Tolerance, physical dependence and withdrawal
Tolerance is a reduced response to the same dose after repeated exposure, whereas physical dependence, the body's adaptation to a drug's continued presence, appears as withdrawal when exposure falls.
Remember
Withdrawal after a drug is reduced shows physical dependence, but on its own it does not show addiction, which is defined by behaviour; physical dependence is also a different thing from tolerance.
Tolerance is a reduced response to the same dose of a drug after repeated exposure. It can develop unevenly between effects. Benzodiazepines (drugs that increase the receptor response to GABA, a transmitter whose binding usually reduces the probability that a mature neurone fires) are a standard example: the sedative effect shows tolerance, yet in this standard example the anxiolytic (anxiety-reducing) effect does not.
Physical dependence is a separate adaptation. The body adapts to a drug that is constantly present, so a withdrawal syndrome appears once exposure is reduced or stopped. This can develop during treatment taken as prescribed. Because the two adaptations are separate, sedation can fade while dependence persists.
Withdrawal is the set of symptoms and signs that appear when exposure falls in a physically dependent person. The brain compensates for sustained enhancement of GABA activity by a drug such as a benzodiazepine, for example by reducing how strongly it responds to inhibition (inhibition means a lower chance of neurones firing). While the drug is present, these changes are hidden. Once it is removed, the compensation is unmasked, so excitation (the opposite of inhibition) can dominate. Abrupt benzodiazepine withdrawal may produce confusion, toxic psychosis or convulsions, which is why withdrawal should be gradual.
Addiction is a behavioural syndrome, defined by impaired control and by continued use despite harm. Withdrawal alone does not establish it, and dependence can develop in people who take a medicine exactly as prescribed, so assuming that a person with withdrawal has been taking more would be unfair.
Key facts
- Tolerance
- a reduced response to the same dose after repeated exposure.
- Effect-specific
- with benzodiazepines, a standard example, the sedative effect shows tolerance, but the anxiolytic effect does not.
- Physical dependence
- the body has adapted to the drug, so withdrawal appears when exposure falls.
- Prescribed use
- dependence can develop in people who take a medicine exactly as prescribed.
- Addiction
- a behavioural syndrome of impaired control and continued use despite harm, which cannot be inferred from physical dependence alone.
- Withdrawal risk
- abrupt benzodiazepine withdrawal may produce confusion, toxic psychosis or convulsions, so withdrawal should be gradual.
Exam traps
- Taking a drug as prescribed does not prevent physical dependence, because withdrawal after reduced exposure is itself evidence of adaptation.
- A withdrawal syndrome after a dose reduction does not diagnose addiction on its own, because addiction is defined by behaviour, not by physiological withdrawal.
- Tolerance, in which the response to a repeated dose becomes smaller, is a different idea from physical dependence, even if it often occurs alongside it.
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