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I I I I I I I I I I I I I I I I I I AJ,Ii. 0,11 ~iw~...eJdcJ Oy ~ N l)'Hncn ~nJ J H Ja/le ka.cn fRea.. LW . Ncr Yir1 V Iw2 1 Current Concepts of Addiction . Jerome H. Jaffe Offire for Treatment Improvement. AA uhul. Drug Abwt, und Mentul Health Admrntstrrutan. Rue•kvtlle, Murylund 20M57 Definitions and conceptual models developed by scientists to explain the essential nature of drug dependence do not always correspond to the concepts and definitions that are useful to others, and they are never entirely independent of the culture in which they are developed. They both influence and are influenced by concepts and definitions used by other groups in contemporary society ( I-3). Cenainly, in con- temporary American society, science has been given no exclusive or proprietary tight to the use of terms such as "drug dependence" or "aekLctton." Many peopie appear to believe that whatever addiction is, it is not just something that is seen with dntgs such as morphine, cocaine, or alcohol. Among the many behaviors that have been labeled "addictions" in the mass media are: eating salt; buying lottery tickew using gasoline, computen, or foreign capital; taking cducatioeal courses; watching television; running; and engaging in sex. Some of these uses of the term are deliber- ately metaphorical. There are behaviun, however, such as gambling and certtun types of sexual behavior, that are viewed as sharing so many features with the excessive use of drugs or alcohol that some clinicians have advocated specific "treatments" for them based largely on approaches which evolved from the treat- ment of alcoholism or drug dependence. Thus it appears that new disorders can be generated by experts and by what is fashionable. Kendler tells us that psychiatric diagnosis "expenences fads," and argues that, despite the need for flexibility, it is preferable that "change lin nosologyl be based on the neceasariiy slow accumulation of research findings, rather than on 'expert opinion' which can be more mercurial than we wish to believe" (4). He points out two advantages of a nosology based on scientific principles (i.e., one involving the generation of hypotheses about the reliability and validity of competing diagnostic schemes). First, it would keep us honest clarifying what we do and do not ktow- thercby preventing premature closure about issues where knowledge is limited. Scc- utxl, it should increase "the credibility of our nosology in the eyes of other menutl health groups and of society at large" (4). While journalists and popular wnten have every nght to use words like "addictioti' and "dependence" metaphorically, when thesc words are used by the helping professions with the implication that there I

I I I I I I I I I I I I I I I 2 CURREM CONCEPTS OF ADDIC7lON are valid and reliable diagnostic entutes to be treated by some equally scientifically validated methods, they cease to be metaphors. Metaphoncal usage tncreases the risk that many diagnoses will be seen as self-serving medicalirrtions of undestrablc behaviors. Such accusations and questions of credibility are discussed later in this chapter. Currently, for researchers and clinicians, the most influential ideas about the nature of drug abuse and dependence are embedded in the Diagnostic and Stntisttcul Manual, Third Edition, Revised (DSM-III-R) (5) and the international Classtfrca- rlon ojDisrases-!l) (lCD-10) (6). These tue, respectively, the official compendia of disorders of the Amencan Psychiatric Association and the Worid Health Organtza- tion. Both of these publicatiau include sections on mental and behavioral disorders due to psychoacdve substance use. In both, the serxioas present brief definitions of the vanous syndrornes and a set of criteria that allows a clinician (tx an epidemiolo- gist) to judge whether a given case meeu the definition. These definitions and the respective criteria are presented in Tables I and 2. While there are certain differ- anees between the deftnitions and critena in the two publications, they share some stntetural or formal features, and their intellectual foundatiorts can be tractd to concepts laid out a decade ago by a WHO Wotidng Group which met in Washing- ton, D.C. ut 1980. The aim of that metting was not merely to attempt to reach consensus on terminoiogy appiicable to drug use and its associated probkms. but also to lay out the assumptwns and the conceptual framework on which the defini- tions and critena might be developed, and to point out wheae research was needed to further our understanding of the telationships among causal factors. The ideas in the WHO Memorandum set forth by the Working Group (7) neptssented an evolution from the alcohol dependence syndrome proposed by Edwards and Gross in 1976 (8). As part of its effort, the WHO Working Group attempted to illtutrate in a schematic diagram how vat~ous bio{ogical, social, and psychological factors might interact with drug-tahing in the development of drug dependence (Fig. 1). REINFORCING EFFECTS Part of Fig. 1(tbe WHO model) presents in simplified form the postulated rela- tionships between drug use and its consequences, and the impact of these conse- quences on the disQosuion to repeat drug use. Intelkcttully, this part of the figure is fumly rooted in contemporary behaviorism and learning theory. The "disposition to use" a drug is iafltteaced by both the aversive and teinfoccing consequences of drug use. Among these consequences (at least for most of the drugs which are associated with dependence), is the development of oeutoadaptive changes, such as tolerartce and physical dependence. Drug effecu ue shown to interact. On any given occa- sioo, drug use produces several effects. It may produce elevation of mood or relief of some antecedent distress or dysphoria. Such effects increase the likelihood that the drug will be used again. That is, in behavioral terms, these effects reinjorce the drug-taking behavioc. In theory, the acute effects of the drug need not be dramatic: I

I I I I I I I I I I I I I I I I I CURRENT CONCEPTS OF A!)I)1C FlUN TABLE 1. Diagnostic cnrena lor psycnoacuve substance dependence (DSM•lll•Ff) A. At least three ot the tolbwing t. supstance onerl taken in larger amounts or over a longer peraa than the person intended 2. persistent des+re or one or more unsuocesstul eNons to cut down or contra substance use 3. a great deal of ume spent in activities necessary to get the substance (e g.. thsft), taking the substance le g., chan smoking), or r.cov.rng trom its eiteds 4. hequsrM nwxrcaWn or w+tAdrawl symptortu w1>'en expected to tuthM maP ro+e obMgatt= at work. sawd, or home (e.g.. does not go b work beCause hung over, goes to school (x work 'lygh,' ntonoated wtr/e taking care of his or her dwaen), or when substance use ts physically hazardous (e.g.. drives when nfoxtcated) 5. trrtportartt soaal, ocarpat+onal, or recreaLonal acttvtbes given up or reduced because a subeiartce use 3 6 continued substance use despite knowledge of having a persistent or recurrent soc+at, psycholog", or physical problem that is caused ar exacerbated by the use ot the substance (e.g., keepe using heroin despite tamry argumsrxs about N, cocane•nauced aepressror+. or having an utcer made worse by drrierq) 7 marked tolerance need tor marketlly increased amourus of the substar>ce (t.e., at least a 50 peroent increase) in order to achieve ntoncatiort or desired effed. of mancedy dimwrst+ed etteet wutt oornrx»d use ol me sam. amourtt Note: The /oNowmg Nwns may not apply b cannabis. halM.ionOgens, or pheneyCbdne (PCP): 8. etwadertsric w+tttdrawai symptoms (see speobc w+tttdrawat syndromes under Psycfwacuw Orgarnc Msntal Disorders) 9. substance often taken to reMew or avoid wnhdawat symptoms B. Some symptoms of the disturbance have pers+sted br at Last i month, or haw ocairred repealsdFy over a kxtger penod tRne. of Cntena for sawnty of psydwactaw sarbetance dependence tvYld: Few. i/ any. symptoms in excess of thoM requred b make tt» dagnos+s. and ttte syrtlplortls resuM in no more fhan nrlC wrtpannsrtt in ocatpattaW hxtctarwtg «n usual social aarvnre or rwnonstrpa with ott,en. btoderate- Stmtptoms or kxtcsaona/ rrtpnrtnent between 'mkd' and •severe.' Severr, Many sytnptoms in excess of tttoee required b make tM dagrtoen. and tM symptoms markedy ntaAere wMh ocaqawnat ttx> ebonrng « with uawl aocrti activities or re/atlonshlpe with dhefs.' M Parbat Remss+on: During ttie pap 6 mmws, some use of tre substance ,na some aymptorns of dependerta. In Full fiems,von: During tew paat 6 monMts. either no use ot the sucstance. or use of the suostance and no sym,pams ot a.p.ndertc.. From ref. S. '8eeause of the avalab4uy of cigarettes and other rwcane oontarrwtg substances and the abeence of a clrrcaqy stgrrlk,anw ncane nto>ucanon syndrome, irnpawment in occupebona/ or sof9a/ tuncUOnYng is not neCeSiary tot a ratng of seYere (V/pDlne Dependence. if the net result of use is to increase the likelihood of future use, the effect is reinforcing. Other effects, such as the initiation of neuruadaptive changes in the CNS-tolerance and physical dependence-may nex be immediateiy apparent, but they may come to influence drug-taking tf the drug use is repeated. Drug use may also produce aversive cunsequences, such as direct and immediate toxic effects, uc delayed damage to body urgana, or impairment uf' the cognitive and bduvNxal I

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I I I I 1 1 I a I I I I I I I CURRENT CONCEPTS OF ADDICTtON 5 Fix.23 Currentty abstinent. but receiving aversrve treatment on averswe or btodung arugs ie g nattrexone or disuttuam) FIx.24 Currentfy usmg the substance Ftx.25 Connnuous use Fix.26 EppsoWC use IdiOsomarual From ret. 6. functioning (see the chapters by Mendelsext et al., and Brust). Aversive conse- quences stxmld lead to avoidance learntng-a tendency to avoid the drug use which produced the aversive effects. For some individuals, the reinforcing effects can be so powerful that they ignore or dismiss the possibility of aversive cottsetluences. They may even persist in using drugs despite aversive effects that are occurring simultaneously with reinforcing effects. Examples of this include cocaine users who continue to use the drug despite increasing anxiety and paruwia; cigarette smokers who .re undeterred by hean attacks or cancer surgery; and heroin users who inject heroin from the same batch which they know produced overdoses in acquaintances. 71te biological basis of reinforcement is the focus of an exciting frontier in neuro- science (9,10) (see also the chapters by Kornetsky and Pornno, and Koob). The WHO model points out that drugs can act as reinforcers of drug-taking behavior in at teast two distinct ways. First, they can produce positive or rewarding effecu. Animals and humans in no apparent distress will work hard to obtain certain drugs for their rewarding effects. Sccond, drugs can also act u reinforcers by alleviating such aversive hedonic states or drives as pain, anger, depression, anxiety, or bore- dom. This form of rernfurcetnent is also called "negative retnforcement." A number of researchers and clinicians believe that this vanety of reinforcement deserves far more attentiott. While it is impressive to observe that animals in no distress will self-administer drugs, people who use drugs to the point where they seek help often report distressing antecedent emotional states which were made less distressing, at least tnitially, by the effects of the drug. According to these workers, the persistent use of certain drugs may represent an adaptive effort, rather than hedonistic pursuit (11,12) (see the chapters by Hesselbrex:k et al., and Kandel). In Fig. 1, such ptedis- posing factors are shown as possible immediate antecedent influences on the dispo- sttion to use drugs. One special variety of negative reinforcement is the relief of withdrawal symp- toms. In theory, once withdrawal pherwmetta begin to occur, relief of withdrawal becomes a parttculatly pcxent mechanism fur reinforcing drug-taking behavior. This is so because for many short-acting agents withdrawal is so recurrent, and because the drug acts so specifically and quickly to alleviate the manifestations of its own withdrawal. On any given occasion, a drug may produce reinftxcing effects by any or all of these means: puaitive reinforcement, alleviating withdrawal, or reducing antecaknt dyaphortc states (13). Hernin is the heart ul' one of the current controversies about the ttature of drug I

~ ~ M wo am ~ ~ 'M " aw No on -no 'IM M M ~ 'Oft w SOCIAL AND INDIVIDUAL ANTECEDENTS i SOCIAL OISTAL ANTECEDENTS •.p. i.riiwy i.r.csFons nsir.ntal en+o w. DISPOSITION DRUG NEURO• TO USE USE ADAPTIVE DRU(3 STATE NrDIV1DUAL W MMAEDIATE ANTECEDENTS urrmq laws siotial p.sswr.s avaNanibty drmopnphic vartaDl.s F+ W DISTAL ANTECEDENTS e.0• w/y Nartinp dnia a*.ftnwe p~andOwrnaeq d ntal sivrrris ~ Md1uED1ATE ANTECEDENTS •.p. mood sares wlthdnwal states a>~ont V AVOIDANCE LEARNING A APPROACH LEARNING A SOCIAL AND INDNIDUAL CONSEQUENCES H AVERSIVE CONSEOUENCES a.o. bxiC 1KKYt raduwd drup afNd oryanic dsYnao• , t TOLERANCE ay~s~v ~~ REMlFORCM CONSEOUENCES •.p. e~ood Mhuw.m.rn ^=601" avvkMiwr or rNiN a wlMarawr symptoms H 4+ t WffHORAWAI SYIrPTOMS t rr1rDSIM FKi. 1. A rprodudion of lh. WHO sd>rmatlc model of drug wa and dependence (Edwards as N., 11b1). Fquras 2 and 3 rpraa.rtl modiflcabons and.iaboratlont of Fip. 1. ~0SM9fi99

I I I I I I I I I I I I I I I I I I CURRENT CONCEPTS UF AUUIC7YUN 7 dependence-one that h8S persisted lur more than a century. Do people keep taking drugs primanly to alleviate wtthdrawal, or do they take them because they continue to ezpenence some of the initial reinforcing effects7 Several major developments have rekindled this issue. The ftrst' ts the discovery that animals with electrodes implanted in the brain work very hard to get an eleetncal current. Electne current to certatn parts of the brain is retnforctng. Certain drugs lower the threshold for the current required to produce these retnforctng effects and tolerance does not appear to develop to this effect (see the chapter by Kurnetsky and Pumrto). The second observattuttiis that animals trained to press a lever to get a drug such as heroin will do so, despite a schedule which prevents the development of physical dependence. This latter observation took on greater stgniticance when it became apparent that the neural systems involved in positive reward were quite distinct anatomically from the neural systems subserving classical opiuid withdrawal syndromes (9,10,14) (see also the chapter by Koub). If drug use is intetntpted, animals, like hutnans, will resume drug-taking long after there is any reasonable likelihuud that this behavior is primarily an attempt to alleviate withdrawal. Thus, it seemed to some researchers that it was unnecessary to postulate relief of withdrawal symptoms as the major motive responsible for either compulsive drug-taking itself or subsequent use that leads to relapse. Wise, a spokesman for the primacy ot positive reinforcements in producing cont- pulsive drug self-administration puts it this way: they are sufficient to do so in the absence of any wittxtrawal distress or ubwous soune of patn or dtscomfort. They are sutficrcnt to account tor the initial development uf drug taktng habits and the rapid re-addktiuu in detuxified pauenta-two phenomena that have always been troublesome fur dependence theory or other negative rctnfursement views .... (14) Wise argues that positive reinforcement and drug craving have as distinct a neural basis and are as biologically palpable as the traditionally more accepted biological basis for withdrawal syndromes and other negative effects; craving may be linked pnmanly to the memory of positive reinforcement, and these cravings, which may be evoked by drug-associated stimuli in the environment, persist long beyond the time associated with measurable withdrawal syndromes. While not dismissing en- tirely the role of withdrawal syndromes in generating compulsive drug-seeking and relapse, he stresses the practical and conceptual distinction between approaches that focus on negative reinforcement and others which attempt to deal with positive reinforcement. It is the emphasis on the tttetnory of positive reinforcement (in the form of eupho- ria) that distinguishes this view uf cnvtng from earlier views which pesstulated that craving is related to conditioned wtthdnwal symptoms evoked by emotions or envi- ronmental stimuli which became associatively linked to the unconditioned wuh- drawal syndrome dunng active drug use (13.15). Both of these tdeas about what drives drug use are distinct from the adapttve perspective which postulates that, ftx some uaen, drugs are used, prtmarily, neither to alleviate withdrawal ntx to induce I

I I I I t I I I I I I I I I I I 8 CURR£NT CONCEPTS OF ADDICTION positive euphona. but to alleviate dysphonc states (11,12). Nevertheless, the idea that cues become linked through learning to drug effects-posurve or negative-ts deeply embedded in the WHO conceptual model, and a large body of research has demonstrated that drug-trclatted'cues can elieit both craving and conditioned with- drawal phenotnettti (9,13.b5-~t9). In his ciaiter O'Brien reviews and presents new findiogs on the rok of karning in the genesis and perpetuation of drug dependence. WITHDRAWAL SYNDROMES STILL IMPORTANT-EVEN IF NO LONGER NECESSARY AND SUFFICIENT Despite the increaced importance now being assigned to positive reinforcement and t6e stimuli which evoke its memory, the WHO nwdel recogntzed the impor- tanx4f withdrawal states (as well as other aversive affective states), as possible motives for ctxttinued drug use. The regular recurrence of withdrawal states and theirraiief by further drug use produces both repeated reinfocremeru of drug-ttikutg behavior, and ample opportunity for environmental and internal stimuli to become linked to withdrawal through karning. Subsequently, sometimes long after there is any measurable withdrawal, nwods or environmental conditions may evoke compo- nents of the withdrawal syndrome and associated urges to use the drug again (10,13, l 5-19). Furthetmore, for many people, some form of negative r+einforce- ment appears to be the dominant mechanism underlying the development and per- sistence of dependence. Included here are nwst peopk who become dependent on benzodiazepines while being treated for anxiety syndromes. Many people who take benzodiazepines for a long period of time find it difficult to stop. In some cases, the difficulty appears to he due to a reappearance of the original symptoms; in others, new distressing symptoms indicative of drug withdrawal emerge (20,21). Ben- zodiazepittes can suppress both kinds of aversive states. In either case the drug is acting as a negative reinforcer in perpetuating drug-taking behavior. While ben- zodiazepines can induce "euphocia" in non-dependent, non-anxious individuals, such instances are infrequent relative to the number of individuals who experietke only relief of anxtety. Several studies report that benzodiazepines are not reliable positive reinforcers in non-alcolrolics, but can induce euphoria in alcoholics or in people with histories of drug abuse (21,22). One way to gauge the role of negative reinforcement (withdrawal symptoms or other aversive affective states) in tfie perpetuation of drug use or relapse is to look at what happens when drugs are used to alter these states. There is now good evideacx that, when psychological interventiotu are held constant, the use of nicotine gum or other forms of non-inhaled nicotine significantly increases the likelihood that ciga- rette smokers who wish to quit will be successful in doing so (23,24). Such non- inhaled forms of nicotine do not induce positive reinforcement compuabk to in- haled tobacco snwke, but do alleviate elements of the tobacco withdrawal syndrome (23-25). A reasonable inference is that nicotine withdrawal, subtle though it may be, is important in continued smoking and in relapse (see the chapter by Jones). I

I I I I I I I I I I I I I I I I CURRENT CONCEPTS OFA!)UICTION 9 The effects o( treating heroin addicts with maintenance doses of oral methadone also supports the cnucal role of opioid withdrawal symptoms tor of aversrve affec- tive states-or both) in the perpetuation of heroin use and in relapse after wtth- drawal. The withdrawal syndrome associated with typical mu opioids appears to have both a more generally recognized acute phase, and a more subtle protracted phase (26,27). In her chapter Kreek discusses the use ot methadone matntenance and its unplicauons for urxkrstanding opioid dependence. Yet the,re remain puzzling inconsistencies that call into question the importance of wtthdatwal relief in generating the patterns ot drug use we currently label "de- pendence." In addition to mu optotd agonists, alcohol, barbiturates, ben- zodiazepines. and nicotine, other categunes of drugs which are not typically self- administered for non-medical purposes also induce biological changes that result in withdrawal syndromes. Included here are certain tncyclic antidepressants (im- iptamine. amunp(yiine), anticholinergics, and kappa opioid agonists (28). The withdrawal syndromes associated with these drugs have little in common other than that they can be descnbed as unleatned responses to the withdrawal of chronically administered drugs. For the most pan, these drugs are not widely abused. Also, some of the withdrawal syndromes which produce the most subtle physiological signs, such as the nicotine withdrawal syndrome (24,25), seem to have a robust capacity to motivate continued smoking despite clear links between tobacco use and a vartety of senous diseases. In contrast, the nsk of experiencing a gettertilistd seizure cannot ensure that an individual will reliably take phenobarbital to proveat it. Humans given opioids which are pnmanly kappa agonists, such as nabtphine, exhibit a number of symptoms when the drug is discontinued. 7lmse may include changes in respiratory rate, runny twae, and insomnia, which are also seen during withdrawal of mu agonists, such as morphine. Yet, there is little or no drug craving associated with this withdrawal (29). Also, animals will not self-administer kappa agonists (30). The inference to be drawn from these examples. and from material to be presented shortly, is that there is little correlation between the visibility or physi- ological senousness of withdrawal signs and their motivational force. The assump- tion is that some syndromes are mure aversrve or less tolerable than others. But at present we cannot predict a priori how aversive a syndrome will be. It is necessary to determine expenmentally, using a vanety of research approaches, how the with- drawal phenomena influence drug-taking behavior. When the role of the withdrawal syndrome in the genesis of drug-taktng behavior and relapse was reviewed by Cap- pell and LeBlanc (31) they concluded that expenmental evidence for the importance of opiutd withdrawal in drug dependence was far firmer than that for ethanol, con- ventional wisdom notwithstanding. Edwards (32) has re-examined the evidence for the importance of alcohol withdrawal in perpetuating alcohol use. He ccncludes ttua while thett is littk or no evidence for the importance of physical dependence on alcohol in animal self-administration models, we should ttot discard "what our trem- ukxts patients have to tell us." Alcohol withdrawal symptoms may be neither neces- sary nor sufficient to perpetuate the consumption of ,kuhol, but they are probably impuxtant and powertul intluences un the patterning of drinking. I

I I I I I I I I I I I I I I I0 CURRENT CONCEPTS OF ADD%CTION It is worth repeating that, in the WHO model, physical dependence (i.e., a with- drawal syndrome) is not the centnl and essential factor in the development of de- pendence. It is also postulated, partly on the basis of ehe rapidity with which depen- detxx may be roinstated, that sotne elements of dependence may persist long affter evidence of physical dependence is no longer detectable. Recognizing the confusion which anses fran the use of a tum such as physical dependence to ttfer to one factor in the genesis of the mon: complex behavioral syndrome, drug dependence, the WHO Metnorvndum suggests that thene might be advantages to replacing pAysi- cd dependence with a new term, such as eeuroodaputtion. OTHER INFLUENCES ON DRUG USING BEHAVIOR Drug and alcohol use and other tnental disotders are frequently associated. Figure I appears to eatphasize the way in which alleviation of aversive mood states might roinfocce drug using behavior. However, the WHO Memorandum itself discusses the complex aad multiple ways in which the phenomena of drug use and mental iliness can interact, with drug use sornetimes irutiating or aggravapng dte course of othes types of psychiatric disorders .nd cettain psychiauic disorders increasing the likelihood of initial drug use, progression to dependence, or relapse following with- drawal. Epidemiological data suggest that pce-existing affective, anxiety, and other disorders increase the probability of developing drug abuse or dependeace (33). Kandel (see chapter) presents data showing that even in community surveys which do not have the same biases as studies of drug users coming to treatmau, drug- or aicohol-dependent individuals have higher rates of other mental disorders. Depres- sion increases the likelihood of becwming a smoker and contiauing to smoke (34). Hesselbrock et al. (see chapter) review the interactions between personality disor- dets (especially antisocial personality) and developrnent and clinical cause of drug and alcohol dependence. Other influences on the disposition to use drugs ato those social factors which determine the availability and costs of a given drug, the attitudes of the larger sociay toward the use of that drug, and att'studes and beltaviocs of an individual's irrur>ediau peer group. The schematic of the conceptual model (Fig. 1) also depicts the influence of more remote antecedents, both social and individual, that may have influenced attitudes toward drug use, such as parental drug use and peer behavtor, early drug experiencts, genetics, and developmental events. Obviously, social and individual factors usteract with each other, as do the eate remote and immediate antecedents of the disposition to use drugs. Schuckit (see chapter) reviews the ge- netics of akohoiism and pcesetus data on the effects of family history of alcoholism on the biology and psychology of offspring. Hesselbrock and coworkers (see chap- tu) report new data showing that family history and antisocial personality independ- endy and additively influence the course of alcohoiism. ~ ~' ZZ ~ ~ GL7 ~ Q0 O C,C I