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.