Evidence for an endorphin dysfunction in methadone addicts: lack of ACTH response to naloxone.

Chronic exogenous opiate administration might be responsible for the acute and protracted abstinence syndrome by producing a prolonged decrease in the availability of endogenous opioids (endorphins). However, the hypothesis that potent exogenous opiates may have anti-endorphin effects has been difficult to test. We have been investigating this hypothesis with neuroendocrine test paradigms which have provided preliminary evidence of anti-endorphin effects for chronic methadone. Naloxone-induced ACTH response data from chronic methadone addicts offers preliminary support for the hypothesis that chronic exogenous opiate administration has anti-endorphin effects. The subjects were 7 male methadone addicts who had been addicted to greater than or equal to 40 mg of methadone and 7 male healthy opiate-naive volunteers. Naloxone failed to produce a significant increase in ACTH in methadone addicts while opiate-naive normal volunteers demonstrated a significant naloxone-induced release of ACTH. Five of the seven methadone addicts ahd no demonstrable ACTH response to naloxone. These impaired naloxone response data reported here for recently detoxified addicts suggest that chronic methadone administration comprises the functional integrity of the endorphin system. Prolonged abstinence, post-detoxification depression and other affective symptoms which contribute to relapse may result from a prolonged endorphin derangement.

Serum prolactin and opiate withdrawal.

To evaluate the dopamine hyperactivity hypothesis for opiate withdrawal, we measured serum prolactin (PRL) in 21 male methadone addicts during significant opiate withdrawal and after clonidine suppression of opiate withdrawal signs and symptoms. We also measured serum PRL in these addicts 4 weeks after they were free of clonidine and opiates. Serum PRL was significantly decreased during opiate withdrawal and after clonidine reversal of withdrawal symptoms when compared to serum PRL measured in the drug-free baseline samples. These data suggest that dopaminergic hyperactivity is present in opiate withdrawal, but may not be related to the signs and symptoms of withdrawal. A noradrenergic hyperactivity hypothesis is proposed to explain the neurobiological system that becomes activated in withdrawal, generates symptoms, and is inhibited after clonidine administration.

Thyroid stimulating hormone and growth hormone responses to thyrotropin releasing hormone in anorexia nervosa.

Ten female patients who satisfied objective criteria for the diagnosis of anorexia nervosa were given 500 microgram of thyrotropin releasing hormone. Thyroid stimulating hormone and growth hormone responses were measured in duplicate by radioimmunoassay. These patients had a low normal delta thyroid stimulating hormone but a delayed peak response. In addition, these patients had pathological growth hormone release in response to thytotropin releasing hormone infusion. Both delayed peak thyroid stimulating hormone and growth hormone response to thyrotropin releasing hormone have been reported for patients with hypothalamic disorders.

Nortriptyline plasma levels and clinical response in patients with familial pure unipolar depression and blunted TRH tests.

We studied the efficacy of nortriptyline (NT) when given in doses which produce tricyclic antidepressant (TCA) levels within the proposed therapeutic "window" in a select patient group to assess the "window" hypothesis in a group of patients that was biologically homogeneous with respect to the TRH test and clinically homogeneous with respect to RDC, DSM III, and Winokur criteria. Pharmacokinetic and dose differences were controlled for by administering a NT dose-prediction test, giving the indicated dose, allowing levels to reach steady state and changing the dose, if necessary, to maintain NT levels within the range of 90-130 ng/ml. Using this protocol nine of ten patients responded to NT. This rate of response for a severely depressed patient group is comparable to response data for ECT and recent European data using regular NT levels to change doses of NT and assess appropriate NT trial duration.