Endorphins, Locus Coeruleus, Clonidine, and Lofexidine:

We review the rodent, primate, and human data which have supported an endorphin-locus coeruleus (LC) disinhibition hypothesis and noradrenergic neuroanatomy for opiate withdrawal. This norepinephrine (NE) hyperactivity hypothesis can explain a large body of clinical and preclinical data and newer and more effective nonopiate treatments. Neuroanatomical, neurochemical, and neurobehavioral data which supported this norepinephrine (NE) hypothesis led to our demonstrationof potent antiwithdrawal efficancy for clonidine and lofexidine in with drawal and naturally occurring panic an danxiety states. WE tested the efficacy of clonidine and lofexidine in opiate withdrawal not only to demonstrate that these medicaitons might be new and important treatments for addicts but also to see which physilogical and affective variables would be completely reversible and thereby attributable to specific agonistic effects on presynaptic alpha-2 receptors on the LC. Near complete opiate withdrawal reversal or opiate substitution by clonidine and lofexidine supports the NE hyperactivity hypotheses. Clonidie and lofexidine have a number of distinct advantages as antiwithdrawal agents. These clinical advantages of clonidine in drug abuse are summarized. We present additional data which supports the hypothesis that chronic exogenous opiate administration may have antiendorphin effects. These data suggesting endorphin dysfunction may explain the protracted abstinence syndrome and high relapse rate among recently detoxified methasone addicts.