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Although not fully understood as yet, a great deal of evidence suggests that the action of cocaine at central dopaminergic (and other adrenergic) neurons may provide the underlying cause of the craving for cocaine. The blocking of the re-uptake of dopamine and subsequent enhanced activity of this neurotransmitter at dopaminergic receptor sites located in the limbic system of the brain, may account for the euphoria associated with cocaine use. The repeated blocking of dopamine in chronic users may lead to a state of functional deficiency of dopamine in these individuals. By blocking re-uptake of the neurotransmitter, less is available in the presynaptic vesicles for use in normal neuronal regulation. In the case of dopamine, that may lead to depression in the user. What is especially insidious is that this depression might last for days or weeks after the last use of cocaine, forming the basis for craving (i.e. drug hunger), which ultimately will end up in bodily harm (Fig. 40).

Drug withdrawal is the process of weaning a patient from a drug to which their body has undergone cellular adaptation, i. e., physical dependence. The goal of drug withdrawal is to accomplish the weaning process with safety while reducing symptoms to a tolerable level. Although withdrawal is often a necessary step in the treatment of addictive disease drug withdrawal alone, no matter how skillfully executed, is not adequate treatment for ‘addictive disease’.

During the last decade evidence has accumulated that pituitary and hypothalamic hormones are precursor molecules for biologically active fragments which affect a variety of brain functions. Examples of precursor hormones for neuropeptides which are involved in behavioural adaptation are adrenocorticotrophic hormone, melano-cyte-stimulating hormone, vasopressin, oxytocin and β-endorphin. The study of the influence of pituitary and hypothalamic hormones on the central nervous system has revealed the existence of peptide hormone fragments devoid of classical endocrine effects affecting motivational, attentional, learning and memory processes. In addition, these hormones generate fragments which modulate drug-seeking behaviour and the development of tolerance and physical dependence on opiates and alcohol, and neuropeptides which are involved in psychopathological processes. These findings suggest that psychopathological disturbances and impairment in mental performance may be caused by hormonal dysfunctions in the brain. Preliminary studies in man corroborate this view.

The WHO expert committee has recognized that different groups of drugs produce different types of dependence and that the type should be specified.

The seven essential elements in the alcohol dependence syndrome are: I. Subjective awareness of compulsion to drink. II. Stereotyped pattern of drinking. III. Increased tolerance to alcohol. IV. Primacy of drinking over other activities. V. Repeated withdrawal symptoms. VI. Relief drinking. VII. Reinstatement after abstinence.

The introduction of benzodiazepines has been one of the major advances in medicine. Time will tell whether it will eventually be regarded as more important than the discovery of penicillin. I mention penicillin firstly because I work at St Mary’s Hospital in London, which has recently celebrated the memory of Fleming’s discovery there fifty years ago. I mention it secondly because the introduction of penicillin altered the attitude of men towards pharmacotherapy and has widely been regarded as ushering in the new era of powerful drugs that dramatically alter the outcome of illness.

The clinical manifestations of a benzodiazepine abstinence syndrome, implying physical dependence, resemble those that occur with sedatives, including barbiturates, and with alcohol, but show some differences of time and degree rather than nature.

One of the prime objectives of medical research over the past 50 years has been the discovery and development of an analgesic agent having the efficacy of morphine without the liability to abuse which characterizes the narcotics. All the opioid drugs introduced during this period have claimed superiority over morphine in terms of abuse potential. Most of them have ultimately failed to live up to the full extent of the claims made; nevertheless several widely used drugs have been less abused than morphine.

Whereas dependence on such drugs as morphine and cocaine has for long been a condition of which both the professional as well as the lay public have been well aware, the same cannot be said for the recognition of states of dependence on hypnotics and stimulating drugs, often wrongly described as minor addictions. In many ways the problems caused by these substances are more important, not only because so many people even today are not fully aware of the possible dangers of taking such drugs to excess, but also because of the much greater number of abusers involved. Second to alcohol (and nicotine), barbiturates and amphetamines are responsible for the bulk of all problems of drug dependence in this country.

A number of experiments carried out in recent years, have emphasized individual differences in reactivity to many psychotropic agents, both in humans and in laboratory animals. This may be due to differences in the rate of absorption, distribution, metabolism, or excretion of drugs; or to differences in the sensitivity of target systems to compounds acting at the central nervous system (CNS) level.

Post-operative pain is a major concern to patients undergoing surgery. Unfortunately many patients find their pain is inadequately treated, partially because of individual variability in analgesic requirements, but more importantly, because too little analgesic is prescribed too seldom or on a PRN schedule. The physician’s fear of narcotic side effects, primarily respiratory depression and physical dependence, are largely responsible for the ineffective use of analgesics. Oftentimes, analgesics are prescribed with flexibility in both dose and schedule, but under these circumstances, because of initial underprescribing and nursing fear of overmedication, minimum doses are given. As a result the patient has less than adequate pain relief and little control in this situation, and, therefore, fears and anxiety compound the problem.

There are several reasons why this book, which deals with dependence on psychotropic drugs, includes a brief (but by no means comprehensive) chapter on alcoholism. Many books on drug dependence say very little about alcoholism. This possibly helps to strengthen the relatively widespread erroneous idea that alcohol is quite a different substance from those other drugs which can lead to addiction. Thus, not infrequently, one encounters alcoholics of many years standing who proudly proclaim that they have hardly ever in their life taken a drug. There can of course be no doubt that alcohol is a drug even if it has become traditionally and culturally widely accepted and domesticated [1], and that although it can be freely bought over the counter without requiring a doctor’s prescription, it is a potentially very dangerous drug that can produce physical as well as psychological dependence. Moreover, although the mass-media nowadays pay much less attention to alcoholism than to other forms of drug dependence, it is only fair to point out that, second to the other freely available dangerous dependence-producing drug, nicotine, alcohol is responsible for a much larger number of individual cases of dependence than any other dependence-producing drug (see Table 1 in Appendix).

Opiates, a large class of “morphine-like” drugs, exert a large range of pharmacological effects, in addition to analgesia. The heterogeneity of effects among opiates has been well known for many years. Most notable in this regard are the properties of the mixed agonist-antagonist opiates of the benzomorphan series. These compounds have been of special interest because of the desirability of developing a drug having morphine-like analgesic effects but lacking addictive potential. Cyclazocine, SKF-10,047 (N-allylnor-cyclazocine), and related drugs of the benzomorphan group differ from classical opiates in displaying psychotomimetic effects in humans and unique behavioral effects in animals (Haertzen, 1970; Holtzman, 1979). The syndromes associated with many of the benzomorphans depend dramatically on the species and vary qualitatively with the dose administered. At low doses many of these drugs produce effective analgesia in humans (Lasagna, 1954; Keats, 1964). In addition, they may clinically antagonize the analgesic and respiratory-depressant effects of classical opiates (Harris, 1964), precipitate a withdrawal syndrome in morphine-addicted patients, and prevent development of addiction to morphine (Martin, 1965). At the same time, these opiates may produce physical dependence when administered alone and a characteristic withdrawal syndrome differing from that of morphine upon drug cessation (Martin, 1965).

An attempt has been made to determine the dependence liability that exists in practice in the case of the benzodiazepines. The existence of such a dependence liability and the extent of the dependence risk has been assessed in four ways: 1. Deliberate experiments in humans to provoke physical dependence. 2. Ex cathedra statements from those working directly in the field of drug abuse. 3. A critical analysis of the published reports of psychological and physical dependence arising in either an abuse or a therapeutic situation. 4. Large-scale surveys of groups of patients.

It is clear from the human experiments conducted by Hollister and others that if benzodiazepines (like most if not all psychotropic drugs) are given in large enough doses for a long enough period, physical dependence can result. It is equally clear from the observations reported on pp. 23 to 40 that dependence can also occur occasionally under conditions of abuse and when benzodiazepines are used medically. It is important to try to assess the level of risk and particularly the level relative to other central nervous system active drugs.

Ethanol was chronically administered to mice to induce tolerance and physical dependence. Ethanol treatment was stopped and withdrawal severity and residual tolerance was measured.