Physical Dependence, Tolerance and Sensitisation
Another factor in the evaluation of drug abuse liability is the assessment of whether the test substance will produce physical dependence, tolerance or sensitisation. Physical dependence is manifest by the occurrence of time-dependent biochemical, behavioural and physiological changes (ie the withdrawal syndrome) that may occur on termination of chronic drug administration and indicates that adaptation to administration of the drug has occurred. The reason why it is important to examine the possibility that adverse effects may occur on the termination of drug treatment as part of the abuse liability assessment package is because such a syndrome could result in drug-seeking behaviour to alleviate the unpleasant effects of drug withdrawal. Tolerance and sensitisation (when the effects of a drug either diminish or increase on repeated administration) are biological phenomena that have been associated with known drugs of abuse for many years.
Specific Physical Dependence, Tolerance and Sensitisation Studies
RenaSci have recently developed a model for assessing physical dependence, tolerance and sensitisation in rats. Animals will be treated chronically with a fixed or esclating doses of the novel substance before spontaneous drug withdrawal. Physical and behavioural symptoms of tolerance and sensitisation (during treatment) and dependence (following withdrawal) will be closely monitored using detailed checklists and compared to those produced by appropriate reference compounds. Physiological responses such as body weight, food and water intake and body temperature will also be measured. Drug treatment will normally be for 2 to 4 weeks and animals will be observed for up to one week following withdrawal.
Physical Dependence, Tolerance and Sensitisation Assessment by Post Hoc Analysis of GLP Toxicity Studies
Assessment of the ability of novel drugs to produce physical dependence, tolerance and sensitisation can often be obtained by post hoc analysis of GLP toxicity studies, performed in a variety of species as an essential part of the drug development process. These studies (which are not performed by RenaSci) contain detailed records of the behavioural and physical signs of the action of the test compound after chronic administration in animals. We use our specialist knowledge to prepare fully-audited GLP compliant reports from these data. Our reports meet the high standards required by the regulatory authorities and have been accepted by the EMA and FDA.
