Drug Dependence Liability/Withdrawal Test

A key component in abuse liability testing is the appropriate evaluation of an objectively verified potential withdrawal or discontinuation syndrome induced by high dose chronic administration of the test article. Creative Biolabs conducts drug dependence liability tests by telemetry for continuous detection and video recording technique, which allows for retrospective review of interesting behaviors.

Introduction of Dependence/Withdrawal Test

The general approach to the evaluation of withdrawal is to treat subjects for a period of 2 to 3 weeks and then evaluate the occurrence of withdrawal syndrome for a sufficiently long time after drug discontinuation (at least 1 week). Withdrawal can either be assessed spontaneously upon cessation of dosing or can be precipitated following administration of a selective antagonist. The former (i.e. spontaneous withdrawal) refers to an abrupt termination of chronic drug administration and is thought to be the most closely model with a withdrawal syndrome that might occur clinically with either medical or non-medical use. The experimental assessment of a spontaneous withdrawal syndrome should be based on the pharmacokinetics of the drug for the species that will be used and should be of a long enough duration to include the biological elimination of the drug. The later typically produces more overt and more easily quantifiable withdrawal signs, but can only be applied when the new chemical entity is an agonist, and when a selective antagonist for the same target(s) is available.

Fig.1 Theoretical schematic of the intensity and duration of the three distinct phases of drug withdrawal syndrome. (Gauvin et al. 2013)

The assessment of withdrawal effect includes normal and abnormal behaviors as well as physiological measures. Physiological measures include heart rate, blood pressure, respiratory rate, and body temperature. This can be readily achieved through the use of telemetry, a novel approach that permits continuous monitoring. Behavioral measurements include both simple observations (e.g., food intake, body weight, tremor, wet dog shakes, and hypothermia) and subtle observations (e.g., dizziness, headaches, anxiety, and fatigue). Moreover, video recording of the study is often applied for the retrospective review of animal behaviors.

The Features of Dependence/Withdrawal Test

• If withdrawal syndrome is observed in the test animals, it means that the likelihood of the test drug producing dependence liability is high. But dependence is not necessarily correlated with abuse liability. Several drugs, for example, the selective-serotonin reuptake inhibitors (SSRIs), can cause dependence but do not possess positive reinforcing properties.
• The dosing frequency and route of administration need to be chosen with regard to the pharmacokinetics (PK) of the test substance, and the dose range should be chosen to cover the upper range of therapeutic exposure levels up to maximally tolerated doses.

For a comprehensive assessment of drug abuse potential, Creative Biolabs also provides other assays:

• Conditioned Place Preference
• Drug Discrimination
• Intravenous Self-Administration
• Locomotor Sensitization

As an undisputed specialist in neurological disease drug development, Creative Biolabs has an extensive range of rodent neurological disease models for drug efficacy studies:

Contact us if you need more information about this procedure or a formal quotation.

Reference

1. Gauvin, D.V.; et al. Current strategies for abuse liability assessment of new chemical entities. A Comprehensive Guide to Toxicology in Preclinical Drug Development. Elsevier Inc. 2013:451-478.

For Research Use Only.