Around 50%-60% of all heroin addicts and patients entering methadone treatment have biochemical evidence of chronic liver disease; over 50% of patients in chronic methadone treatment have persistent liver function test abnormalities (Table 2). ^{6, 7, 9} Nevertheless, in prospective and retrospective studies there has been no evidence of hepatotoxicity due to methadone. Patients with normal liver function at time of admission to methadone treatment do not develop abnormalities of liver function except in the setting of acute viral hepatitis or chronic alcohol abuse. Neither liver function tests nor clinical status were shown to deteriorate during methadone treatment in patients known to be alcohol abusers.

* Abnormal liver function was defined as a plasma SGOT level greater than 30 units. No evidence of hepatotoxicity of methadone was found.

The etiology of chronic hepatic dysfunction observed in methadone-maintained patients is of two types: sequelae of earlier acute infection with hepatitis B virus or non-A non-B virus, and various types of alcohol-induced liver disease (Table 3). ^{6, 7, 9, 11, 12} It has been shown that 10%-12% of adult and adolescent methadone-maintained patients are chronic carriers of hepatitis B antigen, and that approximately 50% of all patients have hepatitis B core antibody.^{6, 9} In a study of maintained patients, all with chronic liver disease, over 96% had some marker of prior hepatitis B infection.¹² The percentage of patients with chronic sequelae due to hepatitis non-A non-B virus is unknown.

It has been shown that, contrary to earlier belief, substantial numbers (about 20%) of street heroin addicts are also chronic abusers of alcohol.^{6, 7, 9, 11} In clinical studies from this laboratory, we found that 25-35% of adult and adolescent methadone-maintained patients are chronic abusers of alcohol, and that in this group of patients, progressive liver disease may occur.

A variety of biochemical and physiological alterations have been observed. Two types of abnormalities commonly observed are alterations in serum protein levels and immunological indices (Table 4).^{6, 7, 9, 15-17} Some of these alterations, such as elevations in levels of serum albumin may be a direct effect of opioid treatment.¹⁶ Others, such as elevated levels of globulins, are more likely due to chronic liver disease or a long history of injection of diverse foreign materials. Thyroid binding globulin levels are also elevated, leading to apparent elevations in T₄ levels. Elevated IgG and IgM levels are observed in patients for years after cessation of parenteral drug abuse. Biological false positive test results for syphilis reflecting abnormal IgM levels are also observed. Lymphocytosis occurs in approximately 20% of patients in methadone treatment for three years or more; abnormal percentages of B cells and abnormal T cell rosette formation have been reported. It has been suggested that some of these alterations in immune function may be due to direct or indirect opioid effects.

In our prospective studies of the physiological effects of chronic methadone treatment, we have observed normal to elevated, rather than depressed, levels of serum albumin in patients at time of admission to methadone treatment, with greater numbers of patients having elevated levels of serum albumin after three years or more of methadone treatment (Table 5). ^6-8 These findings of persistent elevations in serum albumin levels are novel and especially unusual in a population with a high prevalence of chronic liver disease and alcohol abuse. Subsequent studies in adults as well as in adolescents have confirmed these earlier findings.^{9, 15} In addition, normal to elevated levels of serum albumin have recently been observed in a prospective study of alcoholic methadone-maintained patients. This finding is very provocative since alcohol is known to decrease albumin synthesis. Studies carried out in a rabbit model have shown that chronic administration of methadone results in increased intra- and extra- vascular pools of albumin coupled with accelerated (not depressed) degradation of albumin suggesting sustained increases in albumin synthesis.¹⁶

In studies performed by other laboratories, it has been shown that several alterations in respiratory physiology occur during early methadone maintenance treatment including decreased sensitivity of the central nervous system receptors to CO₂, alveolar hypoventilation and arterial hypercapnea (Table 6).^{9, 18-20} Only one alteration in normal respiratory physiology persists during chronic treatment for 12 months or more: a decreased sensitivity of central nervous system receptors to hypoxia.¹⁹ To date, there have been no clinical symptoms reported referable to this alteration. Also it has been shown that the normal hyperventilation of late pregnancy is diminished in methadone-maintained pregnant women.²⁰ Recently it was suggested that endogenous opioids may play a role in normal pulmonary physiology.

Acute administration of short- or long-acting narcotics or of large amounts of endogenous opioids cause diverse and significant biochemical alterations in normal endocrine and neuroendocrine function. It has been of special interest to determine which of these effects persist during chronic long-term methadone treatment and which effects are no longer seen during chronic treatment because of the development of tolerance.^{7-9, 21-37} These findings pertain only to long-acting opioids; there are many endocrine effects to which tolerance does not develop during chronic administration of short-acting narcotics because of their very different pharmacokinetic properties with significant peak levels followed by raped decline to nadir levels three or four times during each 24-hour period. Many findings concerning the acute or chronic effects of opioids on endocrine function that are made using animal models cannot be extrapolated directly to man because, in animals, the pharmacokinetic properties of most narcotic drugs are significantly different. For instance, methadone, which has been shown to have an apparent terminal half-life in plasma of 24 hours in man when conventional techniques are used (and a much longer half-life of approximately 48 hours when more sensitive stable isotope tracer techniques are used, has a plasma half-life of 90 minutes in the rat.^{1, 4, 13, 38-40} Even in apparently carefully executed studies of endocrine function in patients maintained on methadone, it is not always clear whether or not patients with liver disease and/or patients using alcohol or marijuana on a regular basis have been excluded, since these factors can significantly affect endocrine function.¹⁴

Acute administration of short-acting opiates in animal models causes a reduction in FSH and LH levels, a reduction in glucocorticoid levels, and an increase in prolactin levels. In studies of methadone-maintained patients, several workers have found that plasma levels of FSH and LH may be significantly reduced in some patients during the first year of chronic treatment (Table 7). In both prospective and special studies, it has been shown that levels of these hormones returned to normal after two or more years of chronic methadone treatment. However, we have found that testosterone may remain decreased in around 20-30% of patients after one year of chronic treatment.

It has been well-documented that the acute or subacute administration of narcotics to humans results in a predictable significant reduction in plasma cortisol levels, presumably reflecting a reduction in ACTH levels. It has also been shown that during cycles of subacute or chronic morphine administration in former heroin addicts, both cortisol levels and total urinary excretion of glucocorticoids are reduced. However, our group and others have shown that during chronic long-term methadone administration, plasma cortisol levels are within normal range with a brisk but normal circadian variation.^{7, 88, 25, 37} In recent studies to be discussed in more detail, we have also shown that plasma levels of ACTH are normal in patients during chronic long-term methadone maintenance treatment.³⁷ In early studies reported in 1972 and 1974, we have found that during the first 2 months of chronic methadone treatment, significant alterations of function of the hypothalamic-pituitary adrenal axis do exist, as evidenced by abnormal metyrapone test results, indicating reduced hypothalamic-pituitary reserve for release of tropic hormones.^{8, 25} We showed that tolerance develops to this effect after three or more months of stabilized methadone treatment.

In 1997 at another New York Academy of Sciences meeting, we reported the very provocative finding of elevated levels of prolactin in significant percentages of methadone-maintained patients, and also, in a highly controlled study of patients maintained on a steady dose of methadone treatment for more than one year, the intriguing finding of altered prolactin release, without or with absolute elevation in prolactin levels.⁹ Prolactin levels returned to the normal pattern of diurnal variation following detoxification from methadone. These findings are of considerable interest in attempting to understand both the mechanisms underlying the addictive disease process. Since prolactin is normally under tonic inhibitory control by dopaminergic factors, and possibly by dopamine itself, the finding of persistent responsiveness of prolactin release to peak levels of opioids, even during chronic methadone administration when tolerance has developed to most of the endocrine and neuroendocrine effects of opioids, is very compelling. It suggests that even during long-term treatment, methadone may reduce, antagonize, or block central dopaminergic action. Findings of elevated levels of prolactin in patients maintained on methadone have been made by other groups as well.

We have performed studies to elucidate further the effects of chronic methadone treatment of prolactin release as well as on related peptide and steroid hormones in well-classified subgroups of patients, including otherwise health subjects, patients with defined types of chronic lever disease and patients receiving anticonvulsant treatment with phenobarbital and phenytoin, both of which have been shown to lower plasma levels of methadone.³⁵ One methadone-maintained woman has been followed throughout a normal pregnancy with respect to the effects of methadone on prolactin release. All patients were studied in a metabolic research ward after several days of stabilization during which no other drugs were administered. Normal day-night cycles were established and time of meals and doses of methadone were controlled. Blood specimens were drawn through intravenous catheters before (at 9 am) and at 4 hours (1 pm) and at 10 hours (7 pm) after oral administration of the daily dose of methadone. Plasma levels of methadone were determined by gas-lipuid chromatography techniques; peak levels of methadone were observed around four hours after the oral dose. In this group of otherwise health maintained patients, plasma levels of FSH and LH were within normal limits and there was a normal diurnal variation in levels. However, peak plasma levels of prolactin occurred in these patients around 4 hours after the oral dose of methadone, the time when peak levels of methadone were also observed. Actual levels of prolactin exceeded the upper limits of normal in some patients only. In all but one patient, the expected diurnal variation of prolactin levels (with the highest levels in the morning), was altered with peak levels observed at 1 pm, four hours after the methadone dose. Similar findings were made in patients with chronic liver disease and also in patients receiving anticonvulsant treatment, despite the fact that plasma levels of methadone were much lower in this group

In the pregnant methadone-maintained patient, plasma levels of methadone were found to become progressively lower during the third trimester of pregnancy.³⁴ However, peak plasma levels of methadone continued to occur around four hours after oral dosing, and peak plasma levels of prolactin were also observed at that time, even in late pregnancy when prolactin levels were appropriately very high. This responsiveness of prolactin release to peak levels of methadone was thus observed in all subgroups of long-term methadone maintained patients.

It has been reported that catechol estrogens, along with dopamine, may inhibit prolactin release, whereas estrogenic metabolites of estradiol may facilitate prolactin release. We have carried out studies to determine the effects of chronic methadone treatment on the formation of both catechol estrogens and estrogenic 16-hydroxylated metabolites of estradiol in methadone-maintained patients.³⁶ Again, in a controlled clinical research setting, sequential studies using radiometric assay techniques were conducted to determine the extent of estradiol metabolism by each pathway.

There were no differences in catechol estrogen formation in otherwise health methadone-maintained patients as compared with otherwise health unmedicated control subjects. However, catechol estrogen formation was significantly reduced in methadone-maintained patients with chronic liver disease. Further studies are in progress to determine whether catechol estrogen formation is reduced in patients with chronic liver disease who are not receiving methadone.

Significantly increased formation of 16-hydroxylated metabolites of estradiol was found in methadone-maintained patients both without and with chronic liver disease as compared with otherwise health control subjects. Since prolactin response to methadone was observed in patients without as well as with chronic lever disease, it is unlikely that reduced peripheral formation of catechol estrogens is a mechanism underlying this phenomenon. However, the findings of increased production of estrogenic metabolites of estradiol in methadone maintained patients could be of importance.

However, when the same patients were restudied after three or more months of chronic methadone treatment, the response to metyrapone had become normal, with increased urinary excretion of 17-hydroxycorticosteroids indicating the normal release of increased amounts of corticotropin releasing factor and ACTH in response to stress.

Plasma levels of cortisol were also measured simultaneously in these patients. At time 0, which was at 9 am, the mean plasma cortisol level was 18.3 mg/dl; at four hours the mean level was 6.8; and at eight hours after methadone dose, 7.2 mg/dl. Thus, cortisol levels were within normal limits, and a normal and risk diurnal variation in these levels was observed.

To summarize what is known about chronic effects of opioids (in particular, methadone), many interesting physiological and biochemical alterations occur, but there are minimal side effects that are clinically detectable in patients during chronic methadone maintenance treatment. Toxicity related to methadone during chronic treatment is extraordinarily rare. To date there has been only one report of a death due to methadone in any methadone-maintained patient. A man who had suffered from severe chronic constipation during methadone maintenance treatment developed complete obstipation, repeatedly refused medical treatment until the day of his death, and died due to complications of complete intestinal obstruction.⁴²

Although there have been various reports in animal models of neurotoxicity due to very high doses of methadone, to date there has been only one case reported of a neurological problem specifically linked to chronic methadone treatment.⁴³ A 25-year-old man who had a seven-year- history of heroin addiction and poly-drug abuse was admitted to methadone maintenance treatment and within several months began to experience symptoms including light-headedness, dizziness, visual disturbances, speech disturbances and tremulousness. He was seen by a physician because of these problems and two months later was seen by other physicians who published this case report. At that time he had chronic movements of the arms, shoulder, and head and hi speech was abnormal, with stuttering and difficulties in verbalization. His dose of methadone was slowly reduced and within two months he had reached 0 dose of methadone. No other medications were administered. The choreic movements disappeared and his speech returned to normal. Within six months there was no recurrence of chorea while he remained methadone-free. The findings in this case are similar to those which have been reported following treatment with a variety of antipsychotic agents. It was suggested by the authors that possibly more cases of this type would be seen Although this is certainly possible, high dose methadone treatment has been used for over 17 years with approximately 85,000 patients in treatment each year since 1972. Therefore, it is unlikely that neurotoxicity due to chronic methadone treatment will emerge as a major adverse reaction as it has during chronic use of antipsychotic drugs.

It has been suggested that opioids may be effective in the management of some types of psychiatric disorders. Specifically, it has been suggested that opioids may be used as antipsychotic agents, as antidepressant agents, and also may have a role in the management of panic disorders. The pharmacologic agents usually used to treat these disorders at this time should be considered with respect to their side effects and toxicity. There is no specific information at this time concerning interactions between the various psychotropic drugs and the endogenous opioids.

Antipsychotic neuroleptic drugs such as chlorpromazine and haloperidol are primarily used in the management of thought disorder including a variety of schizophrenic disorders: schizophreniform disorder (if it is not self-limited), brief reactive psychosis (if behaviour is dangerous), and also in some cases of atypical psychosis, paranoid disorders, and schizoaffective disorders (Table 8). Neuroleptic agents are also indicated for acute management of psychotic depressed and manic patients. In the chronic treatment of schizophrenia, some clinicians have recommended the routine concomitant use of anti-Parkinson agents because of the very high prevalence of Parkinson-like syndrome in patients receiving chronic neuroleptic treatment. it has also been suggested that opioids might be effective drugs to use in the management of some of these disorders.

Tricyclic antidepressants such as amitriptyline or imipramine, without or with the addition of neuroleptic agents or other types of psychotropic drugs, are indicated for a variety of affective disorders (Table 9). Acute manic episodes may be managed with a neuroleptic followed by chronic treatment with lithium. Major depressive episodes can be managed either with electro convulsant therapy (ECT) or pharmacologically with tricyclic antidepressant without or with acute treatment with neuroleptics. Bipolar disorder is usually managed chronically with lithium although tricyclic antidepressant may be needed in the initial treatment of those patients presenting with depression and neuroleptic agents for agitation. Major depression is usually managed pharmacologically with tricyclic antidepressants initially although again, neuroleptic agents may be needed acutely for destructive behaviour and lithium therapy has demonstrated efficacy as a prophylactic agent. Cyclothymic disorder may be managed chronically with lithium and finally dysthymic disorder may be treated with psychotherapy alone or in conjunction with tricyclic antidepressants or monoamine oxidase inhibitors. Likewise, both phobic disorders and panic disorder are frequently treated with a combination of imipramine and psychotherapy (Table 10).

Side effects, physiological alterations, and toxic reactions due to these various antipsychotic and other psychotropic drugs have been reported extensively but the prevalence of each of these effects is unknown with wide ranges of estimates reported for each effect. These drugs are usually administered on a chronic basis only to patients with significant symptomatology, and often are administered in combination with other drugs which makes precise delineation of type and prevalence of side effects difficult. However, numerous reports of small and large numbers of patients receiving these drugs have appeared and the clinical side effects as well as toxic reaction observed will be summarized.

The clinical side effects of the tricyclic antidepressant drugs such as imipramine and amitriptyline are usually mild (Table 11). They include dry mouth, sweating, dizziness due to hypotension, constipation, disturbed vision, tremor or twitching, hyperactivity, urinary retention, drowsiness, increased sexual desire, palpitations, and blurred vision.^44-52 Of these, the cardiac abnormalities, which have been observed in some patients receiving therapeutic doses, should cause the greatest concern, although apparently the occurrence of these abnormalities becomes significant only when therapeutic doses are exceeded, such as during episodes of drug overdose. Both the phenotiazine neuroleptics and tricyclic antidepressants lower the seizure threshold and must be used with extreme caution in patients with an underlying convulsant disorder. In addition, the anticholinergic effects of neuroleptics and tricyclic antidepressant drugs may increase intraocular pressure and exacerbate glaucoma in some patients.

Clinical side effects or toxic effects of lithium are apparently greater both with respect to prevalence and also potential severity (Table 12).^53-70 Thus close monitoring of doses administered and blood levels of drug achieved are of critical clinical importance. The effects observed include fine or coarse tremor, diarrhoea, nausea and vomiting, drowsiness, tinnitus, blurred vision, fatigue, polydypsia and polyuria, vertigo and unsteady gait, and dry mouth. The prevalence of each of these symptoms in different reports varies enormously; however it seems to be the general consensus that such clinical side effects or toxic effect of lithium are very common during treatment with usual therapeutic doses, and may be expected to occur whenever blood levels of lithium become elevated. In addition there is growing concern about nephrotoxicity and thyrotoxicity in some patients receiving chronic lithium treatment.

Of even greater significance with respect to potential serious morbidity especially when couple with the apparent prevalence, are the clinical side effects or toxic effects observed during chronic treatment with antipsychotic, neuroleptic drugs such as chlorpromazine or haloperidol (Table 13).^{44, 71-82} A variety of movement disorders, some of which resemble Parkinson’s syndrome may be observed clinically, as well as a variety of other adverse effects. These clinical effects include muscular rigidity and tremor, uncoordinated spasmodic movements, involuntary motor restlessness, abnormal movements of face and mouth, dizziness and weakness, nausea and heartburn, constipation, impaired ejaculation, galactorrhea, menstrual abnormalities, drowsiness, impaired vision, and jaundice. These are very serious effects affecting multiple organ systems (Table 14).

Central nervous system effects include acute extrapyramidal disorders (such as Parkinson’s syndrome), dystonia and akatisia, tardive dyskinesia, and somnolence and sedation. Autonomic nervous system effects include ortostatic hypotension, dryness of mouth and other membranes, nausea and vomiting, urinary retention, and constipation or diarrhoea. Skin and eye reactions of a variety of types occur. Hepatic effects include acute drug hepatitis and severe progressive cholestatic hepatitis. Agranulocytosis may occur. Neuroendocrine effects include abnormal menses, elevated prolactin levels, and galactorrhea. It is estimated that some type of serious side effect may occur in up to 90% of patients receiving these drugs.

Tardive dyskinesia is in some respects the most disturbing of the these adverse, toxic reactions since it may occur during, but also following, chronic treatment with a neuroleptic agen, and since this syndrome, which is also called the "cuccolingual masticatory syndrome" may be irreversible (Table 15). No specific treatment is known, although reinstitution or increase in doses of the neuroleptic agent that was used may be beneficial in some cases. However, since the neuroleptic agent itself is clearly implicated in causing this syndrome, many clinicians would recommend discontinuation of neuroleptic treatment and trial of one of a number of diverse agents which have been used with varying degrees of success. The mechanism underlying this disorder is unclear but it is thought to be related to dopamine receptor hypersensitivity, which may occur during chronic treatment with a neuroleptic agent because of chronic receptor blockade, coupled with over-production of dopamine.

In summary, side effects of the antipsychotic agents are multiple and may of them are severe with respect to their morbidity in a variety of organ systems especially the nervous system. During proper usage, side effects and toxic reactions due to lithium are intermediate in their severity, and the side effects and toxicities of tricyclic antidepressants seem to be relatively mild, as are the effects of chronic opioid treatment. It must be emphasized, however, that tolerance and physical dependence, with potential subsequent addiction, develop to the opioids, but not to these other classes of drugs.

Of great interest with respect to an understanding of the mechanism of action of these various psychotropic drugs, and also possibly of the disorders that have been effectively managed by their chronic administration, is that there is one common "side effect" for all of the antipsychotic drugs, the opiates, and other opioids: elevation is plasma levels of prolactin or prolactin release in response to drug occurs during acute and chronic administration of each of these groups of agent (Table 16). Prolactin levels increase and become elevated in response to acute administration of each of these types of drugs; prolactin levels increase to their peak levels in response to the peak plasma levels of drug during long-term chronic administration of one opioid, methadone; and finally tolerance apparently does not develop to these drug effects on prolactin release.

It has been previously suggested by many investigators, in consideration of antipsychotic drug therapy, that elevated prolactin levels may be used to monitor compliance. It has also been suggested that the dopaminergic effect of various antipsychotic drugs may be predicted by prolactin response.⁸³ However, there is still a controversy as to whether abnormalities in dopaminergic function are the central defects in the various psychiatric disorders such as schizophrenia, in which antipsychotic drugs, with their primary action of inhibition of central dopamine function, are effective. In consideration of the potential role of opioids in the management of these diseases, it is of interest that the one neuroendocrine effect to which tolerance does not develop during chronic opioid administration is prolactin responsiveness. Thus, increased levels of prolactin following administration of one of these agents may be a marker of a common effect of antipsychotic drugs, opiates, and opioids, specifically, inhibition of central dopamine function, and such inhibition of central dopamine function may be the major action that makes each of these agents effective in the treatment of the disorders in which they have been proven to be efficacious. Thus, one major, if not sole, abnormality in the various disorders effectively managed by these drugs may be excessive central dopaminergic activity.

ACKNOWLEDGMENTS

The author wishes to thank Dr. Robert A. Schaefer for his many helpful comments and Mr. Jay G. Ruckel and Mrs. Waraporn Wun for assistance in compiling the bibliography and preparing the manuscript.

REFERENCES

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