Relationship between tolerance
and physical dependence
The nature of the relationship between tolerance and physical dependence is not clear. Some of the drugs to which tolerance develops also cause physical dependence, and the drugs of abuse and dependence with which this book is mostly concerned are in this group. For these drugs, physical dependence, with unpleasant symptoms on drug withdrawal, leads to the need to take the drug regularly. This is, of course, a necessary condition for tolerance to develop, which in turn leads to escalating doses, greater physical dependence and so on. Because of this parallel development it has been suggested that a common 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 .
The nature of the relationship between tolerance and physical dependence is not clear. Some of the drugs to which tolerance develops also cause physical dependence, and the drugs of abuse and dependence with which this book is mostly concerned are in this group. For these drugs, physical dependence, with unpleasant symptoms on drug withdrawal, leads to the need to take the drug regularly. This is, of course, a necessary condition for tolerance to develop, which in turn leads to escalating doses, greater physical dependence and so on. Because of this parallel development it has been suggested that a common 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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