Design and interpretation of opiate antagonist trials in dementia.
In view of the reports of possible beneficial effects of naloxone in dementia, rationales and strategies for studying endogenous opiate systems are reviewed. Important considerations in the design and interpretation of clinical investigations using naloxone are also reviewed. The nature and distribution of endogenous opiate systems are summarized from an historical perspective. Endogenous opiate systems are distributed throughout the central nervous system and play important roles in a variety of brain functions, including memory and learning. In view of this, several rationales are evident for studying endogenous opiate systems in dementia, since it is a syndrome in which structures known to contain opiate systems are disturbed, functions modulated by opiate systems are disturbed, and other neurotransmitter systems (functionally linked to endogenous opiate systems) are disturbed. Different strategies for studying endogenous opiate systems are reviewed, including examination of body fluids and pharmacologic challenge studies. Naloxone hydrochloride, a competitive opiate receptor antagonist, is a commonly used pharmacologic agent. The design of a multidose naloxone study of 12 dementia patients is discussed, with reference to the pharmacokinetics, pharmacodynamics, and specificity of naloxone as well as to the nature of the dependent measures selected for this study. No cognitive benefit was observed in this study. Behavioral arousal was observed at naloxone doses, with more evident psychomotor retardation at higher doses. These findings are contrasted with the results of naloxone challenges in other studies. The varying effects of naloxone within and across populations can be conceptualized in terms of the basic and clinical considerations previously discussed. The importance of dose-finding studies is stressed for this and other drug trials.
D000544:Alzheimer Disease / Q000188:drug therapy*; D001519:Behavior / Q000187:drug effects; D002986:Clinical Trials as Topic; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000502:physiology; D006801:Humans; D009270:Naloxone / Q000494:pharmacology / Q000627:therapeutic use*; D011957:Receptors, Opioid / Q000032:analysis
D004723:Endorphins; D011957:Receptors, Opioid; D009270:Naloxone