‘withdrawal syndrome’, which is described in terms of
its consequences:
After the repeated administration of certain dependence producing
drugs, e.g. opioids, barbiturates and alcohol.
abstinence can increase the intensity of drug-seeking behaviour because of the need to avoid or relieve withdrawal discomfort and/or produce physiological changes of sufficient severity to require medical treatment.
Tolerance Tolerance is ‘a reduction in the sensitivity to a drug following its repeated administration in which increased doses are required to produce the same magnitude of effect previously produced by a smaller dose’ 3 . Many drugs, including some that are abused, induce tolerance, and therefore those who take them regularly can consume, without intoxication, far larger doses than can be tolerated by those without prior exposure. For tolerance to develop and to be maintained, the drug must be taken regularly and in sufficient dosage. If drug administration is interrupted for any reason, tolerance is lost and the high dose that was previously tolerated without adverse effect becomes as toxic as it is for the drug-naive individual. This situation arises not infrequently when a drug-dependent individual resumes drug-taking after a period of abstinence – in hospital or in prison for example – and the high dose of drug that he or she had previously been taking regularly and safely may then have fatal consequences. Tolerance does not necessarily develop equally or at the same rate for all the effects of a drug. For example, a very high degree of tolerance develops to the actions of opiates that cause analgesia, mental clouding and respiratory depression (slow and shallow breathing), so that these effects of opiates are not apparent even when the individual is consuming a very high daily dose – as long as that dose level has been reached gradually. However, little or no tolerance develops to the action of opiates on the pupil of the eye or on the bowel so that the same individual usually displays a typically constricted pupil and suffers from constipation. Although tolerance to most of the effects of opiates is apparently open ended (the dose can be gradually increased to any level), this is not true for all drugs. A barbiturate-tolerant individual, for example, can take a dose of barbiturate that would render a non-tolerant individual comatose; there comes a point, however, when a further increase of dose will lead to severe toxicity or death even for someone who is barbiturate tolerant. In this case tolerance can be said to have reached a ‘ceiling’. Tolerance is not completely drug specific. If an individual has become tolerant to the effects of heroin, for example, he or she can take large doses of any other opiate (but not of other classes of drugs). If heroin is withdrawn, the resulting abstinence syndrome can be relieved by the administration of any opiate (but not by any other type of drug). This phenomenon is known as cross-tolerance. Mechanisms of tolerance Tolerance can develop in different ways. Pharmacokinetic tolerance arises when changes in the metabolism or distribution of the drug following repeated administration affect its concentration in the blood and consequently its effect upon target cells. For example, tolerance to barbiturates is partly due to the induction (switching on) of special enzymes in the liver (hepatic microsomal enzymes) by the barbiturates themselves. These enzymes then metabolize (break down) the barbiturates, which can therefore be said to speed their own destruction. An increased dose is then needed to maintain the original effect. Tolerance that is due to changes in specific receptors reflects either a change in receptor density, or an altered response to neurotransmitters, or a change in the availability of the neurotransmitters themselves. Tolerance can also be ‘learned’; that is, the individual learns to cope with the effects of the drug, so that they are less apparent. The most obvious example is the way in which an alcoholic learns to recognize the motor impairment associated with intoxication and how best to overcome it and disguise it by altered behaviour (e.g. walking or driving more slowly). This sort of learned behavioural tolerance only has limited effectiveness.
mechanism is responsible for both phenomena. This hypothesis probably emerged because the drugs which have been studied the longest and most intensively are the opiates, drugs to which open-ended tolerance develops rapidly and on which physical dependence is severe and easily recognizable. Similarly, tolerance develops to some of the effects of alcohol, barbiturates, benzodiazepines and other sedatives, and physical dependence on these drugs is again well known. From observations such as these grew the belief that tolerance and physical dependence are both manifestations of a single, as-yet-unknown neural mechanism. However, tolerance is a very general phenomenon, observed with many drugs. It is, after all, very common in medical practice to start with a small dose of a drug and to increase it gradually as the patient becomes tolerant of the side effects, and physical dependence does not develop in every situation in which tolerance develops. Perhaps the best way to understand the relationship between tolerance and physical dependence is to say that the existence of tolerance, by permitting the administration of large doses of the drug, enables or enhances the development of severe physical dependence, if the drug has a dependence-producing liability as well. Undoubtedly, the two conditions, of tolerance and physical dependence, occur after chronic administration of a wide range of drugs (including tricyclic antidepressants, phenothiazines and anticholinergics) that are not self-administered by animals or usually abused by humans. This serves to emphasize the point that neither tolerance nor physical dependence, separately or together, are sufficient to cause a true state of dependence on a drug. For that, the psychological element, the inner compulsion, must always be present5 .
abstinence can increase the intensity of drug-seeking behaviour because of the need to avoid or relieve withdrawal discomfort and/or produce physiological changes of sufficient severity to require medical treatment.
Tolerance Tolerance is ‘a reduction in the sensitivity to a drug following its repeated administration in which increased doses are required to produce the same magnitude of effect previously produced by a smaller dose’ 3 . Many drugs, including some that are abused, induce tolerance, and therefore those who take them regularly can consume, without intoxication, far larger doses than can be tolerated by those without prior exposure. For tolerance to develop and to be maintained, the drug must be taken regularly and in sufficient dosage. If drug administration is interrupted for any reason, tolerance is lost and the high dose that was previously tolerated without adverse effect becomes as toxic as it is for the drug-naive individual. This situation arises not infrequently when a drug-dependent individual resumes drug-taking after a period of abstinence – in hospital or in prison for example – and the high dose of drug that he or she had previously been taking regularly and safely may then have fatal consequences. Tolerance does not necessarily develop equally or at the same rate for all the effects of a drug. For example, a very high degree of tolerance develops to the actions of opiates that cause analgesia, mental clouding and respiratory depression (slow and shallow breathing), so that these effects of opiates are not apparent even when the individual is consuming a very high daily dose – as long as that dose level has been reached gradually. However, little or no tolerance develops to the action of opiates on the pupil of the eye or on the bowel so that the same individual usually displays a typically constricted pupil and suffers from constipation. Although tolerance to most of the effects of opiates is apparently open ended (the dose can be gradually increased to any level), this is not true for all drugs. A barbiturate-tolerant individual, for example, can take a dose of barbiturate that would render a non-tolerant individual comatose; there comes a point, however, when a further increase of dose will lead to severe toxicity or death even for someone who is barbiturate tolerant. In this case tolerance can be said to have reached a ‘ceiling’. Tolerance is not completely drug specific. If an individual has become tolerant to the effects of heroin, for example, he or she can take large doses of any other opiate (but not of other classes of drugs). If heroin is withdrawn, the resulting abstinence syndrome can be relieved by the administration of any opiate (but not by any other type of drug). This phenomenon is known as cross-tolerance. Mechanisms of tolerance Tolerance can develop in different ways. Pharmacokinetic tolerance arises when changes in the metabolism or distribution of the drug following repeated administration affect its concentration in the blood and consequently its effect upon target cells. For example, tolerance to barbiturates is partly due to the induction (switching on) of special enzymes in the liver (hepatic microsomal enzymes) by the barbiturates themselves. These enzymes then metabolize (break down) the barbiturates, which can therefore be said to speed their own destruction. An increased dose is then needed to maintain the original effect. Tolerance that is due to changes in specific receptors reflects either a change in receptor density, or an altered response to neurotransmitters, or a change in the availability of the neurotransmitters themselves. Tolerance can also be ‘learned’; that is, the individual learns to cope with the effects of the drug, so that they are less apparent. The most obvious example is the way in which an alcoholic learns to recognize the motor impairment associated with intoxication and how best to overcome it and disguise it by altered behaviour (e.g. walking or driving more slowly). This sort of learned behavioural tolerance only has limited effectiveness.
mechanism is responsible for both phenomena. This hypothesis probably emerged because the drugs which have been studied the longest and most intensively are the opiates, drugs to which open-ended tolerance develops rapidly and on which physical dependence is severe and easily recognizable. Similarly, tolerance develops to some of the effects of alcohol, barbiturates, benzodiazepines and other sedatives, and physical dependence on these drugs is again well known. From observations such as these grew the belief that tolerance and physical dependence are both manifestations of a single, as-yet-unknown neural mechanism. However, tolerance is a very general phenomenon, observed with many drugs. It is, after all, very common in medical practice to start with a small dose of a drug and to increase it gradually as the patient becomes tolerant of the side effects, and physical dependence does not develop in every situation in which tolerance develops. Perhaps the best way to understand the relationship between tolerance and physical dependence is to say that the existence of tolerance, by permitting the administration of large doses of the drug, enables or enhances the development of severe physical dependence, if the drug has a dependence-producing liability as well. Undoubtedly, the two conditions, of tolerance and physical dependence, occur after chronic administration of a wide range of drugs (including tricyclic antidepressants, phenothiazines and anticholinergics) that are not self-administered by animals or usually abused by humans. This serves to emphasize the point that neither tolerance nor physical dependence, separately or together, are sufficient to cause a true state of dependence on a drug. For that, the psychological element, the inner compulsion, must always be present5 .
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