The risk of a novel drug to cause physical dependence after prolonged administration is the final investigation in the regulatory Safety Pharmacology package. Withdrawal-induced physical dependence often occurs after the development of pharmacological tolerance to a drug’s effects and, therefore, monitoring for signs of tolerance with repeated administration is an important aspect of the assessment.
RenaSci has developed a model for evaluating withdrawal-induced physical dependence in rats and validated it using both opiates and benzodiazepines.
Similarities and differences: The on-dose and physical dependence
signs produced by opiates and benzodiazepines
Animals are administered the test compound for a minimum of 28 days before the abrupt termination of dosing (spontaneous drug withdrawal). Behavioural, physiological and physical signs are evaluated during test compound administration (to assess pharmacological tolerance) and physical dependence on withdrawal are recorded daily using detailed checklists of over 40 different items.
Effects of repeated morphine administration on various
physiological signs in the on-dose and withdrawal phases
Behavioural profile of morphine in a 28-day tolerance/dependence test
All physical dependence liability studies in rats can be performed to GLP.
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