We became interested in possible opioid actions on the endocrine system several years ago. This study will review the most important discoveries relating exogenous opioids to the endocrine system in man. The endogenous opioid, enkephalins/endorphins, may play important roles in the endocrine system. This topic is outside the scope of this study. We also studied the immunological consequences of opiate addiction in man, and effects which are much less attributable to the opioids per se.

 

This report centers on observations made amongst opiate addicts while using street drugs, during methadone maintenance treatment, and after detoxification.

 

ENDOCRINE OBSERVATIONS

 

The endocrine system has multiple, interlocking components. It usually has both stimulatory and inhibitory hormones and the balance between the two opposing forces tends to maintain homeostasis. Thus many key body components are kept within an optimal metabolic range. Many of the hormones are regulated by their own blood concentrations or by the products of their target organ secretion. Both long feedback systems, most extensively worked out for the hypothalamic-pituitary-adrenal (or thyroidal or gonadal) axes, exist as well as short feedback loops where a pituitary hormone may influence its own secretion via a short feedback loop to the hypothalamus.

 

Study of the opioid effects on hormones must then consider, not only the results of an acute bolus of opioids on a blood concentration of a specific hormone, but also on the dynamics of hormone secretion. Also there are important cellular adjustments that follow long term opioid administration. Tolerance to the agonist effects of opioids occurs with sustained administration (Muslin, 1964; Pradhan, 1977; Eddy, 1965).

 

Since tolerance develops at non-uniform rates to various opioid agonist effects (Pradhan, 1977) with some (analgesia) rapid, other (antidiarrheal) slowly and other (pupillary) slight if at all, it is important to examine the endocrine effects of exogenous opioids in subjects who have been receiving a fixed daily dose of an opioid (methadone usually) for many months to allow for the complete expression of tolerance.

 

The chronic opioid users, who are most stable, best documented, most available for study, and most likely to follow an appropriate protocol in which specified baseline conditions are desired, are the methadone maintenance recipients.

 

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

 

Several animal and human studies raise questions about the effects of acute opioids on the HPA axis (Kokka, 1974; George, 1976; Fishman, 1977; Van Vugt, 1980). Some data suggest the opioids stimulate ACTH-cortisol release, and others imply that there may be lesser ACTH-cortisol secretion after opioids than would be expected without them (Briggs, 1955; Reier, 1973; McDonald, 1959). Because of its importance, careful study of the HPA axis in relation to opioids is warranted.

 

Most data are reassuring, indicating that the HPA axis was normal or near normal in the non-tolerant subjects given acute opioids. The low-tolerance (street drug using) opiate addict (Table 2), usually had normal plasma cortisol and near normal levels ACTH when resting (unstimulated) conditions (Ho, 1977; Cushman, 1970). HPA dynamics revealed normal responses to exogenous ACTH (Eisenman, 1961); insulin hypoglycemia, which measures the HPA axis response to stress, is normal (Cushman, 1970). Metyrapone, an adrenal inhibitor of 11 b hydroxylase which reduces plasma cortisol and invokes ACTH secretion via the feedback route, produced initially a low response in urinary 17 ketogenic steroids in a small number of patients. Later their responses were normal (Cushman, 1970).

 

The tolerant methadone recipients, tolerant to 40-100 mg of oral methadone daily, showed normal plasma cortisol levels for the most part, normal increases in HPA axis after metyrapone and insulin hypoglycemia (Cushman, 1981) and normal cortisol secretion rates (Hellman, 1975).

 

HYPOTHALAMIC-PITUITARY GONADAL AXIS

 

In contrast to the HPA axis, there are abundant data showing opioid related adverse effects on the HPG axis. Clinical reports of infertility, fluctuating libido, erectional problems, delayed orgasm, disordered menstruation are common (Cushman, 1972; Wieland, 1970). Seventy to ninety percent of females, who reported normal menses prior to opiate addiction, had menstrual disturbances during addiction. Since most were normal after detoxification (Santen, 1975; Gaulden, 1964; Stoffer, 1968), the data strongly suggest that something associated with addiction was causative of their menstrual abnormalities.

Hormone studies have been extensively performed on males. Resting (unstimulated) blood levels of FSH, LH, and Prolactin are listed in Table 3. Low LH and to a much lesser extent low FSH levels were frequent amongst low tolerance, street drug opiate addicts (Azizi, 1973; Brambilla, 1979). Prolactin levels were variable. With high tolerance as to methadone, most patients had normal LH, FSH, and prolactin levels (Cushman, 1974). Stimulation of LH/FSH levels with exogenous LRH were subnormal in a group of Italian street addicts (Brambilla, 1979), but normal amongst a group of methadone maintained patients (Dent, 1975).

 

Plasma testosterone levels amongst opioid addicts ranged widelyewith many individual values below the range of normal (Mendelson, 1975; Cushman, 1973; Cicero, 1975). Amongst methadone-maintained patients the plasma testosterone (T) levels tended to be lower in those who had high daily methadone dose; an inverse relationship between plasma T and daily methadone was found. In an inpatient controlled setting, acute opioids lowered plasma LH and T, and their discontinuation was accompanied by a rapid return of plasma T to normal (Mendelson, 1975).

 

PRL rises in the normal subject after an acute bolus of opioids (Fishman, 1977; Cushman, 1974). This phenomenon is well studied with animals. Considerable evidence imply that it may involve dopamine at the hypothalamic level. Opioid tolerant persons, usually, but not invariably, retain their capacity to augment their PRL level after additional opioid doses (Cicero, 1975). Most male opioid users had normal estradiol levels (Azizi, 1973) and secretion rates (Cushman, 1974).

 

Amongst females, hormone studies have been relatively sparse. In detailed studies of a few females with histories of oligo-amenorrhea by Santen (1975), there was less evidence of hypothalamic inhibition of LH surges and anovulation. To what extent these findings apply to the other female addicts is unclear.

 

THYROID

 

The thyroid-TSH axis appears to function normally in both low and high levels of opioid tolerance. The major finding was in the laboratory measurements of thyroid function. Common amongst street addicts was a high serum thyroxine (T4), and reduced T3 resin uptakes (Webster, 1973; Azizi, 1974). Their euthyroid status was attested to by their normal TSH and free T4 levels. The difficulty seemed to be related to augmentation of the binding capacity of Thyroxine Binding Globulin (TBG). This abnormality, which may relate to liver disease or to relatively low androgenicity appeared to become less common after methadone maintainence treatment (Webster, 1973; Table 4).

 

IMMUNOLOGICAL

 

Application of immunological tools to human opioid addicts disclosed a variety of abnormalities.

Heroin itself is poorly antigenic (Azizi, 1974); hence very little of the humoral changes could be accounted for by the development of anti-heroin antibodies. On the other hand, circulating immune complexes were common (Smith, 1975; Bayer, 1976; Table 5). Yet very little immune complex disease manifestations were observed. Occasionally, a heroin addict will show the nephrotic syndrome with immune bodies identified in the glomeruli, but very few patients show arthritis, purpura, vasculities, etc. Studies of cell mediated immunity are far from complete and have produced conflicting results. Blast transformation using phytohemagglutinnin may or may not be altered in heroin addiction (Ortona, 1979). Our studies of E rosette (early type) amongst opioid addicts found a mixed bag, which defied interpretation (Brown, 1974); others (Cushman, 1973) found a depression. The're did not seem to be impairment of delayed tuberculin type skin test hypersensitivity in the addict.

 

On the other hand, there are numerous abnormalities in the other arm of the immune system. Antibody classes, especially IgM and to a lesser extent IgG, were often abnormally high amongst individual addicts, as well as being strikingly high amongst populations of addicts compared to controls. No changes in IgA or IgD were found (Cushman, 1973; Grieco, 1973).

 

With methadone treatment, perhaps related to sharp reduction in the rates of parenteral drug use, serial IgM levels tended to return to normal in a prospective study. Other clinical antibody measurements are high amongst opioid addicts (Millian, 1971). Rheumatoid factors, and the biological false positive tests for syphilis (BFP) were only a few of the many more common antibody titers which were found to be inappropriately high (or abnormally present) amongst opioid addicts. Other antibody levels, as anti CMV or anti hepatitis B, are probably high as a consequence of infection. Ratio of BFP fell with methadone treatment, time, and possibly amelioration of liver disease (Table 6; Cushman, 1974).

 

Since heroin is poorly antigenic, since the increased serum IgM was primarily seen amongst parenteral drug users rather than those using intranasal route for drug administration, and since many infections with yeasts, bacteria, fungi, protozoa, and viruses have been observed amongst opioid addicts, it may be presumed that the humoral immunological changes were caused by diluents, filter, infections, or contaminants acquired along with the opioid rather than caused by the opioid per se.

 

IN CONCLUSION

 

The opioid user may have a variety of endocrine disturbances, most importantly involving the hypothalamic-pituitary-gonadal axis. No clinically significant problems with the ACTH-cortisol were found. Laboratory testing of thyroid function showed high TGB capacities, but no abnormality in thyroid function.

 

The cell mediated immune system, inadequately studied, may be near normal since the present adverse data are not convincing. The humoral immune' system appears vigorous, if not over stimulated, responding to a variety of antigens. Methadone treatment generally was accompanied by fewer abnormalities, with the exception of testosterone, where an inverse relationship with dose of methadone and plasma testosterone was observed. Methadone treatment was usually accompanied by fewer endocrine and humoral abnormalities after compared to before treatment.

 

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