naloxone and Anorexia-Nervosa

Psychopharmacologic treatment is playing a greater role in the management of patients with eating disorders. In this paper, we review randomized, placebo-controlled trials (RCTs) conducted in anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and other eating disorders over the past 3 years. Fluoxetine remains the only medication approved for an eating disorder, that being BN. RCTs of antipsychotics in AN have had mixed results; the only agent with some evidence of efficacy is olanzapine. One study suggests dronabinol may induce weight gain in AN. Preliminary studies suggest lack of efficacy of alprazolam, dehydroepiandrosterone, or physiologic estrogen replacement in AN; erythromycin in BN; and the opioid antagonist ALKS-33 in BED. In BED with obesity or overweight, bupropion may cause mild weight loss without seizures, and chromium may improve glucose regulation. Also in BED, three RCTs suggest the stimulant prodrug lisdexamfetamine may reduce binge eating episodes, and another RCT suggests intranasal naloxone may decrease time spent binge eating. There remains a disconnection between the size of eating disorders as a public health problem and the lack of pharmacotherapy research of these conditions.

Topics: Administration, Intranasal; Anorexia Nervosa; Anti-Obesity Agents; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Baclofen; Binge-Eating Disorder; Bulimia Nervosa; Bupropion; Central Nervous System Stimulants; Chromium Compounds; Humans; Lisdexamfetamine Dimesylate; Morphinans; Naloxone; Narcotic Antagonists; Obesity; Randomized Controlled Trials as Topic

Recent reports have indicated that the incidence of anorexia nervosa and bulimia has increased over the last several years. Both of these syndromes present serious treatment challenges to clinicians and in an effort to deal more effectively with these disorders several pharmacological interventions have been attempted. This article reviews the range of pharmacological interventions used with anorexia nervosa and bulimia patients. The purpose of the review is to present our current knowledge regarding the efficacy of these medications and to offer methodological recommendations that will enhance future research efforts.

Topics: Adrenocorticotropic Hormone; Anorexia Nervosa; Antidepressive Agents, Tricyclic; Chlorpromazine; Cyproheptadine; Dopamine; Feeding and Eating Disorders; Female; Humans; Hyperphagia; Levodopa; Lithium; Lithium Carbonate; Male; Naloxone; Phenytoin; Pimozide; Serotonin; Zinc

In anorexia nervosa alterations in the hypothalamic-pituitary-gonadal unit were previously thought to have been connected to an increase of endogenous opiate tone. The authors tried to prove that the replacement of normal endogenous steroid levels could restore the functional coupling between opiatergic and luteinizing hormone-releasing hormone (LH-RH) neurons in patients with anorexia nervosa. Pulsatile LH-RH therapy has been used to achieve normal ovarian activity. The authors studied gonadotropin levels before and during intravenously (IV) pulsatile LH-RH therapy (50 to 100 ng/kg body weight/90 to 120 minutes) in three anorexia nervosa and two weight loss amenorrhea patients, during both placebo and naloxone administration (2 mg IV bolus plus 4 mg infusion lasting 120 minutes). Before therapy, naloxone administration did not significantly change gonadotropin levels in three out of five patients, while a decrease in gonadotropin levels was observed in the other two subjects. During LH-RH therapy, normal pituitary-gonadal activity was demonstrated and ovulatory cycles were found in all patients. Naloxone administration did not change gonadotropin release during LH-RH therapy. Data could support the hypothesis of either a primitive impairment of LH-RH neurons, or an alteration in central regulation of LH-RH pulsar in anorexia nervosa.

Topics: Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Body Weight; Estrogens; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Naloxone; Progesterone

Anorexia nervosa is a primarily psychiatric syndrome of self-induced weight loss due to an intense fear of becoming obese. Numerous endocrine abnormalities occur in anorexia nervosa patients, and in many respects these alterations reflects the endocrinology of reduced energy intake. However, the basic mechanisms of those alterations are far from being understood. In an attempt to understand the disrupted mechanisms of the hypogonadotropic hypogonadism of the anorectic state, we studied 10 anorectic women in the acute phase of their illness; all met the DSM III criteria. On each patient, two tests were performed with either saline as control or infusion of the opioid antagonist naloxone, and both LH and FSH levels were measured. Four mg of naloxone as bolus was used, followed by a naloxone infusion of 2 mg/h for 4 h. Compared with the pattern of normal women, naloxone did not increase in the anorectic patients either LH or FSH levels nor pulsatility. This result suggests that endogenous opioid peptides are not implicated in the low gonadotropic situation of anorexia nervosa. An alternative explanation could be that the low estrogenic "milieu" of these patients could mask the opioid action. To test this second possibility, another group of 7 anorectic women after partial weight recovery were challenged with estrogen administration. Compared with the pattern of normal women volunteers, all the anorectic patients but one presented an abnormal response in both LH and FSH levels after estrogen administration. In fact, the negative feedback and the delayed positive feedback of LH after estrogen were absent in these patients. Interestingly enough, the only patient with near-normal LH response to estrogen was considered fully recovered by the Psychiatric Unit. Several alterations in the hypothalamic-pituitary-adrenal axis has been reported in anorexia nervosa. Seven anorectic patients and 7 aged-matched women were challenged by ACTH 1-24, 250 micrograms (i.v.) and the ratio of increments in adrenal steroid products to precursors monitored. ACTH-induced increments in cortisol with respect to increments in 17-OH-progesterone was similar in anorectics and controls. On the contrary, the ratio of increments of androstenedione with respect to increments in 17-OH-progesterone were greater in anorexia nervosa than controls. These results suggest that in anorexia nervosa the 11-beta-21-alpha-hydroxylase system is normal but a deficient 17-20 desmolase system is present. Fi

Topics: Amenorrhea; Anorexia Nervosa; Corticotropin-Releasing Hormone; Cosyntropin; Endorphins; Estradiol Congeners; Feedback; Female; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Naloxone; Ovary; Pituitary Hormones, Anterior; Pituitary-Adrenal System

In anorexia nervosa (AN) luteinizing hormone (LH) release is often impaired during opioid blockade. We investigated whether a restoration of the endogenous sex steroid milieu, together with a rise in central serotonergic tone, could increase LH responsiveness to Naloxone (NAL) in seven young women affected by AN. The spontaneous pulsatility of gonadotropins and their response to gonadotropin-releasing hormone (GnRH) and NAL challenges were tested before and after 13 days of pulsatile GnRH treatment and oral administration of L-5-hydroxytryptophan. Low and unpulsatile gonadotropin levels, responsive to GnRH, but not to NAL, were found before treatment. Pulsatile GnRH brought about a quasi-normal secretory pattern and 17 beta-estradiol increased to preovulatory levels in six of seven patients. On day 13 the lack of response to NAL administration was still present, however. A neuroendocrine disorder seems to be present in AN, which appears more complex than in other forms of hypothalamic amenorrhea.

Topics: 5-Hydroxytryptophan; Adolescent; Adult; Anorexia Nervosa; Female; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Menstrual Cycle; Naloxone; Serotonin

Previously, we have shown that in the opposite extremes of nutritional status, obesity and anorexia nervosa (AN), growth hormone (GH) response to growth hormone-releasing hormone (GH-RH) is not inhibited by the ingestion of a normal 800-cal meal consumed at lunch time (1 PM), which is at variance with results in normal subjects. However, in obese patients the postprandial increase in GH response to GH-RH is inhibited by an infusion of naloxone (NAL). In this study we have tested anorectic patients, performing the following tests at 1 PM: GH-RH test (50 micrograms IV) or, in a different day session, NAL (1.6 mg/h, starting 30 minutes before GH-RH) + GH-RH test (50 micrograms IV). The tests were performed in the following three different experimental conditions: (1) short-term fasting studies (lasting from breakfast), (2) long-term fasting studies (from midnight of the day before) and (3) postprandial studies (after a standard meal consumed 1 hour before the test). In AN, the GH response to GH-RH was not influenced by NAL infusion at 1 PM, in both short- and long-term fasting studies (short-term fasting: peak values after GH-RH alone, 26.5 +/- 6.5 ng/mL, during NAL, 28.0 +/- 3.3 ng/mL; long-term fasting: peak values after GH-RH alone, 32.2 +/- 6.8 ng/mL, during NAL, 30.6 +/- 4.0 ng/mL). A partial NAL-inhibitory effect was instead observed in postprandial studies, as evidenced by the calculation of areas under the curve ([AUCs] 1,662.1 +/- 90.0 after GH-RH alone v 1,090.5 +/- 245.4 ng/mL/h during NAL).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Anorexia Nervosa; Eating; Endorphins; Fasting; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Naloxone; Time Factors

We examined the functional status of the hypothalamic-opioid system involved in LH secretion and the pituitary LH sensitivity and reserve in patients with anorexia nervosa were studied during body weight loss and weight recovery. We measured the temporal relationship between weight recovery, expression of hypothalamic-opioid activity and pituitary GnRH responsiveness, and resumption of ovulatory cycles.. Five patients with anorexia nervosa were prospectively studied during weight loss and amenorrhoea, subsequently when they reached their ideal body weight but still remained amenorrhoeic and thereafter every 6 months until resumption of ovulatory cycles; one patient was studied only during weight loss, two during ideal body weight and amenorrhoea and one during ideal body weight and ovulatory cycles. Blood was sampled every 10 minutes over a 16-hour period on two alternate days. On study day 1 (control day), patients received two sets of saline infusion every 6 hours and one saline bolus at the beginning of the seventh hour; on study day 3 (experimental day), they received a saline infusion during the first 6 hours, an intravenous bolus of naloxone (20 mg) at the beginning of the seventh hour and then a continuous naloxone infusion (1.6 mg per hour) during the ensuing 6 hours. Pituitary LH sensitivity and reserve were assessed on both study days by the subsequent administration of 5 and 95 micrograms of GnRH 4 hours before the completion of each sampling period. Patients in ideal body weight and ovulatory cycles as well as five normal menstruating women included in the study for comparative purposes, were studied during the midluteal phase of a cycle.. LH, oestradiol and progesterone were determined by radioimmunoassay. Areas under the LH curve were calculated by the trapezoid method; LH pulse detection was carried out by the program Cluster.. Naloxone administration to patients with anorexia nervosa in the weight loss phase, did not significantly modify their serum LH levels nor the characteristics of its pulsatile secretion. Administration of the opioid blocker induced a significant increase in serum LH concentrations only in those patients in ideal body weight and amenorrhoea who resumed ovulatory cycles within the 6 months following the last study as well as in patients with an ideal body weight and ovulatory cycles and in normal controls. All patients and subjects who responded to naloxone administration exhibited significant increases in the area under the LH curve, mean LH pulse amplitude and peak area. Patients in ideal body weight and amenorrhoea who did not resume ovulatory cycles within the 6 months following the study days, did not respond to naloxone administration. There were no significant correlations between the magnitude of LH response to naloxone administration and the baseline levels of serum oestradiol and progesterone. All patients exhibited significant pituitary LH responses to both GnRH doses, regardless of the stage of the disease; however, the pituitary responsiveness shown by patients in ideal body weight was significantly higher than that presented by patients in weight loss. There were no significant differences between the responses to GnRH exhibited by patients in ideal body weight and amenorrhoea who responded to naloxone administration and those shown by patients in the same clinical condition but who were insensitive to opioid blockade.. The re-establishment of hypothalamic-opioid inhibitory activity involved in LH secretion in patients with anorexia nervosa during the phase of weight gain predicts imminent restoration of ovulatory cycles. Pituitary LH response to exogenous GnRH during weight recovery does not accurately predict the outcome of the disease regarding reinitiation of menstrual cycles; however, it might be an indicator that the normal function of the hypothalamic-pituitary axis is being restored.

Topics: Adolescent; Adult; Anorexia Nervosa; Female; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Luteinizing Hormone; Naloxone; Ovulation; Pituitary Gland; Secretory Rate; Weight Gain; Weight Loss

Anorexia nervosa (AN) is frequently associated with anomalies of growth hormone (GH) and prolactin (PRL) secretion. We studied the GH and PRL responses to GHRH1-44 (50 micrograms IV) and the effect of a naloxone infusion (1.6 mg/hr), started 1 hr before GHRH administration, on this response in 12 female patients with AN, aged 15-30 yr, and in seven normal women, aged 19-27 yr, during the follicular phase as controls. In AN, GHRH induced an increase in GH levels similar to that observed in normal subjects. A significant inhibition of the GH response to GHRH was observed during naloxone infusion, similar to the inhibition in normal female subjects during the follicular phase. PRL levels showed a significant increment after GHRH alone and a slight, nonsignificant, PRL increment after GHRH during naloxone infusion in AN patients. In contrast a slight PRL decrease was observed after GHRH, both before and during naloxone infusion, in the normal subjects. Our study demonstrates that endogenous opioids play a role in influencing PRL secretion in patients with AN different from their role in normal subjects.

Topics: Adolescent; Adult; Anorexia Nervosa; Endorphins; Female; Follicular Phase; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Infusions, Intravenous; Naloxone; Prolactin

Opioid peptides and catecholamines play an important role in the control of appetite, behaviour and hormonal secretion. To evaluate the role of the opioid and adrenergic systems in the hormonal dysfunction of anorexia nervosa (AN), we investigated the effects of naloxone and clonidine on serum GH, LH, FSH, beta-endorphin, TSH, prolactin and cortisol concentrations in 35 women with AN. Basal plasma beta-endorphin concentrations were significantly lower than those in healthy controls. The response of beta-endorphin to clonidine in the AN patients was increased, whereas the response of beta-endorphin to naloxone was decreased. Basal serum cortisol concentrations were significantly higher in the AN patients than that in the controls. There was a significant increase in the cortisol response to naloxone in the controls but a lack of cortisol response to naloxone in the patients with AN. Naloxone produced a significant increase in LH release in the controls during the luteal phase of the menstrual cycle, as well as in the majority of AN patients. Clonidine caused a diminution of LH in the controls and did not alter LH in the patients. After clonidine injection, a significant increase in GH release was observed in both groups of subjects. If these disturbances persist after normalization of body weight, it might suggest that altered opioid and adrenergic activity is an aetiological factor in the pathogenesis of anorexia nervosa.

Topics: Adult; Anorexia Nervosa; Clonidine; Endorphins; Female; Follicle Stimulating Hormone; Growth Hormone; Hormones; Humans; Hydrocortisone; Luteinizing Hormone; Naloxone; Prolactin; Radioimmunoassay; Sympathetic Nervous System; Thyrotropin-Releasing Hormone

Topics: Administration, Topical; Anorexia Nervosa; Female; Humans; Naloxone; Pupil

The relationship between arousal and efficiency of the brain is shown by the inverted U of the Yerkes-Dodson curve. Measuring arousal has been difficult because the three types of arousal (EEG, behaviour and autonomic) do not change in unison. From Magoun's work, arousal can be stimulated via the reticular formation or from parts of the cortex. Kyotorphin (Tyr-Arg) causes widespread excitation when applied to the cortex and may represent this mechanism: it is then inhibited only by noradrenaline. The hippocampus causes stimulation of arousal to persist after the exciting stimulus stops and can itself be stimulated into long term potentiation. The latter may be related to the onset of compulsive behaviour which appears to occur only with excessive stimulation of arousal. The opioid dynorphin is the main stimulator of the hippocampus and can cause long term potentiation. Inhibition of opioid activity by continuous naloxone infusion facilitates weight gain in anorexia and in some will abolish the compulsive drive. Other opioid antagonists need to be found for the more severe compulsive behaviour patients.

Topics: Anorexia Nervosa; Arousal; Body Weight; Brain; Compulsive Behavior; Electroencephalography; Endorphins; Energy Metabolism; Hippocampus; Humans; Naloxone; Reticular Formation; Sleep Stages

The aim of this study was to evaluate the role of endogenous opiates in the mechanism of decreased LH secretion in women with anorexia nervosa. For this purpose the effect of opiate receptor blockade with naloxone on LH, FSH, PRL, and beta-endorphins secretion was studied in 24 women with anorexia nervosa and 7 normal women. Serum LH, FSH, PRL, beta-endorphin-like substance, ACTH, and cortisol concentrations were measured before and after opiate receptor blockade after a single iv dose of 0.2 mg/kg naloxone or saline. Mean serum LH and FSH concentrations increased significantly after naloxone in the normal women. Eleven patients had a significant increase in serum LH concentrations in response to naloxone and 13 did not respond to naloxone with an increase in LH concentration. In the first group the basal LH values were higher than those in the second group. In the majority of patients in the first group amenorrhea preceded the wt loss, whereas in most patients in the second group amenorrhea appeared during the phase of wt loss. Naloxone did not alter pulsatile LH secretion in 6 women. No effect of naloxone on serum FSH and PRL concentrations was found. A significant increase in beta-endorphin-like substance levels after naloxone administration occurred in patients with anorexia nervosa. However, serum ACTH and cortisol concentrations were not altered in response to naloxone. In conclusion, the increase in LH release after opiate receptor blockade by naloxone suggests that endogenous opiates may play a role in the mechanism of inhibited LH secretion at least, in the majority of those women with anorexia nervosa in whom amenorrhea preceded wt loss. The results also point to a different mechanism of ACTH and beta-endorphin secretion in patients with anorexia nervosa.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Anorexia Nervosa; beta-Endorphin; Endorphins; Female; Follicle Stimulating Hormone; Humans; Hydrocortisone; Luteinizing Hormone; Naloxone; Prolactin; Sodium Chloride

The evidence for stress activation of endorphinergic systems suggests a physiological role in endogenous analgesic and anti-anxiety regulation which would provide a reserve in emergency situations. The possibility of involvement of these systems in psychiatric illness arises from the psychotogenic and anxiolytic properties of some opiates. The endorphin-excess and -deficiency hypotheses of schizophrenia are reviewed in the light of naloxone's small but statistically significant antipsychotic action, and the activation of endorphinergic systems in the course of neuroleptic therapy. The hypothesis that endorphinergic deficiency may be present in endogenous depression is reviewed. Although alterations in beta-endorphin immunoreactivity measured peripherally and in CNS have not been substantiated, therapeutic trials using a mu-receptor agonist have shown promise of a rapidly-acting antidepressant effect. ECT is accompanied by increases in plasma beta-endorphin immunoreactivity.

Topics: Animals; Anorexia Nervosa; Arousal; Brain; Electroconvulsive Therapy; Endorphins; Humans; Mental Disorders; Mood Disorders; Naloxone; Receptors, Opioid; Schizophrenia; Stress, Physiological; Substance-Related Disorders

Topics: Anorexia Nervosa; Female; Humans; Luteinizing Hormone; Naloxone; Receptors, Opioid

Endogenous opiates are involved in the control of pituitary gonadotrophin and PRL secretion, and possibly of food intake. Both hyperprolactinaemia and weight loss (especially in anorexia nervosa) are frequently associated with amenorrhoea and an absence of gonadotrophin pulsatility. Since it has been suggested that increased endogenous opiate tone may operate in both conditions, we infused high-doses of naloxone into twelve patients with amenorrhoea of whom five had hyperprolactinaemia and seven had weight-loss related amenorrhoea. Eleven of the twelve patients had low levels of oestradiol (less than 50 pmol/l). Naloxone induced a marked rise in both LH and FSH levels in all of the five hyperprolactinaemic patients. In contrast, the patients with weight-loss amenorrhoea responded to naloxone with only a small or no rise in gonadotrophins. There was no consistent change in PRL in either group of patients. It is concluded that in hyperprolactinaemia, but not weight-loss amenorrhoea, there is an important endogenous opiate-mediated tonic inhibition of secretion of hypothalamic gonadotrophin releasing hormone.

Topics: Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Estradiol; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Naloxone; Prolactin

The effects of a constant intravenous infusion of naloxone in doses ranging from 3.2 to 6.4 mg/day were studied in a group of patients with anorexia nervosa. Patients showed a significantly greater weight gain during the infusion compared with the periods before and after naloxone. Plasma β-hydroxybutyrate and non-esterified fatty acid levels fell during the infusion. It is suggested that, in man, naloxone has an antilipolytic effect in vivo.

Topics: Adolescent; Adult; Anorexia Nervosa; Body Weight; Fatty Acids, Nonesterified; Female; Humans; Hydroxybutyrates; Infusions, Parenteral; Lipolysis; Naloxone

Topics: Animals; Anorexia Nervosa; Endorphins; Humans; Naloxone