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This study was performed to determine the amounts of methadone and unconjugated metabolites excreted in feces of otherwise healthy methadone maintained patients and to determine whether the metabolism and elimination of methadone, as assessed by analysis of feces, is altered in patients with liver disease. The method for analysis of fecal homogenates was modified from the methods previously developed by our laboratories for the quantitative measurements of methadone and its metabolites in urine, using chemical ionization mass spectrometry with direct probe insertion of specimens to improve sensitivity of analysis. Analysis of fecal homogenates from unmedicated volunteer patients showed that interferences at the mass range of interest (m/z 264 to 326) were usually very small, even smaller than those found in analyses of unmedicated urine specimens, and therefore would not introduce significant error into analysis. Nineteen patients stabilized in chronic methadone treatment for over two years were studied, including five otherwise healthy males and 14 patients with chronic liver disease (nine males and five females). Fecal collections were made over 24 h periods. Three consecutive fecal samples were collected over the required number of sequential 24 h intervals. Each of these fecal conditions was analysed separately. Each analysis was made in triplicate, following extraction procedures. The concentrations of methadone and unconjugated metabolites varied due to biological, pharmacological, and analytical factors and ranged from 3.8 ng ml-1 to 42 micrograms ml-1 of fecal homogenate. The relative concentrations of each, in descending order, were pyrrolidine, pyrrolidone (plus hydroxymethadone), methadone, pyrroline, and methadol.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of chronic treatment with methadone, a long-acting opiate agonist, and naltrexone, a long-acting opiate antagonist on brain immunoreactive beta-endorphin (IR-beta-EP) concentrations were studied in the rat. Male rats were treated for 30 days with either methadone, 2.5 mg/kg/day; naltrexone 2 mg/kg/day, or saline. In a repeat experiment, rats were treated for 36 days with either methadone 2.5 mg/kg/day; naltrexone 4 mg/kg/day, or saline. Brain regions were homogenized in 0.2 N HCl and assayed for IR-beta-EP by RIA. No change in the IR-beta-EP content of the hypothalamus, thalamus, midbrain, or amygdala was measured in either experiment after methadone treatment. Naltrexone, however, significantly lowered brain IR-beta-EP in both experiments. In the first study hypothalamic IR-beta-EP fell from 189 +/- 17 (SEM) to 132 +/- 7.0 ng/g wet weight of tissue after naltrexone treatment (p less than 0.01). In the second experiment naltrexone lowered IR-beta-EP in the hypothalamus from 23.4 +/- 3.6 to 15.5 +/- 1.2 ng/mg protein (p less than 0.005). Similar decreases in the IR-beta-EP content of the thalamus (from 6.74 +/- 0.59 to 4.59 +/- 0.38 ng/mg protein) and amygdala (from 1.31 +/- 0.08 to 0.90 +/- 0.10) were also measured (p less than 0.01). We conclude that occupancy of opiate receptors by an opiate antagonist reduces brain levels of IR-beta-EP and suggests that chronic opiate receptor blockade may result in a compensatory increase in brain beta-EP release.

Two patients with long-standing idiopathic chronic constipation, which responded only to large daily doses of laxatives and additional suppositories and enemas, were treated with the specific opioid antagonist, naloxone, on a single-blind crossover basis. Both patients responded to naloxone treatment, with increased passage of faeces and increased wet and dry faecal weight. Although naloxone is poorly absorbed after oral administration, there was a positive response during oral as well as intravenous treatment, suggesting that the primary effect of naloxone is at specific opiate receptor sites in the myenteric plexus and other neural and endocrine cells of the intestinal wall.

Cerebral spinal fluid (CSF) levels of methadone were measured in nine methadone maintenance patients requiring lumbar punctures for medical or surgical treatment. Concurrent serum methadone levels were also determined. The CSF concentration of methadone in all cases was a fraction of the corresponding serum level--ranging from 2 to 73%. The CSF concentrations of methadone ranged from 0.010 to 0.097 ng%. Peak methadone levels in CSF appeared approximately 3 - 8 hours after methadone administration.

Elevated levels of serum albumin have been noted in patients on chronic methadone maintenance and in heroin addicts. This observation was investigated in rabbits maintained on daily methadone 4 mg per kg of body weight after a period of 3 months on increasing dosage to assure drug tolerance. Albumin distribution and metabolism were measured with tested lots of 125I rabbit albumin. Studies were made before and again after the attainment of the methadone maintenance state. Albumin distribution was altered markedly with a shift of intravascular albumin to extravascular sites. Associated with this change, the serum albumin level rose by an average of 0.5 g per 100 ml. Albumin degradation increased by 32% from 248 to 327 mg per kg per day. The total exchangeable albumin pool increased 35%, or 3.6 g. Since the exchangeable albumin pool increased in the face of an increment in albumin degradation, albumin synthesis must have increased even further to account for this change. Although the specific factors responsible for these alterations in albumin metabolism and distribution are not known at present, to date, this hyperalbuminemic hypercatabolic state is not produceable in any other clinical or experimental situation.

Intravenous drug users are the second largest group to develop the acquired immunodeficiency syndrome, and they are the primary source for heterosexual and perinatal transmission in the United States and Europe. Understanding long-term trends in the spread of human immunodeficiency virus among intravenous drug users is critical to controlling the acquired immunodeficiency syndrome epidemic. Acquired immunodeficiency syndrome surveillance data and seroprevalence studies of drug treatment program entrants are used to trace seroprevalence trends among intravenous drug users in the borough of Manhattan. The virus entered this drug-using group during the mid-1970s and spread rapidly in 1979 through 1983. From 1984 through 1987, the seroprevalence rate stabilized between 55% and 60%--well below hepatitis B seroprevalence rates. This relatively constant rate is attributed to new infections, new seronegative persons beginning drug injection, seropositive persons leaving drug injection, and increasing conscious risk reduction.

Because opioid antagonists acutely produce rises in serum beta endorphin, we studied beta endorphin levels in 21 former opiate addicts chronically taking naltrexone. The mean AM (19.5 pg/ml) beta endorphin level was higher than the AM mean for 39 normals under 40 years old (12.1 pg/ml) (t = 3.2, p less than 0.001); the mean PM level for the naltrexone treated patients was 13.6 pg/ml. Four patients had beta endorphin levels more than 2 S.D. above the mean for the normals (greater than 26.4 pg/ml), and six others had relatively elevated PM levels. Thus, 47% (10/21) had abnormal patterns of beta endorphin levels. We had previously reported abnormally high cortisol levels in these patients, and AM cortisol correlated with AM beta endorphin levels (r = 0.7, p less than 0.001). We concluded that sustained beta endorphin elevations may occur during chronic naltrexone treatment.

The hepatitis D virus (HDV; previously called the "delta agent") is a defective organism which can replicate only in the presence of the hepatitis B virus (HBV). We tested the serum of 95 substance abusers, all of whom had sufficient evidence of chronic liver disease to warrant a liver biopsy, for hepatitis D virus antibody (anti-HDV). Anti-HDV was detected in five of eight hepatitis B surface antigen (HBsAg)-positive patients and 12 of 87 (14%) HBsAg-negative patients. Antibody to the hepatitis B core antigen (anti-HBc) was the sole hepatitis B marker in eight of the 12 (67%) anti-HDV-positive, HBsAg-negative patients but in only 14 of 75 (19%) anti-HDV-negative, HBsAg-negative patients (P less than 0.005). None of the anti-HDV-positive, HBsAg-negative patients had detectable IgM anti-HBc in the serum or hepatitis D antigen in liver tissue, and they had similar clinical features and liver biopsy diagnoses to HBsAg-negative patients without anti-HDV. We conclude that anti-HDV in HBsAg-negative substance abusers reflects infection with HDV and HBV in the distant past and does not indicate more severe liver disease than that seen in HBsAg-negative patients without anti-HDV.

Parenteral drug users have a high prevalence of infection with human immunodeficiency virus (HIV), the etiologic agent of acquired immune deficiency syndrome (AIDS). New York City has had a prolonged and extensive epidemic of HIV infection and AIDS. In this study, we analyze, in relation to antibody to HIV (anti-HIV), available data from sera from parenteral drug users collected in New York City during 1978 through 1983 in the course of studies of liver disease. Among parenteral users of both heroin and cocaine, 30 (52%) of 58 had anti-HIV, compared with six (13%) of 48 injectors of heroin only (P less than 0.0001). Only two (11%) of 18 white patients were HIV-infected, compared with 34 (39%) of 88 black or Hispanic patients (P = 0.03). No other factors studied were linked to anti-HIV. In a multiple logistic regression, anti-HIV was significantly more common in parenteral users of both cocaine and heroin (P less than 0.0001), black patients (P = 0.02), and Hispanic patients (P = 0.049). We conclude that parenteral users of both cocaine and heroin as well as black and Hispanic patients were disproportionately HIV-infected during the early years of the HIV epidemic. Use of cocaine and heroin as well as ethnicity were independently linked to anti-HIV. Measures to prevent or treat drug use, HIV infection, and other medical problems while addressing the specific needs of cocaine users and black and Hispanic patients are urgently needed.

When an orally administered opiate agonist is systemically bioavailable, the relative activity of that opioid in delaying gastrointestinal transit (GIT) depends on its relative action at central and peripheral sites. This in turn depends on the density of opioid receptor specific subtypes at those sites of action in the species under study. In rats the kappa selective agonist U-50,488H has no effect on GIT. We have found that this same agonist is equipotent to mu agonists morphine and 1-methadone in delaying the orocecal transit of a charcoal meal when administered orally to guinea pigs. Thus, both kappa as well as mu receptor subtypes are involved in the mechanisms of opiate induced slowing of GIT in the guinea pig in contrast to the rat. Interspecies differences must be considered when determining the contribution of opiate receptor subtypes to the mechanisms of opiate-induced constipation.

Chronic liver disease is common in methadone-maintained patients. We studied the disposition of this drug in 14 patients with biopsy-proved chronic liver disease and five otherwise healthy subjects receiving methadone maintenance treatment. The patients were divided into three groups based on the severity of liver disease, with group I having the most severe disease. The apparent terminal half-life of methadone was longer in group I than in group II and III (moderate and mild chronic liver disease, P less than 0.01) and the contrast group (P less than 0.05). All other kinetic indices determined for group I and all kinetic indices in groups II and III were essentially the same as those in the contrast subjects or in the other patient groups. Seven patients, including al five in group I, had flattened plasma methadone concentration-time curves. The data suggest that the maintenance dosage of methadone need not be changed in stable chronic liver disease.

Binding of methadone in body tissues limits the rise in plasma concentration and prolongs the pharmacological action in patients receiving a daily maintenance dose. An opiate with equal intrinsic activity but greater binding affinity would, therefore, be a better drug than methadone for maintenance treatment; it would be safer when taken in a single dose and longer in its duration of action when taken on a regular schedule.