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Tolerance and withdrawal


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Definition: tolerance is the development of the need to increase the dose of a drug to achieve the same effect previously achieved with a lower dose.


  • Duration of therapy is the major factor associated with onset of tolerance and physical dependence and continuous infusions induce tolerance more rapidly than intermittent and enteral therapy.
  • Tolerance begins within 48 hours of continuous infusion but typically takes 2-3 weeks of regular intermittent use to develop to a clinically significant extent.
  • Long-term pharmacodynamic tolerance can persist for months to years in some individuals.
  • The mechanisms are poorly understood but probably involve changes in receptor number (down-regulation) and modulation of intracellular signalling pathways leading to receptor desensitisation.
  • Genetics also play a role in both response to opioids and the development of tolerance and physical dependence but its clinical importance is still being defined.
  • Physical dependence also develops to some degree after only 48 hours of continuous infusion but requires 4 weeks of regular intermittent use to become established.
  • Discontinuing a drug after physical dependence is established will produce a typical withdrawal abstinence syndrome.

About the authors

  • Tessa Davis is a Consultant in Paediatric Emergency Medicine at the Royal London Hospital and a Senior Lecturer at Queen Mary University of London.


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