The physical dependence and withdrawal syndrome produced by chronic opioid use represents a significant hurdle for those patients seeking treatment. Available pharmacological detoxification agents are circumscribed and the use of some are rigorously regulated. Recent advances in neurobiology suggest that central noradrenergic and glutamateric processes are intimately involves in the development of opioid physical dependence and withdrawal. These studies will evaluate the ability of four novel medications whose effects are exerted through these neurotransmitter systems for their ability to attenuate or block opioid withdrawal using controlled laboratory procedures. The targeted study drugs are 1) lofexidine, an alpha2-adrenergic receptor agonist, 2) memantine, a non competitive NMDA receptor antagonist, 3) lamotrigine, a NA+ channel blocker with indirect glutamate antagonist properties, and 4) acamprosate, a post-synaptic glutamate antagonist; each drug will be evaluated in a separate study. Participants will be healthy adult volunteers who are physically dependent on opioids (n=10/study). Participants will be stabilized as outpatients for a period of at least 4 weeks on methadone (30 mg p.o./day) prior to inpatient admission. These studies will employ a model of antagonist precipitated withdrawal; this method has been shown to replicable, generalizable to spontaneous withdrawal, and well-tolerated by opioid-dependent patients. The effects of acute pretreatment with each test agent (placebo and 3 active doses) on the subjective and physiological response to intramuscular challenge with placebo or naloxone (0.` & 0.3 mg) will be evaluated during controlled experimental sessions. Using this design, the safety and pharmacodynamic profile of each novel drug will be characterized alone, and the efficacy of those agents to suppress withdrawal will be evaluated over a range of test doses and two different withdrawal intensities. These studies will provide new information about the safety and pharmacodynamic effects of these novel agents, may provide some insight into the neural mechanisms which underlie opioid physical dependence in humans, and, most importantly, will serve as a first step in the development of new pharmacotherapeutic strategies for the treatment of opioid withdrawal.
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