed to tor (antagonist); 5-HT = serotonin; MT and MT = 1 and 2 receptor 17,22,23 1 2 ferences have been noted. be identical to classic benzodiazepine hypnotics on the basis of the common subtypes. p. Although oxazepam produces drug-liking and some drug reinforcement, in the mechanism of action. e. Half-life = t (elimination half-life) of drug or active metabolite; when only a 1/2 table it is ranked lower among benzodiazepines because in prospective studies it aa. Methaqualone was first marketed in the United States in 1965. In the United States, range was available, the mean of the minimum and maximum values of the range is produced less liking and choice than diazepam27,76; in prospective studies, high doses in response to significant abuse, it was moved to Schedule II in 1973 and to provided. produced peak liking ratings that were delayed up to 8 hours after drug administra- Schedule I in 1984. Methaqualone abuse remains a significant public health prob- 76 f. Peak time = tmax (time to peak blood concentration); when only a range was avail- tion ; in retrospective studies of polydrug abusers, it was the benzodiazepine that lem in some countries.108 able, the mean of the minimum and maximum values of the range is provided. was least likely to be used “to get high or to sell”24,32; and drug abuse clinicians iden- bb. Although diazepam is not officially approved for use as a hypnotic, it is included as 97 g. Based on intravenous drug self-injection in nonhuman primates. tify its liking or abuse liability as particularly low among the benzodiazepines.24,77 a comparator because it is a frequently abused benzodiazepine sedative, it is h. Summarizes results from prospective double-blind studies in subjects with histories q. Although triazolam was, for a time, the most widely prescribed hypnotic in the efficacious as a hypnotic, and off-label use as a hypnotic occurs.109,110 of drug abuse (see reference 98) with outcome measures of drug self-administra- world, there are only a few reports documenting abuse.24,60–62 cc. Although respiration is well-maintained in GHB anesthesia, deaths attributable to tion, choice, or subjective ratings of liking/disliking or positive/negative drug r. Although zolpidem produces drug-liking similar to triazolam, in the table it is GHB, most often in combination with other drugs, have been reported.43,47 It seems effects.Also summarized are retrospective questionnaire studies of drug abusers and ranked lower because in prospective studies it also produced a profile of somatic likely that the steep dose-effect profile with GHB42 and the variability of the dose drug abuse clinicians. symptoms (queasy, emesis, dizzy)59,71,72 that may decrease its likelihood of abuse, and concentration of GHB on the illicit market contribute to the risk of inadvertent over- in a retrospective study of polydrug abusers it was less likely than diazepam and dose death. 25 to be liked. References continued on page 4 Takeda-ClinPsych 3/8/06 4:05 PM Page 4

4 CLINICAL UPDATE

Abuse Potential of Sleeping Agents: Liability Varies Among Agents Continued from page 1

that is inconsistent with accepted vealed that 14% of people taking (“Ecstasy”) or .17 Another sur- 2.American Academy of Sleep Medicine. 12. National Institutes of Health. National medical practice and demonstrated hypnotic agents during the previous vey found that 19% of Americans 18 International Classification of Sleep Dis- Heart, Lung, and Blood Institute. therapeutic efficacy). .Although recent year had taken these agents daily for orders Revised: Diagnostic and Coding Insomnia. NIH Publication No. 95- years of age and older who used 3801. October 2005. Available at: 15 Manual. Westchester, Ill: American studies suggest that some hypnotics longer than a year, despite product sedatives during the previous year Academy of Sleep Medicine; 2001. http://www.nhlbi.nih.gov/health/pub- may have long-term efficacy, the labeling indicating that these hyp- fulfilled diagnostic criteria for de- 3. Hatoum HT, Kania CM, Kong SX, lic/sleep/insomnia.pdf. Accessed Janua- benefits and risks (eg, memory notics should be prescribed only on a pendence (addiction) or abuse; this Wong JM,Mendelson WB. Prevalence of ry 15, 2006. impairment, increased risks of acci- short-term basis. Similarly, surveys in rate of abuse is higher than that for insomnia: A survey of the enrollees at 13. Griffiths RR, Johnson MW. Relative dents and falls) of such chronic use western Europe showed that 72% of marijuana, , pain killers, five managed care organizations. Am J abuse liability of hypnotic drugs: A con- 13 Man Care. 1998;4:79-86. ceptual framework and algorithm for have not been adequately explored. current users of hypnotic agents had alcohol, tranquilizers, , differentiating among compounds. 18 4. Leger D, Poursain B. An international With chronic use, patients may report been taking their medications for and inhalants. survey of insomnia: Under-recognition J Clin Psychiatry. 2005;66(suppl 9):31-41. 16 that the hypnotic is ameliorating longer than a year. and under-treatment of a polysympto- 14. Griffiths RR, Weerts EM. Benzo- their symptoms; however, it is impor- A second pattern of hypnotic Conclusion matic condition. Curr Med Res Opin. diazepine self-administration in humans tant to recognize that patients are abuse is referred to as recreational Insomnia is a prevalent condition 2005;21:1785-1792. and laboratory animals: Implications for unlikely able to distinguish between abuse.Typically, recreational users are associated with significant morbidity, 5. Roth T, Roehrs T. Insomnia: Epidem- problems of long-term use and abuse. and the potential for dependence and iology, characteristics, and consequences. Psychopharmacology (Berl). 1997;134:1-37. their original symptoms versus the males between 18 and 25 years of age Clin Cornerstone. 2003;5:5-15. abuse should not dissuade clinicians 15.Woods JH, Katz JL, Winger G. Benzo- emergence of phenomenologically who use drugs obtained illegally for 6.Thase ME. Correlates and consequences diazepines: Use, abuse, and consequences. similar withdrawal symptoms (ie, the purpose of becoming intoxicated from prescribing sedative/hypnotic of chronic insomnia. Gen Hosp Psychiatry. Pharmacol Rev. 1992;44:151-347. 14 drugs when clinically indicated. A rebound insomnia). Patients may be (“high”). Recreational abuse of 2005;27:100-112. 16. Ohayon MM, Lader MH. Use of psy- unable to quit and may continue to benzodiazepines, especially diazepam range of compounds that differ in 7. Benca RM. Consequences of insomnia chotropic medication in the general use the medication to relieve or and flunitrazepam among abusers of their potential for problematic use and its therapies. J Clin Psychiatry. 2001; population of France, Germany,Italy,and 62(suppl 10):33-38. the United Kingdom. J Clin Psychiatry. avoid withdrawal symptoms. This multiple drugs, is well documented.13 and toxicity are available, now rang- ing from agents with virtually no 8. Ohayon MM. Epidemiology of insom- 2002;63:817-825. type of use often occurs at therapeu- This type of abuse usually involves nia: What we know and what we still likelihood of abuse (eg, ramelteon, 17. Johnston LD, O’Malley PM, Bachman tic doses, but it can involve dose individuals in the illicit need to learn. Sleep Med Rev. 2002;6: JG, et al. Overall teen drug use continues escalation and visits to multiple (with attendant legal and health haz- trazodone) to those with varying 97-111. gradual decline, but use of inhalants physicians to obtain prescriptions. ards) and is associated with overdose, degrees of likelihood of abuse and/or 9. Stoller MK. Economic effects of insom- rises. University of Michigan News and Quasitherapeutic abuse of sedative/ memory impairment, risk of acci- toxicity. A complete review of these nia. Clin Ther. 1994;16:873-897. Information Services; Ann Arbor, Mich; December 21, 2004. Available at: 14 characteristics is provided in the 10. Charney DS, Mihic SJ, Harris RA. hypnotic drugs occurs in patients dents, and withdrawal syndrome. www.monitoringthefuture.org. Accessed Table on page 3. Hypnotics and sedatives. In Hardman with and without histories of alcohol Although this type of abuse is less JG, Limbird LE, Gilman AG, eds. Aug 5, 2005. or drug abuse, but it is more likely common than the quasitherapeutic Goodman & Gilman’s The Pharmacological 18. Substance Abuse and Mental Health to develop among substance abusers, abuse, a US survey showed that 10% References Basis of Therapeutics, ed 10. New York, Services Administration. Results from elderly patients, or patients treated and 11% of high school seniors illic- 1.American Psychiatric Association. Diag- NY: McGraw-Hill; 2001; pp 399-428. the 2003 National Survey on Drug Use nostic and Statistical Manual of Mental and Health: National Findings. (DHHS for chronic pain.14 itly used barbiturates and tranquiliz- 11. Mendelson WB. A review of the evi- Disorders, Fourth Edition. Washington, dence for the efficacy and safety of tra- Publication No. 04 3964). Rockville MD: A 1990 survey by Balter and ers, respectively, a slightly higher rate DC: American Psychiatric Association; zodone in insomnia. J Clin Psychiatry. 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Table. Relative Abuse Liability of Hypnotic Drugs Continued from page 3

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