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~ ~ GOODMAN and GJLMANs 1 I I I I I The Pharmacological Basis of Therapeutics EIGHTH EDITION I I I I I I I I 14 ~ PERGAMON PRESS ,~ Member oJtita,zzuell AIacmillan Pergamon Publishing Corporation ~ New York • Oxford • Beijing • Frankfurt • Sao Paulo • Sydne,v • Tok~yo • Toronto W tD Ca 00 . ~ ~ I

I i I I I I I I I I I I I I I I I I CHAPTER 22 DRUG ADDICTION AND DRUG ABUSE Jerome H. Ju.f.fe As far back as recorded history, every society has used drugs that produce effects on mood, thought, and feeling. Moreover, there were always a few individuals who digressed from custom with respect to the time, the amount, and the situation in which these drugs were to be used. Thus, both the nonmedical use of drugs and the problem of drug abuse are as old as civiliza- tion itself. Problems of Terminology. Drug abuse refers to the use, usually by self-administra- tion, of any drug in a manner that deviates from the approved medical or social pat- terns within a given culture. The term con- veys the notion of social disapproval, and it is not necessarily descriptive of any partic- ular pattern of drug use or its potential ad- verse consequences. Since this definition is largely a social one, it is not surprising that for any particular drug there is a great variation in what is considered abuse, not only from culture to culture but also from time to time and from one situation to another within the same culture. For example, in Western society, chronic intoxication with alcohol is considered drug abuse, yet on certain occasions gross intoxica- tion with alcohol is not. The use of medically pre- scribed opioid analgesics for the relief of pain is quite proper: however, the self-administration of the same drugs, in the same dosages, for relief of depression or tension or to induce euphoria is con- sidered flagrant abuse. Government agencies refer to any use of an illicit substance as drug abuse, regardless of the conse- quences or ubiquity of such use. In this context, even the occasional use of opioids or marihuana is considered drug abuse, but that of alcohol or to- bacco is not. In contrast, the occasional use of il- licit drugs does not constitute evidence of a psychi- atric disorder unless it leads to adverse effects for the individual (see American Psychiatric Associa- tion. 1987). In this context, patterns of drug use that do lead to adverse effects may be referred to as drug abuse, even though they do not meet estab- lished criteria for drug dependence (see below). Nonmedical drug use is a term that en- compasses behaviors ranging from the oc- casional use of alcohol to compulsive use opioids, and includes behaviors that trtaya may not be associated with adverse effects . Nonmedical drug use may consist in eXp~ mental use of a drug on one or a few oc4, sions, because of curiosity about its eff~ or to conform to the expectations of p~ groups. It may also involve casual or ~~r~ reational" use of modest amounts of a d~ for its pleasurable effects, or circumstan~ use, in which certain drug effects an sought because they are helpful in pani4 lar circumstances, as when students p truck drivers take amphetamines to allevt, ate fatigue. These various forms of notk medical use may then lead to more inten; sive patterns of use in terms of frequencya amount and, in some cases, to patterns ~ dependence or compulsive drug use. Drug Dependence. One of the hazards in the use of drugs to alter mood and feeling u that some individuals eventually develop a dependence on the drug. They continue to take it in the absence of medical indica, tions, often despite adverse social and med- ical consequences, and they behave as if the effects of the drugs are needed for con. tinued well-being. The intensity of this "need" or dependence may vary from a mild desire to a "craving" or "compui. sion" to use the drug, and, when the avail. ability of the drug is uncertain, individuaLc may exhibit a preoccupation with its pro. curement. Drug dependence can be defined as a syndrome in which the use of a drug is given a much hiYher priority than other behaviors that once had higher value. The dependence syndrome is not absolute, but exists in degrees, and its intensity is gauged by the behaviors that are associated with the useofthe drug. No sharp line separates drug dependeaa from nondependent but recurrent drug use. In its extreme form. drug dependence is associated with compulsive drug-using behavior, and it exhibiuthe characteristics of a chronic relapsing disorder (ser Edwards et al.. 1981). 522 I

I I I I I I I I I I I I I I I I GENESIS oF DRUG USE AND DEPENDENCE 523 , pependence on a drug per Se is not necessarily cause for concern. If the substance used has low toxicitY and is relatively inexpensive (e.g., caf- feine), a drug-using behavior may meet the criteria for dependence but may not constitute a significant ntedical or social problem. More commonly, how- ever, drug dependence is detrimental both to the user and to society. However, in weighing detri- mental effects, one must consider both the pattern of use by a given individual and the available alter- natives. For example, many would take the view that some individuals should be permitted to take opioids under appropriate supervision if the alter- native is severe psychiatric impairment or uncon- trolled use of opioids or other destructive psycho- active agents. Drug dependence is commonly, but not neces- sarilY, associated with the development of toler- ance and physical dependence. Tolerance has de- veloped when, after repeated administration, a given dose of a drug produces a decreased effect or when increasingly larger doses must be taken to obtain the effects observed with the original dose. Physical dependence refers to an altered physiolog- ical state (neuroadaptation) produced by the re- peated administration of a drug, which necessitates the continued administration of the drug to prevent the appearance of a withdrawal or abstinence syn- drome that is characteristic for the particular drug. The theoretical bases for the phenomena of toler- tnce and physical dependence are discussed below. The existence of drug dependence has re- cently been defined based on the presence of three or more of the following criteria (see American PsYchiatric Association, 1987): (1) taking the sub- stance more often or in larger amounts than in- tended: (2) unsuccessfuI.efforts to terminate or re- duce drug use; (3) large amounts of time spent W-quiring or using the drug or recovering from its egects; (4) frequent intoxication or withdrawal sYmDtoms; (S) abandonment of social or occupa- Ooaal activities because of drug use; (6) continued tse despite adverse psychological or physical ef- kets; (7) marked toletance; and (8) frequent use of dk drug to relieve withdrawal symptoms. t ~+ =' Addiction. The term addiction, like the 1erm abuse, has been used in so many ways tliat it can no longer, be employed without lhrther qualification or elaboration. How- "ef, it is not likely that the term will be ped from the language. In this chapter, 0 v term addiction is used to connote a se- degree of drug dependence that is an me on. a continuum of involvement drug use. The term conveys a quanti- t rather than a qualitative sense of the to which drug use pervades the total h`nty of the user and of the range of tances in which drug use controls r's behavior. Anyone who is ad- a aea would be considered drug dependent by the criteria described above. However, the term addiction cannot be used inter- changeably with physical dependence as that term is used here. It is possible to be physically dependent on drugs without being addicted and, in some special circum- stances, to be addicted without being physi- cally dependent (see below). The use of the terms drug dependence, to denote a behavioral syndrome, and physi- cal dependence, to refer to biological changes that underlie withdrawal syn- dromes, causes confusion. To reduce some of this confusion, the term neuroadaptation has been proposed as a substitute for physi- cal dependence (see Edwards et al., 1981). GENESIS OF DRUG USE AND DEPENDENCE Whether the use of a drug is socially ac- ceptable or subject to extreme disapproval, many factors determine who will experi- ment with the drug and experience its ef- fects; other factors influence who will con- tinue to use it casually and who will progress from casual to intensive or com- pulsive use. Experimentation is largely a matter of availability, curiosity, the attitude and drug-using behavior of one's friends, the social acceptability of a given form of drug use, the risks believed to be associated with experimental use, and the tendency of the individual to seek out novel situations and respect social norms. The emphasis here will be on the interactions of man and drug, and on those aspects of the interaction that are relevant to clinical situations and to the development of dependence. Drugs as Reinforcers. Man's tendency to take drugs is shared with other mammals. Laboratory animals can learn to self-admin- ister most of the drugs commonly used for nonmedical purposes, including opioids, barbiturates, ethanol, anesthetic gases, local anesthetics, volatile solvents, central nervous system (ChFS). stimulants, phen- cyclidine, nicotine, and caffeine. Whether an animal will self-administer a drug de- pends on a number of factors, including-the properties of the drug itself, the route of administration, the size of . the individual

I I I I I I I I 1 I I 1 I I ~ I 524 DRUG ADDICTION AND DRUG ABUSE [Chap. 22) dose. the amount of work required to ob- tain a dose and the time between the work and the drug administration (schedule of reinforcement), the presence of other drugs, and the kinds of drugs the animal has been given previously (see Johanson and Schuster. 1981). With certain notable ex- ceptions, animals given continuous access show patterns of self-administration that are often strikingly similar to those exhib- ited by human users of the same drug. Such observations suggest that preexisting psy- chopathology is not a requisite for initial or even continued drug taking, and that drugs themselves are powerful reinforcers, even in the absence of physical dependence. Drugs are not equally powerful as reinforcers in animals. Nicotine is self-administered under a nar- rower range of conditions than are opioids or co- caine: caffeine is a relatively weak reinforcer, and it is often quite difficult to train animals to self- administer ethanol. To date, there is no reliable ani- mal model for the self-administration of can- nabinoids. Some drugs (e.g., chlorpromazine) are never self-administered; they appear instead to have aversive properties, and animals learn to avoid behaviors that result in small injections of such agents. On the other hand, animals will press a lever more than four thousand times to get a sin- gle injection of cocaine, and when given free ac- cess. they generally self-administer high daily doses that may produce severe toxic effects and induce self-mutilating behavior. With stimulants such as amphetamine and cocaine, periods of self- imposed abstinence alternate with periods of drug administration: generally the animals die of toxic effects and inanition after a period of several weeks of continuous use. If saline solution is substituted for cocaine or amphetamine, there is a burst of rapid lever pressing for several hours, then abruptly all responding ceases and is not resumed. However, a small "priming" dose of a reinforcing drug reinitiates the drug-taking behavior. Animals self-administering morphine gradually raise the daily dose over a period of weeks, then self-admin- ister the drug at a steady rate that avoids both gross toxicity and withdrawal symptoms. When saline solution is substituted for morphine, however, the animal continues to press the lever (except during the peak of withdrawal) and does so at a slow but steady rate over a period of weeks (see Johanson and Schuster. 1981). Drug-using behavior and reinforcement can be- come linked with environmental signals (e.g., a light or tone), such that the signals function as sec- ondary reinforcers. Drug-seeking behavior may then persist for long periods with only occasional reinforcement by the drug itself (see Young and Herling, 1986). Mechanisms of Primary Reinforcement. The reinforcing effects of a number of psychoactive drugs involve dopaminergic systems that originate in the ventral tegmental area (VTA) of the brain and make connections with the nucleus accumbens and either directly or indirectly with the limbic cor- tex, ventral pallidum, and frontal cortex. Activa. tion of this mesocorticolimbic system by electrical stimulation, a variety of drugs, or natural reinforc- ers (e.g., food) results in release of dopamine in the nucleus accumbens. This release is associated with rewarding or reinforcing events (Hernandez and Hoebel, 1988: Koob and Bloom. 1988; Wise, 1988). No category of drugs acts exclusively on the mesocorticolimbic system, and different classes of pharmacological agents activate the dopaminergic system by different mechanisms. For example. µ. and S-agonist opioids inhibit neurons that tonically inhibit dopaminergic neurons in the VTA, while cocaine causes an increase in the synaptic concen- tration of dopamine by inhibition of its reuptake. Amphetamine has similar effects on reuptake of dopamine, and it also releases the neurotransmitter from intracellular stores. Drugs that are reinforcing also decrease the intensity of electrical stimulation in the VTA or medial forebrain bundle needed to produce reinforcing effects. Dopaminergic antago- nists such as pimozide or opioid antagonists raise the threshold for electrical self-stimulation. Tolerance and Physical Dependence. In addition to the primary reinforcing effects, other factors come into play during long- term drug use that profoundly affect the pattern of use and the likelihood that the drug use will be continued. Among these factors are the capacities of some sub- stances to produce tolerance and/or physi- cal dependence. These phenomena, as pre- viously defined, are often assumed to be inextricably linked to each other and to the problem of compulsive drug use. Neither of these assumptions is valid. Tolerance and physical dependence develop not only with opioids, ethanol, and hypnotics but also after long-term administration of a wide variety of drugs that are not self-adminis- tered by animals or used compulsively by man. Such drugs include anticholinergics; dopaminergic antagonists, and imipramine. Rebound withdrawal effects may also be seen after abrupt discontinuation of f3-adrenergic antagonists, Ca'-`-channel blockers, or a:-adrenergic agonists (see Raftery, 1984). Nor.does physical depend- ence invariably occur in every situation where tolerance develops. Tolerance is a general phenomenon observed with a host of substances, and many independent mechanisms are involved (see Chapters 1 and 2). T It is possibl quired pharm and pharmac, results from ci erties of the a duced concen drug action. T increased rate ance has relati of action and c threefold dec namic toleran within affectec reduced in the the drug. Whe ated. toleranca to a greater dea behavioral "c( capacity to ea impaired) than daily on a mo the ataxic effec before the test ment of tolerar ted. Similar re ditions and the observed with mines. (See Tabakoff and Tolerance not develop opioid drugs ance to sorr others are r to opioids is duration anc algesic, eup CNS-depres marked ele, dose. AlthotL opioids may more rapidl~ to adaptatior to the drug's Although t sarily affect t it can affect the amount produce a gi, use of incre: hance the ri other proble obtained illic Tolerance tc markable rapi( attain a dosag within 10 day administration 5

I (Chap. 221 i stems that or ginate (VTA) of the brain ~ nucleus accumbens with the limbic cor- )ntal cortex. Activa- system by electrical or natural reinforc- of of dopamine in the .se is associated with I ts (Hernandez and 1988; Wise, 1988). exclusively on the i different classes of te the dopaminergic ISs. For example, µ- urons that tonically in the VTA. while he synaptic concen- ion of its reuptake. ts on reuptake of ie neurotransmitter that are reinforcing 1 bundle needed to electrical stimulation paminergic antago- id antagonists raise :-stimuiation. IDependence. In nforcing effects, )lay during long- tndly affect the elihood that the d. Among these ~ of some sub- e and/or physi- nomena, as pre- i assumed to be other and to the ~; use. Neither of Tolerance and op not only with I notics but also tion of a wide iot self-adminis- •ompulsively by nticholinergics; ftnd imipramine. ects may also Iontinuation of Ca'-+-channel i agonists (see ,hysical depend- every situation Tolerance is a ved with a host y independent isee Chapters 1 I GENESIS OF DRUG USE AND DEPENDENCE It is possible to distinguish two varieties of ac- quired pharmacological tolerance: dispositional and pharmacodynamic. Dispositional tolerance results from changes in the pharmacokinetic prop- erties of the agent in the organism, such that re- duced concentrations are present at the sites of drug action. The most common mechanism is an increased rate of metabolism. Dispositional toler- ance has relatively little effect on the peak intensity of action and does not usually result in more than a threefold decrease in sensitivity. Pharmacody- namic tolerance results from adaptive changes within affected systems, such that the response is reduced in the presence of a given concentration of the drug. When behavioral phenomena are evalu- ated, tolerance usually develops more rapidly and to a greater degree when the effect of the drug has a behavioral "cost" to the organism (i.e., when the capacity to earn a reward or avoid punishment is impaired) than when it does not. Thus. rats tested daily on a moving belt develop more tolerance to the ataxic effects of ethanol when it is administered before the test than afterward: the slowest develop- ment of tolerance occurs when daily testing is omit- ted. Similar relationships between behavioral con- ditions and the development of tolerance have been observed with opioids. marihuana. and ampheta- mines. (See Goudie and Demellweek, 1986: Tabakoff and Hoffman. 1987.) Tolerance to Opioids. Tolerance does not develop uniformly to all the actions of opioid drugs. There may be complete toler- ance to some actions, while responses to others are relatively unaltered. Tolerance to opioids is characterized by a shortened duration and decreased intensity of the an- algesic, euphorigenic, sedative, and other CNS-depressant effects as well as by a marked elevation in the average lethal dose. Although animals that are tolerant to opioids may metabolize them somewhat more rapidly, most of the tolerance is due to adaptation of cells in the nervous system to the drug's action. Although tolerance itself does not neces- sarily affect the likelihood of continued use, it can affect patterns of use by increasing the amount of drug that must be taken to produce a given effect (e.g., euphoria). The use of increased amounts may in turn en- hance the risk of toxic effects or produce other problems if the drug is expensive or obtained illicitly. Tolerance to opioid drugs can develop with re- markable rapidity. Former morphine addicts can attain a dosage of 500 mg of morphine per day within 10 days. However, even with prolonged administration of opioids to experimental animals, 525 there appears to be little tolerance to the facilita- tory effect of such drugs on electrical self-stimula- tion of the brain or to their capacity to serve as discriminative stimuli (see Kornetsky et al., 1979). At some doses, the degree of tolerance to opioids depends on the environmental conditions under which they are given (see Goudie and Demellweek. 1986). Certain forms of long-lasting residual toler- ance are also apparent: animals and human sub- jects previously dependent on opioids become physically dependent more rapidly on reexposure. Tolerance to Ethanol, Barbiturates, and Related Hypnotics. Animals made tolerant to barbiturates or ethanol show signifi- cantly less sedation and ataxia than do non- tolerant animals at the same blood concen- trations. However, as the blood concentrations are increased, there is pro- gressively less difference between tolerant and nontolerant animals in the degree of CNS depression. In contrast to the toler- ance seen with opioids, animals tolerant to ethanol or barbiturates show only modest elevation of the lethal blood concentration. If the use of the CNS depressant has pro- duced only ataxia and has been insufficient to depress respiration to some degree, there is little or no tolerance to the respiratory- depressant and lethal effects of the drug. It appears that only those systems that have been challenged or altered by the agent dis- play tolerance to its effects (Okamoto et al., 1978). In the case of barbiturates such as pento- barbital, ethanol. and a number of nonbar- biturate hypnotics (glutethimide, mepro- bamate, etc.), a more rapid enzymatic degradation of the drug can also be demon- strated in tolerant animals. Thus, in the same animal, both pharmacodynamic and dispositional tolerance contribute to the decreased duration and intensity of the re- sponse to a given dose of drug. With these groups of drugs. as with the opioids. tolerance does not directly increase the probability of continued or compulsive use. However, toler- ance to toxic effects may not develop in parallel with tolerance to CNS depression and, in the case of ethanol particularly, the consumption of more drug in order to obtain CNS effects may increase the likelihood of direct damage to organs such as the brain and liver. Furthermore, the shortened duration of action may increase the frequency of drug taking. thereby increasing the number of times that drug-taking behavior will be reinforced. Some aspects of tolerance to general CNS de- 0

I I I ~ I I I 1 I I I I I I I I I 526 DRUG ADDICTION AND DRUG ABUSE pressants develop with surprising rapidity. Thus, in man, when the blood concentration is falling after administration of a large dose of ethanol, the signs and symptoms of intoxication disappear at a con- centration that was associated with gross intoxica- tion when the blood level was rising. The degree of such acute CNS tolerance (as measured by the blood concentration of the drug when signs of ataxia disappear) seems directly related to the depth of the CNS depression that was produced by the drug. Acute tolerance also appears to develop with some benzodiazepines (Rosenberg and Chiu, 1985). It is not clear whether the mechanisms un- derlying acute tolerance are related to those in- volved in the tolerance that develops over longer periods. Tolerance to ethanol and related general CNS depressants has been reviewed by Smith (1977) and Tabakoff and Hoffman (1987). Tolerance to CNS sympathomimetics, nicotine, cannabi- noids, and psychedelics is also discussed under clinical characteristics of their abuse. Physical Dependence. Physical depend- ence has been studied after long-term ad- ministration of opioids, CNS depressants (ethanol, barbiturates, related hypnotics, and benzodiazepines), amphetamines, co- caine, cannabinoids, phencyclidine, and nicotine. The withdrawal symptoms associ- ated with many of these classes of agents are generally characterized by rebound ef- fects in those physiological systems that were initially modified by the drug. For example, CNS depressants elevate the sei- zure threshold, but spontaneous seizures may be seen during their withdrawal. Am- phetamines and cocaine alleviate fatigue, suppress appetite, and elevate mood; with- drawal from these drugs is characterized by lack of energy, hyperphagia, and depres- sion. However, it is not certain whether all the complex patterns of signs and symp- toms seen during withdrawal from µ- agonist opioids or general depressants should be considered rebound effects, nor whether such a generalization is applicable to the syndromes observed after abrupt withdrawal of drugs such as nicotine, caf- feine, clonidine, or opioids that do not act at µ receptors. The time required to.produce physical dependence on any drug depends on a num- ber of factors, but the most important for many drugs seem to be the degree to which the drug alters CNS function and the conti- nuity of this alteration. However, whether a withdrawal syndrome is clinically observ- (Chap. 221 able depends on the criteria for withdrawal symptoms, the sensitivity of methods used to detect withdrawal, and the rate at which the drug is removed from its site of action. Patients who have received therapeutic doses of morphine several times a day for I to 2 weeks will have only mild symptoms that may not be recognized as withdrawal symptomatology when the drug is stopped; symptoms are even less pronounced when the opioid is one that is slowly eliminated (such as levorphanol or methadone). How- ever, if the drug is not simply discontinued but an opioid antagonist (naloxone) is used to induce withdrawal, it is possible to dem- onstrate withdrawal symptoms in man 6 to 8 hours after a single therapeutic dose of morphine, indicating the presence of an otherwise-subclinical level of physical de- pendence (Bickel et al., 1988; Heishman et al., 1989). In short, the phenomenon of physical dependence on opioids is initiated by the first dose, and this rapid develop- ment ;has important clinical implications (see below). The time required to produce physical dependence with general CNS depressants or benzodiazepines is likewise short; when rapidly metabolized drugs are used, the ear- liest signs of rebound excitability can be detected after surprisingly brief periods of CNS depression. A single large dose of eth- anol produces an elevation of the threshold for chemically induced seizures that is fol- lowed by a period of subnormal threshold. After 3 days of continuous exposure to eth- anol, mice develop marked physical de- pendence, with spontaneous seizures upon abrupt withdrawal. In cats, a withdrawal syndrome can be precipitated with a spe- cific benzodiazepine antagonist 24 hours after administration of flurazepam (Rosen- berg and Chiu, 1985). In man, it may re- quire weeks of mild intoxication with short- acting barbiturates to produce clinically sig- nificant physical dependence, but some patients who are kept deeply intoxicated (semicomatose) for 16 to 20 hours per daY, for 10 to 12 days, become so physicallY dependent that they develop seizures and delirium on abrupt withdrawal. If rebound changes in the EEG or insomnia are used ass criteria, only 1 or 2 weeks of ordinary dos= age at night is enough to induce low levels I

I I I I I I I I I I I I I I I I I GENESIS OF DRUG USE AND DEPENDENCE of phYsical dependence on CNS depres- sants and benzodiazepines (see Woods et al., 1987). The early onset of the adaptational pro- cesses that eventually produce grossly ob- servable withdrawal symptoms has obvious implications not only for the problem of deciding just when,physical dependence is present but also fos the problem of deter- mining the causes of drug dependence or compulsive drug use. It is quite conceivable that individuals who use short-acting drugs to induce euphoria or reduce tensions can perceive a relative dysphoria or an exacer- bation of these same tensions (rebound ef- fects) as the drug effects wane. Such in- creases in unpleasant feelings might then contribute to the motivation to repeat the use of the drug, and the alleviation of with- drawal phenomena might increase the ef- fectiveness of the drug as a reinforcer of drug-using behavior. Similar subtle post- drug-use effects are also seen with amphet- amines, cocaine, short-acting benzodiaze- pines, and possibly with nicotine. The relationship of tolerance and physical de- pendence to drug-seeking behavior and compulsive drug use is complex and differs with drug catego- ries. For example, it is difficult to show in animal models that physical dependence on ethanol in- creases ethanol intake (see Cappell and LeBlanc, 1981; Winger, 1988). The notion that physical de- pendenceincreases drug-seeking behavior and the reinforcing effects of the drug is best established for the opioids, but even with this group of drugs other factors appear to be more potent determi- nants of behavior. For example, although some degree of physical dependence develops in medical Patients who receive opioids regularly for more than a few days, the overwhelming majority of such Patients do not exhibit drug-seeking behavior and do not become compulsive users. Even those who administer such drusss to themselves for brief peri- ods discontinue the drug when the medical condi- tion is relieved. A large proportion of the young men who served in the United States Army in Viet- oatn used heroin, and; about half of this group be- canZ physically dependent. Nevertheless, a sub- "anUa1 percentage simply stopped their use of heroin before their rettun to the United States, and ?any did so without benefit of any special treat- ctent (see Robins; 1974). Similarly, many patients Who develop some degree of physical dependence mthe course of treatment with benzodiazepines are ." to tolerate low-level withdrawal symptoms .00n discontinuation, whilee others seem less able to doso• Wide individual differences in the capac- to'tolerate withdrawal symptoms are also seen cigarette smokers. The basis for this vari- 527 ability is still not clear. Thus, although some com- pulsive users attribute their drug problems entirely to "getting hooked" (either iatrogenically or in the course of using drugs illicitly), physical depend- ence is currently viewed not so much as a direct cause of drug dependence but as one of several fac- tors that contribute to its development and to the tendency to relapse after withdrawal (see below). Degree of Physical Dependence and Locus of Changes. Although it is possible to demonstrate changes in the biochemical and physiological prop- erties of tissues (e.g., brain, intestine) in dependent animals (see Redmond and Krystal, 1984; Tabakoff and Hoffman, 1987), the degree of physical depend- ence in the whole organism is still measured by the severity of the withdrawal syndrome produced ei- ther by abrupt withdrawal or by use of drug antago- nists. It is now quite clear that changes occur through- out the entire neuraxis during the development of physical dependence on CNS depressants, benzo- diazepines, and, probably, ethanol (see Smith, 1977; Rosenberg and Okamoto, 1978). In view of the distribution and widespread effects of endoge- nous opioid-like peptides (see Chapters 12 and 21), it is not surprising that adaptive changes to the administration of exogenous opioids and with- drawal phenomena can be demonstrated through- out the autonomic and central nervous systems. Withdrawal hyperexcitability is observed in decer- ebrate animals, in the spinal cord of man, and in animals after cord transection. With local adminis- tration, the spinal cord or other structures can be made physically dependent on opioids with mini- mal involvement of the rest of the CNS (see Yaksh and Noueihed, 1985). Neural structures that sub- serve the expression of the classical manifestations of physical dependence on opioids appear to be dis- tinct from those that are critical for the reinforcing effects of these agents (see Koob and Bloom, 1988; Wise, 1988). Cross-Dependence. The ability of one drug to suppress the manifestations of physical dependence produced by another and to maintain the physically dependent state is referred to as cross-dependence. Cross-dependence may be partial or com- plete, symmetrical or asymmetrical. Most sedative-hypnotics show a reason- able degree of cross-dependence with each other and with ethanol and the benzodiaze- pines. There is also some cross-dependence between barbiturates and volatile anesthet- ics. Although the mechanism of action of these agents differs, it is thought that they all share some capacity to influence the Cl- channel that is regulated by gamma-amino- butyric acid (see Nutt et a1.,.1989; see also Chapter 17). ;, Cross-tolerance and cross-dependence I

I I I I I I I I I I I I I I ~ I I I 528 DRUG ADDICTION AND DRUG ABUSE among opioids deveiop only between those agents that act at the same type of opioid receptor (see Chapter 21). Thus, physical dependence induced by a specific 8 agonist may be adequately suppressed by a less specific agent such as morphine that acts at both µ and S receptors, but that induced by morphine is only partially suppressed by a specific S agonist. This is an example of asymmetrical cross-dependence. If a long-acting drug such as methadone is substituted over several days for mor- phine, abrupt discontinuation produces a withdrawal syndrome characteristic of the long-acting drug rather than that of mor- phine. This aspect of cross-dependence has important clinical implications, since the withdrawal symptoms that occur with drugs with longer half-lives (methadone, phenobarbital, diazepam) are generally less severe but more protracted. This phenome- non is the basis for the substitution treat- ment of physical dependence for both opi- oids and CNS depressants. Mechanisms of Physical Dependence. Most theories postulate some form of CNS counteradapta- tion to the agonistic actions of the drugs. In view of knowledge of negative-feedback control of the activities of neurons by recurrent neural pathways and of the activities of regulatory molecules (such as receptors) and important metabolic pathways, it would be amazing if such counteradaptation did not occur. In the case of opioids and CNS depressants, long-term administration produces a"latent coun- teradaptation" in neural systems affected by the drugs that becomes manifest in the form of rebound or overshoot phenomena when the drugs are stopped or when an antagonist is administered. The underactivity of neural systems that often follows discontinuation of cocaine or amphetamine can also be viewed as a manifestation of latent counter- adaptation. A number of mechanisms have been proposed to explain these changes, some of which help to account for the observation that physical dependence is generally accompanied by tolerance, and that the two phenomena develop and decay at about the same rate. However, there is growing evidence that for some drugs, notably ethanol, it is possible to distinguish the mechanisms responsible for tolerance from those responsible for physical dependence (see below). For any given drug, it is likely that a complete explanation of physical de- pendence will require a description of the adaptive changes induced in cells that express specific re- ceptors for the drug and thus are directly affected (within-system adaptation), as well as those in- duced in other neural systems that are indirectly affected by the drug (between-system adaptation) (see Koob and Bloom, 1988). (ChaF The mechanisms responsible for opioid-inc physical dependence are among the most oughly studied. Although an increase in the nu of opioid receptors follows the long-term adt tration of antagonists, the continuous admin tion of opioid agonists does not change the nu or affinity of such receptors in the CNS (see et al., 1984; Morris et al., 1988). However, . tive changes in the second messenger system are altered by stimulation of opioid receptor be detected. For example, in some brain re (such as the locus ceruleus) the effects of µ opioids include inhibition of adenylyl cyclas action mediated by the inhibitory guanine nt tide-binding regulatory protein, G;; this eff shared with aZ-adrenergic agonists. The long administration of morphine causes a compens increase in adenylyl cyclase activity, and exce production of cyclic AMP may be partially re sible for the rebound excitability of neurons locus ceruleus that typically occuts during c withdrawal. Moreover; the common intrace mechanism helps to explain the utility of clor and other a2-adrenergic agonists in supprc some elements of the opioid withdrawal sync (see below). However, changes in the activ adenylyl cyclase in the locus ceruleus do n< velop as rapidly as do some manifestations of ical dependence, and failure to find similar ch in other regions of the CNS indicates that mechanisms must also be operative (see D et al., 1988). These mechanisms may in changes in the linkage of opioid recepto other effector systems, including K' cha (Aghajanian and Wang, 1987; Christie et al., I In addition, long-term administration of mor decreases the synthesis of proenkephalin i striatum, and some aspects of opioid withd may reflect a lag in the return of enkephalir centrations to normal (Uhl et al., 1988). Addi discussion of the mechanisms involved in tt velopment of dependence, tolerance, and drawal syndromes can be found in Redmon Krystal (1984), Tabakoff and Hoffman ( Koob and Bloom (1988), and Nutt and colle (1989). Learning, Conditioning, and Rels Within the framework of learning th( drug use, whether casual or compul can be viewed as behavior that is t tained by its consequences; conseque that strengthen a behavior pattern are forcers. Drugs may reinforce the ant( ent drug-taking behavior by inducing surable effects (positive reinforcemen by terminating some aversive or unplv situation (negative reinforcement), as i a drug alleviates pain or anxiety. Som pects -of reinforcement that are linke more remote consequences are not e ~ ; 20463998'70.

I I I I I I I I I I I I I I I I I I GENESIS OF DRUG USE AND DEPENDENCE 529 categorized. This is the case when control of weight is a stated motive for continued use of nicotine or other drugs. Secondary or social reinforcement entirely indepen- dent of pharmacological effects may also play a role, as is the case when drug use results in special status, membership in a desired group, or the approval of friends. Sometimes social reinforcement maintains initial drug-using behavior until the individ- ual comes to appreciate the primary drug effect or becomes tolerant to some initial aversive effects of the particular drug. This seems to be the case with many young peo- ple who do not like the initial effects of to- bacco or who perceive nothing pleasurable about the initial effects of smoking mari- huana. Although it is not as widely appreci- ated, many naive individuals find the ef- fects of an initial dose of heroin, with its associated nausea and vomiting, somewhat unpleasant; however, social reinforcement may maintain the behawior until tolerance develops to these effects. The development of physical dependence opens possibilities for another variety of reinforcement; each time drug use allevi- ates withdrawal distress the antecedent drug-using behavior is further reinforced. Even when tolerance attenuates the ini- tial reinforcing effects, drugs that induce certain varieties of physical dependence produce a regularly recurring sense of dys- phoria or distress that is immediately eliminated by another dose of the drug. Dysphoria need not be severe for its regular alleviation to reinforce behavior. During the withdrawal state, drug use can simulta- neously alleviate distress and in some cases produce euphoria, a particularly powerful reinforcement (see Wikler, 1980). The correlation is not always high be- tween the degree to which withdrawal from a given class of drugs threatens physical well-being and the degree to which with- drawal generates aversive states and in- creases the reinforcing effects of the drug. Withdrawal from nicotine never threatens physical well-being, but it regularly moti- vates continued smoking. By contrast, some users of ethanol or hypnotics elect to stop such use abruptly, even though doing so may cause delirium and life-threatening seizures. It is uncertain to what extent the positive rein- forcing (euphorigenic) effects of drugs continue to contribute to their reinforcing effects once toler- ance develops. After as little as 5 days of self- administration of ethanol or heroin in a laboratory setting, alcoholics or heroin addicts show more depression, dysphoria, and anxiety than a sense of well-being. In the case of opioids, however, there is a brief period immediately after each dose when mood is elevated (Meyer and Mirin, 1979). Patients tolerant to most of the effects of large doses of methadone still experience some positive effects on mood at about the time the concentration of metha- done reaches peak values in plasma after each daily dose. The significance of such positive reinforcing ef- fects also varies with the class of drug. For exam- ple, many people who become dependent on ben- zodiazepines continue to take them, not for their positive reinforcing effects, but to avoid emergence of antecedent anxiety or of withdrawal symptoms (Busto et al., 1986; Woods et al., 1987). Both ac- tions are properly considered examples of negative reinforcement. A protracted period of physiological and psycho- logical abnormalities commonly follows the acute syndrome caused by withdrawal of opioids, and this condition can persist for weeks. Since the sub- jective sense of not being quite normal is immedi- ately relieved by very small doses of opioid drugs, the protracted abstinence syndrome may predis- pose to relapse by creating a prolonged period of increased vulnerability, during which the effects of opioids are especially reinforcing (see Cushman and Dole, 1973; Martin et al., 1973). Such a pro- tracted state may also exist following withdrawal of other drugs that cause dependence. After with- drawal of ethanol, other CNS depressants, or ben- zodiazepines, sleep and mood may be disturbed for many weeks. It is not clear how long the anhedonia associated with withdrawal of cocaine or ampheta- mine persists (see below). In both animals and man, drug effects, with- drawal phenomena, and relief of withdrawal symp- toms by drugs can be conditioned to environmental stimuli. Such conditioning helps to explain how the rituals and circumstances surrounding drug use can act as secondary reinforcers, and how the mere taking of an inert pill or the use of a needle and syringe containing no drug can evoke the feelings (including euphoria or relief of withdrawal symp- toms) previously produced when the pill or syringe contained an active substance. The observation that withdrawal distress can become conditioned to the environment in which it occurs may underlie reports that former opioid addicts may experience sensations very similar to withdrawal symptoms, including an intensified craving for drugs, when they return to an environment where drugs are available. Alcoholics may have similar experi- ences, particularly when they are exposed to the sight and smell of alcohol. The conditions that elicit the most severe withdrawal and the most intense "craving" are those associated with the availability and use of the drug, rather than those associated with withdrawal (e.g., being offered some heroin or I

I I I I I I I I I I I I I I I I I 530 DRUG ADDICTION AND DRUG ABUSE cocaine by a friend or watching someone else use the drug). These are also the circumstances that increase craving in recently abstinent alcoholics and cigarette smokers. Moreover, such stimuli can elicit craving and the memory of drug-induced eu- phoria without other elements of drug withdrawal (Childress et al.. 1986; O'Brien et al., 1988). Posi- tive reinforcing effects and memories of these ef- fects evoked by a variety of stimuli may be suffi- cieAt in some individuals to account for the initial development of drug taking, escalation to compul- sive drug use, and relapse after successful detoxifi- cation (see Wise, 1988). Nevertheless, evidence is good that continuation of use is primarily moti- vated by avoidance of withdrawal (see below). Vulnerability. In man, drugs may pro- duce effects experienced as pleasurable, novel, or tension-reducing, but these ef- fects are not such powerful reinforcers that repetitive drug use is inevitable. Much re- search has centered on why some indi- viduals stop after experimentation, others continue drug use but do not become dependent, and still others become compul- sive drug users. Individuals who later become regular users of socially disapproved drugs or abus- ers of ethanol tend to be more impulsive, more interested in new experiences, more rebellious with respect to social norms, less tolerant of frustration, and less concerned with avoiding self-harm. Early childhood aggression is also a predictor of later prob- lems with drug use. Certain psychiatric di- agnostic categories are regularly overrepre- sented among those who seek treatment for alcoholism and drug dependency. These include depressive disorders, anxiety dis- orders, and antisocial personality (Roun- saville et al., 1982; Hesselbrock et al., 1985). Despite these findings, no single rec- ognized addictive personality or constella- tion of traits has been identified that is equally applicable to all varieties of drug- dependent individuals. Indeed, given the different pharmacological effects of various drugs, it would be surprising if all depen- dent drug users were similar. There are many factors that could contribute to increased vulnerability to continued or compulsive drug use. Some individuals may experience a more intense response to the initial reinforcing properties of the drugs, such as a more intense euphoria or a more profound reduction of unpleasant feelings of anger, depression, or anxiety. Such intense reac- [Chap. 22] tions, in turn, could be due to differences in sensi- tivity to drug effects or to initially higher levels of distress. Thus, for some, drug use may be viewed as self-treatment for internal distress. Although the agent selected or the pattern of use may sometimes run counter to social norms, for some individuals the alternative may be a state of tension, anger, or depression that may be felt to be intolerable. On the other hand, the contributory factors may be entirely social, as in the case of young people who continue to smoke cigarettes more to conform to the pressures from friends than because of an espe- cially intense need for the pharmacological effects of nicotine. Still other possibilities include differ- ences in intensity of adverse effects of the drugs or in the intensity of withdrawal phenomena as expe- rienced by different users (see above). For any given pattern of continued,drus use the outcome is the result of an interaction between social, biologi- cal, and environmental factors. Genetic Factors. Evidence for a genetic predis- position to alcoholism is'gr.owing.: For example, rats bred to prefer ethanol over water spontane- ously drink enough to become physically depen- dent, recover from acute intoxication at higher blood alcohol concentrations, and retain tolerance longer (Li, 1988). In man, two types of alcoholics have been described, each with distinct personality profiles and different patterns of inheritance, onset of problem drinking, and subjective responses to alcohol (see Cloninger et al., 1989). Although no clear genetic basis for vulnerability to other forms of drug abuse has yet been demonstrated, there is some evidence for a genetic contribution to antiso- cial personality, which is a risk factor for both alco- holism and most other drug dependence. Sociological Factors. Social factors have a major influence on which individuals have access to various drugs, and social attitudes, as well as the laws of any given country, determine which drugs are acceptable for casual or "recreational" use and which are prohibited. In addition, the nature of a society often determines the kinds of unpleasant feelings induced in its members, as well as the kinds of behaviors that are viewed as socially ac- ceptable. In general, when the use of a drus is widely accepted, the number of users tends to be large and their personal characteristics quite di- verse. When a particular form of drug use meets with severe disapproval, those who use it despite such sanctions tend to be very different from the average person in society in terms of attitudes and emotional adjustment even before use. Conse- quently, a high proportion may become compulsive users, sometimes leading to the conclusion that the particular drug is "more addicting" than those drugs used by larger and more diverse populations. Drugs may indeed differ in the degree to which theY induce dependence, but the ratio of experimentei•s to addicts is not always a valid measure of the lia- bility of a drug to cause dependence. Those who use any legal or illegal drug are likelY to use more than one drug. Futthermore, the use of more socially acceptable drugs, such as ethanol or tobacco, and the use of marihuana (sometimes known as "gateway drugs") precede the use of 1 2046399872