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I I I I I I 1. /ifl,~ /tff.. va. 24. Supp. :. p0 5144, tM frima0 u Grat firttaue. 002:•11S6/9o 13 00 - 00 : 1970 pt.qmw Prat p+c THE NOSOLOGY OF ABUSE AND DEPENDENCE HERBERT D. KLEBER* •Yale University School of Medicine and the Dtrector. Substance Abuse Treatment Untt. Connecticut Menul Health Center. New Haven, Connecticut, U.S.A. Summar,v-Phystctans who prescnbe benzodiazeputes often are asked by their patients if these drugs might be addicting or have potential for abuse. Clarifying these concepts is difficult because of numerous "gtay areas" of drug use and confusion over ttxdtcal cntena for such tetms as "addtcuon", ' depetdence". and "tolennce". Many of the efforts to clarify the terminology regarding substance habrtuatton, abuse. and addictton have resulted in addiuonaW confusion. They have resulted in overiapptng definitions of abuse and dependence. the injection of morai judgements into sctenttfic tams, and difficulty separaung the diagnoses of the physical dependence tcaused by prolonged use of a wide vanety of drugs. many of whtch are never abused) from that of phystcal dependence secondary to an abusive pattem of use. This article will trace the history of the various definitions currently in use. and will suggest newer terminology to nsplace misleading or erroneous terms. INTRODUCTION I I In order to understand the nosological and conceptual confusion that physicians and patients have in regard to certain properties of the benzodiazepine category of drugs. it is necessary to clarify and discuss some of the historical and definitional aspects regarding drug use and abuse. The current definition of misuse is the use of legitimately obtained drugs in a manner or amount other than prescribed in order to produce a certain psychological state, such as the use of a prescribed cough suppressant medication containing codeine to get high rather than to suppress cough. - This definition, however, can create confusion regarding the legitimate use of prescribed drugs. For example. patients may use the prescribed medication to relieve symptoms other than those for which it was originally prescribed, such as using sleeping pills during the day to reduce anxiety. Another issue in the interpretation of the term "misuse" concerns the source of the medication: the drug may be used legitimately (to relieve insomnia). but be obtained illegitimately (from a fnend rather than a physician). HISTORICAL DEFINITIONS OF ABUSE I I I I ZINBERG et al. ( 1978) have noted that "it was not until the early twentieth century that the nonmedical use of certain substances"...became "a problem of drug abuse. evoking enough...public concern to lead to legal regulation". After the Civil War. morphine became associated with widespread addiction via Address correspondence to Herbert D. Kleber. M.D.. Director, Substance Abuse Treatment Unit. Connecticut Mental Health Lenter. 34 Park Street. New Haven, CT 06519. U.S.A. 57 I

I I I I I I I I I I 1 I I I 58 HoteExr D. Kt.ESEit nonmedical use. known as "the soldier's disease". However, this was regarded mainly as evidence of character weakness, not of criminality. Up to the first decade of the twentieth century, large amounts of opiates were used in patent medicines and apparently a higher rate of opiate addiction existed at that time than exists now (LINDESMITH. 1965). BRECKER (1982) noted that the predominantly rural. white women who suffered from opiate addiction were viewed with pity rather than contempt. MusTo (1973) has pointed out that the term "drug abuse" apparently was applied first to the use of cocaine by Southern blacks early in the twentieth century and then to the smoking of opium by Chinese Americans. In both cases. he believes this term represented fear of a despised minority. With the passage of the Harrison Narcotic Act in 1914, the use of heroin and morphine was included in the term "drug abuse." In the next decades the use of unprescribed opiates shifted. in the public mind. from a bad habit into a criminal activity (ZIyBERG et al., 1978). At the same time, the meaning of "addiction" changed also. Addiction formerly meant a habit, good as well as bad. In 1902. DR. CHARLES TowNs described a so-called "addictive triad": increased craving, growing tolerance, and a withdrawal syndrome when the drug is withheld (MusTO: 1973). By 1910 to 1920, the word had become linked to the culturally disapproved use of certain drugs. Today the term usually refers to the physical dependence following the continued and heavy use of opiates. barbiturates. or alcohol. TowNs' concept of the "addictive triad" is more difficult to demonstrate medically than it first appears. "It is difficult to define 'increased craving' (or the later version, 'overwhelming need') precisely, or to limit those notions to drug abuse. The very choice of the term 'craving' indicates the subtle biases behind the definition. The adjectival form is 'craven.' which means cowardly. Craving itself connotes disrepute. weakness, and a sense of desperation that may lead to anti-social and even criminal behavior" (ZINBERG et al.. 1978). The term "tolerance" is also not as simple as it first appears. "While there is a physiologically increasing accommodation to a substance, the phenomenon of 'growing tolerance' is not a straightforward one. The capacity of different individuals to deal with different amounts of substances without development of tolerance has become obvious" (ZtNBERG er al., 1978). It has been noted with regard to the benzodiazepines that personality factors may be more important than dose in the development of withdrawal symptoms during gradual reduction from diazepam (TYRER er al.. 1984). Those with withdrawal symptoms had significantly greater lability, sensitivity, impulsiveness, and resourcelessness than those without. MEDICAL DEFINITIONS OF ABUSE Medically, abuse is often defined as nonmedical use. Non-ntedical use may involve either use of a medically sanctioned drug for a different purpose. e.g. use of a sleeping pill to produce a drunken state or use of a drug that has no currently recognized medical purpose (e.g. mescaline). Thus, the 1972 American Psychiatric Association definition of drug abuse is noted below (GLASSCOTE tt al., 1972): Drug abuse refers to "the illegal. nonmedical use of a limited number of substances. mo•t of them drugs. which have properties of altering the mental state in ways that are considered I

I I I I THE NOSOIOGY OF ABUSE AND DFlfNDENCE 5q by social norms and defined by statute to be inappropriate, undesirable, harmful. threatening, or. at a minimum, culture alien". A more recent definition of drug abuse is the non-prescriptive use of psychoactive chemicals to alter one's psychological state and, as a result of such alteration, the individual, others around him/her. or society incur some harm. The vagueness of the terms "misuse" and "abuse" led a recent World Health Organization (WHO) Expert Committee to recommend that these terms be abolished and replaced with Unsanctioned Use. Hazardous Use. Dysfunctional Use, and Harmful Use (Table 1). TABLE 1. (WHOi Exrm coWMrnU DERnmoru OF ABUSE I I I I I I I I I I I I • Unsanctioned Use-Lise of a drug that is not approved by a society or a group within that society. Who dtupproves should be made clear when the term is used. The term implies the acceptance of disapproval as a fact in its own nght, without having to determine or justify its basts, e.g. certatn psychedelics. • Hazardous Use-Use of a drug that will probably lead to harmful consequences for the user---etther to d,vsfunction or to harm. This category essentially includes Ux idea of risky behavtor, e.g. smoking I pack of cigarettes a day. • Dysfunctional Use-Ux of a drug that is leading to impaired psychological or social funcuonrng (e.g. loss of )ob. or marital problems . • Harmful Use-Use of a drug that is known to have caused the particular person nssur damage or mental illness. ADDICTION AND HABiTL'AT7Oti All drug taking behaviors were related to TOWNS' triad initially. When it was no longer possible to explain the use of substances that did not produce physical dependence in those terms. the concept of psychological habituation was developed. In 1957. WHO published an official definition that included both physiological and psychological habituation. Drug addiction was defined by WHO as a state or period of chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). Its characteristics include (1) an overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means: (2) a tendency to increase the dose: (3) a psychic (psychologicali and generally a physical dependence on the effects of the drug: and (4) detrimental effect on the individual and/or society. Drug habituation is a condition resulting from the repeated consumption of a drug. lts characteristics include (t) a desire (but not a compulsion) to continue taking the drug for the sense of improved well-being which it engenders: (2) little or no tendency to increase the dose: (3) some degr-e of psychic dependence on the effect of the drug but absence of physical dependence and hence of an abstinence syndrome: (4) detrimental effects. if any. primarily on the individual. I

I I I I I I I I I I I I I I I I I I EA HFJtafJt7 D. KLEaex In the above definitions. habituation tended to be the definition of addiction minus the aspects of physical dependence-namely craving, tolerance, and a withdrawal syndrome. Addiction involved "compulsion" while habituation involved "desire". The difference between the two lies in the strength of the seeking. and there was an implicit assumption that physiologic addiction is more overpowering than psychological habituation. However. it was soon noted that some individuals could be physically dependent on a drug without compulsive use patterns and vice versa. The tendency of the withdrawal syndrome. or fear of it. to "compel" drug seeking and drug use behavior clearly differed for the same drug in different circumstances. For example, cocaine. which leads to less physiological dependence than heroin. can have even greater "addicting" potential. In 1964. WHO recognized sufficient additional flaws in the definitions and formed a new expert committee, using the concept of "dependence" as its crucial variable (Table 2). Dependence. either psychic or physical, or both, arose after periodic or continued use of a particular drug. The characteristics varied with the drugs. Thus, persons with morphine-type dependencies had both psychic and physical dependence. and persons with cannabis-type (marijuana) drug dependencies had only psychic dependency. The definitions relied on the same ambiguous and difficult concepts of psychic and physical dependence abused earlier and also resulted in being used in a form of circular reasoning. Thus, the definition of drug dependence which was developed to describe a particular form or pattern of drug use became an explanatory concept: If the question of why an individual was constantly using drugs was raised- the common answer was, "Because they are dependent on drugs". Thus the term "drug dependence" had become per se, the explanation of the pattern of drug use (ZtHaERC ef al.. 1978). ABUSE AND DEPENDENCE DSM-IlI DEFINiT1OIvS In 1980. the Diagnostic and Statistical Manual of Mental Disorders. Third Edition ( DSM- I11) (1980) partially solved the difficulties with the concepts of psychic and physical dependency by using two terms: abuse and dependence. Abuse was defined as including a pathologic pattern of use. impaittnettt in social or occupational functioning, and duration of TA&E 2. WoRw HEu-n+ oaoarmAnoN i WHO) t>efltr+navs. 1964 ' Deug Dependence-A state of psychic or physical dependence. or both. on a drng, ansing in a person following admtnistratron of that drug on a penudtc or conttnuou.s basts. The charactensttcs of such a state will vary with the agent involved. • Psychic Dependence-A condition in which a drug produces "a feeling of satisfaction and a psychic drive that requires periodic or continuous admtntsnanon of the drug to produce pleasure or to avoid dtscomfoct". • Physical Dependatce-An adapuve state that manifests itseif by inten- sive physical disturbaxes when the administration of the drug is sus- pended. These disturbances. i.e. the withdrawal or abstinence syn- dtomes. are made up of specific arrays of symptoms and signs of both psychic and physical nature that ast characteristic of each drug type. I

7Iff NcsoLOOY oP AlusE AND DeFI1DFIJCE 61 I I I I I I I I I I I I I the disturbance for at least one month. Dependence was defined as being manifested by tolerance, withdnwal, or both. Some drugs. e.g. opioids. sedatives, and amphetamines, had categories of both abuse and dependence. Cocaine, which was not believed in 1980 to.cause tolerance or withdrawal, was included only in the Abuse category while tobacco was included only in the Dependence category. The full definitions of sedative abuse and dependence are in Table 3. The DSM-III definitions of abuse and dependency, however, make no distinction between dependence and legitimate, long-term medical use of an opiate or sedative which results in TAat.E 3. DSM-tII o+AoMosnc cItrrEun Fott t,,vternrRArE on stMt>au.Y ACTING sEDAnVE OR HYlT/OTK' ,R6usE A. Fatum of patholoEicat use: inabihry to cutdown or stop use: intoxrcuwn thra+ahout the day: fnaquent use of the equivailent of 600 mg or more of secobubital or 60 mg or more of ditzepam: amnestc penods for events that occurred while intoxicated. B. Impatrment in socul or occupattoeal functioning due to substaace use: e.g. fighu. loss of frxrbs, absence from worle. loss of tob, or legal difficulties (other than a single arrest due to possession. purchase. or sale of the substance). C. Duration of disturbutce of at least one month. D. Tolerance: need for markedly increased amounts of the substance to ochieve the desired effect. or markedly administered effect with regulu use of the same atnowft. E. Withdnwal: developtnent of barbutuate or similarly acting sedative or hypnotic wtthdrawal after cessation of or teducuon in substance use. tolerance and which, with abrupt cessation, is likely to result in withdrawal. Also under DSM-III, opiate and sedative dependence with no abuse are considered psychiatric disorders: whereas similar states related to chronic use of anti-hypertensive agents or tricyclic antidepressants are not. In addition, there was no provision for severity of dependence. These problems led to the changes found in the Diagnostic and Statistical Manual of Mental Drsordtrs, Third Editiorr, Revised (DSM-II1-R) (1987) (Table 4). The Abuse and Dependency categories have been abolished and the category of Substance Dependence has been reestablished (with the exception of an Abuse residual category for individuals who have never met the Dependence criteria). Of the nine items listed, three are necessary for the diagnosis. and each is modified further as mild. moderate. or severe. DEPENDENCE Because of the problems in terminology not rectified by DSM-III. the WHO and ADAMHA convened an International Working Group and in 1980 issued a report concerning the terminology of drug dependence. They defined dependence as "a syndrome manifested by a behavioral pattern in which the use of a given psychoactive drug or class of drugs is given a ~ ~ N CJt I

I I I I I I I I I I I I I I I I I I 62 HFJIBFJtT D. KLEBER TABIF 4, BSM-IILR qAGNOSTK CRftERU FOR PsYC}IOACrtvE SUBSTANCE pEPENDFliCE A. At lezu three of the following must be prtsent. I. Substance often taken in larger amounts or over a longer penod than the person intended: 2. Persistent desire or one or more unsuccessful efforts to cut down or control subuu-ce use. 3. A great deal of time spent in activities necessary to get the substance (e.g. chain smoktng), or recovenng from its effects: 4. Frequent intoxication or withdrawal symptoms when expected to fulfill ms,pr rote obligations at work, school, or home 'e.g. does not go to work because hung over, goes to school or work "htgh". intoxicated while taking care of his or her chtldren). or when substance use is physicilly hazardous (e.g. dnves when tntozicatedl: 5. Important social. occupauortal, or rscrsauonal activities given up or reduced because of substance use: 6. Continued substance use despite knowledge of having a persistent or recurrent social. pcychologtcal, or physical problem that is cauxd or - exacerbated by the use of the substance i e.g. keeps using herorn despite family arguments about it. cocaine induced desxessrun, or has an ulcer made worse by drtttktngl: 7 Mariced tolerance: need for tnarkedlv increased amouttu of the substance ( t.e. at least a 50% trtcreaset in order to achieve intoxication or desired effect: or markedly diminished effect with continued use of the same 7lfrlolint: Note. Tht followin,t items moY not app(Y to cannabis. hallucuwRens, or phenc%rlydrRe r PG'P ): S. Chanctenuic withdrawal symptoms (see specific withdrawal syndromes under psychoactive substance tnduced organic merttal dtsoniers ): 9. Substance often taken to relieve or to avoid withdrawal symptoms: B. Some symptoms of the disturbance have persisted for at kast one month, or have occurred rtpeatedly over a longer period of time. much higher priority than other behaviors that were once at higher value...Not all the components need always be present. or not always present with the same intensity.... "The dependence syndrome is not absolute but is a quantitative phenomenon existing in degrees. The intensity of the syndrome is measured by the behaviors that are elicited in relation to using the drug, and by the other behaviors that occur secondary to drug use...No sharp cut-off point can be identified for distinguishing drug dependence from non- dependent but recurrent drug use." At the extreme the "dependence syndrome is associated with compulsive drug using behavior". The word "dependence" tends to be used in the scientific literature to convey two different ideas: (1) A behavioral syndrome that implies corttpulsi ve. out of control use, and (2) physical dependence. or, alterations in neural systems manifested in tolerance and in withdrawal when the chronically administered drug is discontinued or displaced from its receptor. Unfortunately, this dual use of the word dependence leads to both semantic and conceptual confusion. No close parallel exists between the capacity of a drug to produce I

i I I I I I I I T¢ (VOSOLOGY Oi AaUSf ,wo DM-*roe4cE 6a tolerance and its reinforcement potential. Thus. the International Working Group recommended restricting the term "dependence" to the beh,avioral syndrome prevlousl-~ described and substituting the tettn, "neuro-adaptation" for physical dependence. It is of interest that the chronic use of many drugs, including tricyclic anti-depressants and beta- adrenergic blockers, brings about neuro-adaptive changes. Abrupt discontinuation of these is followed by withdrawal phenomenon, but not by drug seeking behavior. Specific patterns of benzodiazepine dependence have been proposed (LAux et al.. 1984). Unfortunately, these proposals are often simplistic, confuse tolerance and physical withdrawal with dependence, and ignore the evidence that high dose dependency can be either similar to low dose dependency or episodic and binge-like. The proposed patterns are as follows. Benzodiazepine prinwry low-dose dependency at therapeutic dosage The extent of primary low dose dependency has been recognized only recently. In addition to case reports of mild abstinence syndromes, reports of a few controlled trials of benzodiazepine withdrawal from therapeutic doses have been published (BusTO et al.. 1986). Benzodiazepine primary high-dose dependency Patients who develop primary high dose dependency usually take two to five times the normal therapeutic dosage (LAUX et al.. 1984). With the higher dosage. physical dependence can develop within three weeks. In most cases. however. the drugs have been taken for years. Patients with this type of dependency are at greater risk of developing toxic benzodiazepine syndromes and severe withdrawal reactions (MARKS, 1978). Benzodiettpine secondory dependency (multiple drug abuse) Secondary dependency arises in the context of multiple drug abuse and/or alcoholism. Some authors claim that these cases are much more frequent than primary benzodiazepine dependency. emphasizing the high frequency of alcohol abuse. MARKS (1983) suggests that it is more helpful to refer to "withdrawal reactions" rather than to "dependence" in relation to the benzodiazepines. In studies in which therapeutic doses are abruptly stopped. the key variables in determining whether withdrawal symptoms occur appear to be those of duration of use and personality. At less than four months of use of benzodiazepines. the incidence is "virtually nil unless alcohol, other sedatives or opiates are also being taken(Bus7o et al., 1986). The incidence of significant withdrawal symptoms is less than 5% after one year. but after longer than one year it appears to rise sharply. TYRER (1984) notes that individuals taking the drugs for psychiatric problems are more likely to experience withdrawal symptoms than those using them for neurological purposes (e.g. seizure disorders or spasticity). Some patients may stop the benzodiazepines abruptly without withdrawal symptoms because they feel they no longer need the effect. Others, particularly panic disorder patients. may be unable or unwilling to stop the medications because of fear of losing the therapeutic effect and re-experiencing unpleasant psychological symptoms, although no withdrawal symptoms are likely to occur. The same

I I I I I I I I I I 1 I I I 64 HERDEJtT D. KLEDER category of drug may be (I) used but not abused and without physical dependence. (2) used but not abused and with physical dependence, (3) abused without physical dependence (as in a binge pattern of use). (4) abused with physical dependence. CONCLUSION Many of the attempts to define the concepts of dnug habituation, abuse, and addiction have resulted in additional confusion. The confusion is a result of overlapping definitions of abuse and dependence, injection of moral ideas into scientific terms, and difficulty in separating a diagnosis of physical dependence caused by prolonged use of a wide variety of drugs-matty of which are never abused-,and the physical dependence secondary to an abusive pattern of use. In regard to the benzodiazepine-type drugs, some patients may use the drug (1) at usual therapeutic doses for relief of anxiety or depression and not display withdrawal symptoms even on abrupt cessation: (2) as above but display withdrawal symptoms with abrupt withdrawal or even with gradual withdrawal; (3) periodically for a"high," especially combined with alcohol: (4) regularly at high doses for a chronic drunk and manifest withdrawal symptoms on abrupt stopping. REFERENCES BRECHER. E. M.. & THE EDtTORS OF COwSUMER REPORrS. (1972) LJcJt and Illicit DrYts' The Consumers Lnton Guide to Drae Ahuse Boston Ltttle. Brown Co. BLSTO. L.. SELLE1t5. E. M.. NARA%JO. C. A.. CAMELL. H.. SANCHEZ•CRAJS. M.. & SYUORA. K. (1986) Withdrawal reaction after long•term therapeutic use of benzodtazepmes. N Engl. J. Med. 315. 854-859. Dtatnnsric & Stattsru'al Manuai of Mental DJsorders. Third Eduton. (1980) Washtngton. D,C.: American Psychtatnc Assocuuon. Dtagnosttc & Stattstrcal Manual o/ Mtntal Dtsordtrs. Third Editron. Rtrtsed. (1987) Washington. D.C.: Amerscan Psychiatric Associauon, GLASSCOTE. R. M.. SUSSEx. J. N.. JAFFE. 1. H.. BALL. J.. & BRU.L. L. (1972) The Treatment of Drug Abuse Pr»Rrams. Prohltms. Prosptcts Washington. D.C.: American Psychutttic Assoctation. LALx. G.. & PLRYE..R. D. A. (1984) Benzodiazepines-mtsuse, abuse and dependency. Am. Fam Phvstcran 30. 139•147. LJNDEsMtTH. A. R. (1965) The Addict & the Law' Bloomington. Indiana: Indwta University Press. M..RKS.1. (1978) TThe Brncodtaceptnts. Usr. Orerust. Misuse. Ahtve. Lancaster. England: MTP Press. M..RKS.1. (1983) The benzodiazepmes: an international perspective. J Psvchoactivt Drurs 15. 137• 148, Mtaro. D. F. (1973) The Amerre an Disease. OrttJns of Narcotic Controls. New Haven. Conn: Yak Untversttv Press. TYRER. P. J.. & SElvEwRIGHT. ,1. (19g4) Identification and management of benzodtaZeplne dependence. POsrqrad Med J 60 ( suppl 2). 41-46. ZJNeERC. N. E.. HAROtNC. W. M.. & Arst.ER. R. (1978) What is drug abuse? J. DrvR Issues 8. 9•35. I