Substitution drug development for drug dependence treatment

For the treatment of intravenous drug abusers, substitution therapy (or maintenance therapy), i.e., the therapeutic administration of mu opioid receptor agonists of moderate intrinsic efficacy (e.g., buprenorphine) to considerable intrinsic efficacy (e.g., methadone, morphine, heroin) and long duration of action, has proven much more effective and widely used than the administration of simple opioid antagonists such as naltrexone. Thus, at a pragmatic level, the drug abuse treatment community has recognized that in the initial phases of therapy, the recovering addict has to be provided with a pharmacotherapeutic agent that produces essentially the same intrinsic stimulus effects as the drug of abuse that the addict had originally consumed. If this initial need of the recovering addict is not recognized, dropout is most likely, jeopardizing any further therapeutic interventions such as psychotherapy or sociopsychiatric rehabilitation. In the present drug development project, it is proposed to synthetize compounds from the cinnamoylaminocodeinone series and test them for their ability (i) to provide enough positive reinforcing effects to be accepted by recovering intravenous drug users, (ii) to maintain these positive reinforcing effects at a level that is sufficient to guarantee patient compliance, (iii) to attenuate the reinforcing effects of any subsequently consumed drug of abuse such as heroin, cocaine, and alcohol, thus extinguishing the drug seeking behavior of the patient , and (iv) to protect the recovering addict from a fatal overdose of any subsequently consumed opioid. With respect to all these features, the novel compounds are expected to be distinctly superior to the currently used compounds methadone and buprenorphine. A clinical team will help us (a) to evaluate the preclinical data obtained in the proposed project with respect to their clinical usefulness and (b) to advance the most successful candidate compound(s) to clinical testing.

For the treatment of intravenous drug abusers, substitution therapy (or maintenance therapy), i.e., the therapeutic administration of mu opioid receptor agonists of moderate intrinsic efficacy (e.g., buprenorphine) to considerable intrinsic efficacy (e.g., methadone, morphine, heroin) and long duration of action, has proven much more effective and widely used than the administration of simple opioid antagonists such as naltrexone. Thus, at a pragmatic level, the drug abuse treatment community has recognized that in the initial phases of therapy, the recovering addict has to be provided with a pharmacotherapeutic agent that produces essentially the same intrinsic stimulus effects as the drug of abuse that the addict had originally consumed. If this initial need of the recovering addict is not recognized, dropout is most likely, jeopardizing any further therapeutic interventions such as psychotherapy or sociopsychiatric rehabilitation. In the present drug development project, it is proposed to synthetize compounds from the cinnamoylaminocodeinone series and test them for their ability (i) to provide enough positive reinforcing effects to be accepted by recovering intravenous drug users, (ii) to maintain these positive reinforcing effects at a level that is sufficient to guarantee patient compliance, (iii) to attenuate the reinforcing effects of any subsequently consumed drug of abuse such as heroin, cocaine, and alcohol, thus extinguishing the drug seeking behavior of the patient , and (iv) to protect the recovering addict from a fatal overdose of any subsequently consumed opioid. With respect to all these features, the novel compounds are expected to be distinctly superior to the currently used compounds methadone and buprenorphine. A clinical team will help us (a) to evaluate the preclinical data obtained in the proposed project with respect to their clinical usefulness and (b) to advance the most successful candidate compound(s) to clinical testing.