Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial.

AIMS: To evaluate the safety and efficacy of an 8 mg/day sublingual dose of buprenorphine in the maintenance treatment of heroin addicts by comparison with a 1 mg/day dose over a 16-week treatment period. As a secondary objective, outcomes were determined concurrently for patients treated with two other dose levels. DESIGN: Patients were randomized to four dosage groups and treated double-blind. SETTING: Twelve outpatient opiate maintenance treatment centers throughout the United States. PARTICIPANTS: Two hundred and thirty-nine women and 497 men who met the DSM-III-R criteria for opioid dependence and were seeking treatment. INTERVENTION: Patients received either 1, 4, 8 or 16 mg/day of buprenorphine and were treated in the usual clinical context, including a 1-hour weekly clinical counseling session. MEASUREMENT: Retention in treatment, illicit opioid use as determined by urine toxicology, opioid craving and global ratings by patient and staff. Safety outcome measures were provided by clinical monitoring and by analysis of the reported adverse events. FINDINGS: Outcomes in the 8 mg group were significantly better than in the 1 mg group in all four efficacy domains. No deaths occurred in either group. The 8 mg group did not show an increase in the frequency of adverse events. Most reported adverse effects were those commonly seen in patients treated with opioids. CONCLUSIONS: The findings support the safety and efficacy of buprenorphine and suggest that an adequate dose of buprenorphine will be a useful addition to pharmacotherapy.

Choice of rating form for evaluating anxiolytics.

The HAM-A has been a popular tool for assessing the anxiety status of patients. However, when studying anxiolytics, HAM-A presents problems. It includes 89 signs and symptoms grouped under 14 major items. Redundant symptoms appear in several items, and different symptoms under the same item may have variable severity, resulting in inconsistent ratings. In addition, evaluation of all 89 symptoms is time consuming and cumbersome, especially when frequent ratings are required in studying patient response to pharmacotherapy. The WARS was specifically designed to quantify symptoms of anxiety for the study of anxiolytics. It contains 12 one-word items, expressing all the relevant and commonly occurring psychic and somatic symptomatology relevant to anxiety. Symptomatology due to medication is rated separately on a side-effect scale. The WARS is thus more sensitive in detecting therapeutic changes. Because of its simplicity and lack of ambiguity, the WARS can be accurately and effortlessly completed in studying anxiolytics.

Hydrogen peroxide-induced glutathione depletion and aldehyde dehydrogenase inhibition in erythrocytes.

To study relationships between lipid peroxidation and aldehyde dehydrogenase (ALDH) inhibition, the Stocks and Dormandy model of H2O2-induced lipid peroxidation in erythrocytes was employed. Hydrogen peroxide treatment of erythrocytes and erythrocyte lysates caused a dose-dependent inhibition and depletion of ALDH and reduced glutathione (GSH) respectively. Complete ALDH inhibition and glutathione depletion occurred before significant lipid peroxidation was detected by HPLC analysis of malondialdehyde-thiobarbituric acid adducts. Hydroxyl radical scavengers did not antagonize the hydrogen peroxide-induced enzyme inhibition. Studies with the iron chelator desferrioxamine suggested that the hydrogen peroxide-induced ALDH inhibition was mediated by iron in erythrocyte lysates but not in semi-purified (and Chelex-treated) ALDH preparations. Glutathione peroxidase reduction of H2O2 exhibited an anomalous GSH dependence which was not in agreement with the accepted reaction mechanism. Reduced glutathione also antagonized the hydrogen peroxide-induced ALDH inhibition by possible complex formation with the enzyme. A hypothetical model is presented which accounts for the observed responses to hydrogen peroxide.

Erythrocyte aldehyde dehydrogenase: assay of a potential biochemical marker of alcohol abuse.

Erythrocyte aldehyde dehydrogenase (ALDH; EC 1.2.1.3) may be a new biochemical indicator of alcohol abuse. An improved assay for it is described and characterized. We found that expression of erythrocyte ALDH activity in terms of hemoglobin was valid, and preferable to expression in terms of erythrocyte volume. A normal reference interval was determined from results for 375 healthy subjects (236 men, 139 women). We compared these data with results for 109 men admitted to our alcohol detoxification program. The mean erythrocyte ALDH of the alcohol abusers was 30% lower than our mean value for men (p less than 0.001). Values did not change between the time the patient presented for admission and greater than 48 h later (when blood-ethanol concentration was zero). Other variables that affect erythrocyte ALDH activities--changes in pH, temperature, other assay conditions, and drug treatments such as disulfiram and nitrate anti-anginals--are discussed.

Effects of acute and chronic morphine treatment on methadone analgesia and metabolism.

Morphine sulfate (5 mg/kg s.c.) given 30 min prior to administration of methadone prolonged methadone analgesia and increased the brain level of methadone measured 60, 120 and 180 min after administration of methadone. Rats rendered tolerant to morphine analgesia by subcutaneous implantation of two pellets, each containing 75 mg of morphine base, for 1-3 days showed cross-tolerance to methadone analgesia regardless of the presence or absence of morphine pellets. Decreases in the brain concentrations of methadone measured at 60 and 120 min time points accompanied the decreased analgesia. Neither acute nor chronic morphine pretreatment affects the biotransformation of methadone. The results suggest that the cross-tolerance to methadone analgesia seen in chronic morphine-implanted rats was partly associated with a decrease in the brain concentration of methadone occurring by a mechanism not directly related to a change in the biotransformation of methadone. In view of the known inhibitory effect of chronic morphine pretreatment on drug metabolism, our findings might demonstrate a unique phenomenon between morphine and methadone.

Enhanced development of dispositional tolerance to methadone by desipramine given together with methadone.

Rats given 2-day oral administration of methadone (15 mg/kg, twice on day 1 and once on day 2) by gastric tube developed dispositional tolerance to methadone analgesia as demonstrated by a decrease in analgesic response and by an increase in methadone metabolism. The increased metabolism of methadone was evidenced by a decrease in brain concentration of 14C-methadone and increases in the percentages of total 14C in liver or urine as 14C-water-soluble metabolites (14C-WSM) after the rats were challenged with a test dose of 14C-methadone. Two-day pretreatment with a combination of desipramine (DMI) (10 mg/kg, ip) and methadone (15 mg/kg, po) enhanced the development of dispositional tolerance to methadone analgesia which was evidenced by a greater decrease in the brain concentration of methadone and a greater increase in methadone metabolism as compared to those changes in rats pretreated with only methadone. Repeated treatment with DMI alone neither decreased the analgesic effect of methadone nor stimulated methadone metabolism. It is suggested that DMI given together with methadone promoted the induction of methadone metabolism in the liver by prolonging the enzyme-stimulating state of methadone, thus enhancing the development of dispositional tolerance to methadone.

Erythrocyte aldehyde dehydrogenase and clinical chemical markers of alcohol abuse and alcoholism.

An improved method for the measurement of erythrocyte aldehyde dehydrogenase (ALDH) activity was developed and used to determine the enzyme activity in 38 male Caucasian patients admitted to this VA Medical Center for alcohol detoxification. Patients who had been treated within a year prior to the study with any drug known to inhibit ALDH, such as disulfiram, were excluded from the study. In agreement with previous reports, the erythrocyte ALDH levels were decreased relative to non-alcoholic controls. However, no useful correlation was found between the erythrocyte ALDH levels and any of 35 standard clinical chemical and hematological parameters including those that indicated alcoholic liver disease.

Case report of barbiturate-induced enhancement of methadone metabolism and withdrawal syndrome.

A methadone maintenance patient with a decreased plasma methadone level, possibly due to phenobarbital-induced acceleration of methadone biotransformation, experienced opioid withdrawal symptoms. This finding suggests that when phenobarbital is used with methadone the plasma methadone level must be monitored.

Effect of plasma protein binding on the uptake of methadone and diazepam in the isolated perfused rat lung.

The pulmonary uptake of the basic (pKa 9.1) lipophilic amine (methadone) and a nonbasic (pKa 3.4) lipophilic amine (diazepam) was compared in a single pass isolated perfused rat lung (IPL) preparation. The radiolabeled drugs were infused into the IPL for 10 min followed by a 30-min drug-free perfusion. If the perfusate (Krebs-Ringer bicarbonate buffer) contained 4.5% bovine serum albumin, the rapid and extensive uptake observed for methadone (32.4% of infused amount) was similar to that reported for other basic lipophilic amines. Uptake of the nonbasic diazepam was slight (3.4% of infused amount). These results are consistent with the idea that basic amines accumulate in lung tissues to a great extent. However, if the bovine serum albumin was omitted from the perfusate, diazepam uptake in the IPL increased about 10-fold while methadone uptake increased only slightly. This observation, together with the extensive binding of diazepam to plasma albumin, suggested that plasma protein binding was a major factor in limiting the pulmonary accumulation of this nonbasic lipophilic amine. Since many nonbasic drugs are known to have a high affinity for plasma albumin, the observed dependence of pulmonary drug accumulation on basicity of the amine may be related to the plasma protein binding as well as the characteristics of the interaction of amines with pulmonary tissue.

Uptake of l-alpha-acetylmethadol (LAAM) and its analgesically active metabolites, nor-LAAM and dinor-LAAM, in the isolated perfused rat lung.

The pulmonary uptake of l-alpha-acetylmethadol (LAAM) and its major analgesically active metabolites, nor-LAAM and dinor-LAAM, was studied during a single pass through the isolated perfused rat lung (IPL). The radiolabeled drugs were infused into the IPL for 10 min followed by a 30-min drug-free perfusion. All three drugs were extensively taken up into the IPL; however, dinor-LAAM, the least lipophilic, accumulated to the greatest extent. Their rates of efflux from the IPL with time could be described by the sum of three exponentials and 20-25% of each compound accumulated in a "slowly effluxable pool," suggesting a highly sequestered pool of drug in the lung. These findings suggest that tissue sequestration of the active metabolites is equal to or greater than LAAM itself. Such tissue sequestration could limit the sequential metabolic activation or inactivation, and serve as a reservoir of the active compounds. These factors favor the persistence of LAAM and its active metabolites in the body, thus prolonging the opiate-like effects after LAAM administration. The data also indicated that the relationship between drug basicity or lipophilicity and extent of uptake is complex and it is difficult to associate a particular physicochemical property with the extent or character of pulmonary drug uptake.

Brain and plasma levels of methadone and their relationships to analgesic activity of methadone in rats.

The levels of methadone in brain and plasma of rats after acute administration of several different doses of methadone were measured at several time points and relationships to analgesic activity were examined. Both brain and plasma levels of methadone as well as the analgesic activity of methadone, expressed as analgesic area and as percentage of maximum possible effect, were all increased by increasing dosage. All these measurements dropped rapidly after reaching the peak levels 30 min after administration of methadone. At the time of maximal analgesia, the analgesic effect of methadone was quantitatively related to both brain and plasma levels of methadone with 50% of the analgesic maximum possible effect corresponding to the concentrations of 1.44 nmol/g and 0.52 nmol/ml of methadone in brain and plasma, respectively. Our data suggest that measurement of changes in the plasma concentration of methadone at the time of maximal analgesia reflects changes in the brain concentration of methadone and may provide an index of changes in the analgesic effect of methadone.

Disulfiram and erythrocyte aldehyde dehydrogenase inhibition.

During disulfiram therapy erythrocyte aldehyde dehydrogenase (ALDH) was fully inhibited. The time for total loss of erythrocyte ALDH activity ranged from 36 to 120 hr. In contrast to the 85% recovery of in vitro disulfiram-inhibited ALDH activity, this in vivo disulfiram-ALDH inhibition could not be reversed by mercaptoethanol. It is proposed that the in vivo and in vitro mechanisms of ALDH inhibition by disulfiram differ. Erythrocyte ALDH activity can be readily monitored to determine patient compliance and is an accessible model for investigations of in vivo mechanisms of drug inhibition. Because the disulfiram-inhibited erythrocyte ALDH is not regenerated until new erythrocytes are made (120 days), a significant portion of the extrahepatic acetaldehyde metabolic capacity remains inhibited for long periods after disulfiram is discontinued. Thus, the recidivistic patient who discontinues disulfiram and waits several days (to regenerate liver ALDH activity) before drinking will be exposed to even higher ethanol-derived blood acetaldehyde levels than usual, which may induce further alcohol-associated organ damage and alcohol dependence.

Further efficacy evaluation of doxpicomine for postoperative pain.

In this single-dose, double-blind study, the analgesic activity of 400 and 200 mg doxpicomine was compared with 100 and 50 mg meperidine and placebo when given intramuscularly in 102 subject patients experiencing severe postoperative pain. Results indicate that 400 mg doxicomine is similar to 100 mg meperidine in analgesic activity, onset, and duration of action. Side effects were of the same order as those produced by other centrally acting analgesics.

Uptake and efflux of 1-alpha-acetylmethadol (LAAM) and methadone in the isolated perfused rat lung.

The pulmonary uptake of 1-alpha-acetylmethadol (LAAM) and methadone was studied during a single pass through the isolated perfused rat lung (IPL). The IPL was perfused for 10 min with perfusate containing various concentrations of one of the radiolabeled drugs, followed by a 30-min drug-free perfusion and the amount of radioactivity in the pulmonary venous effluent was used to estimate uptake and efflux of the drugs with time. Both drugs were extensively taken up by the IPL; however, LAAM uptake was significantly greater than that of methadone. The amount of each drug taken up was a nonlinear function of concentration in the perfusate, suggesting saturability of the major uptake processes. During drug-free perfusion LAAM and methadone previously accumulated were released from the lung at two different efflux rates; however, a third, more rapid efflux process for methadone was also evident. The total venous effluent collected during the drug-free perfusion contained a significantly greater fraction of the accumulated methadone as compared to LAAM. Calculation of the total amount of each drug effluxable at the observed rates indicated that another pool for both drugs existed in the lung that did not efflux at an observable rate. The accumulated LAAM remaining in this "slowly effluxable pool" was significantly greater than methadone. These data demonstrate a greater pulmonary uptake and tissue sequestration of LAAM as compared to methadone, and may be one of the contributing factors in the persistence of LAAM and its active metabolites in the body.

Study of penfluridol and chlorpromazine in the treatment of chronic schizophrenia.

This study presents data on the use of penfluridol, a once-a-week orally administered, antipsychotic agent, in the treatment of chronic schizophrenic patients. Fifty-nine patients participated in the initial dose titration segment during which doses of penfluridol were adjusted weekly until the patients' condition became stabilized. The starting dose did not exceed 60 mg per week, and the maximum weekly dose did not exceed 140 mg. Forty-one of these patients continued on to participate in a double-blind comparison of penfluridol with chlorpromazine. Maximum doses did not exceed 140 mg per dose per week for penfluridol and 7350 mg per week for chlorpromazine in the double-blind segment. Patients were abruptly switched from their previous neuroleptic medication to penfluridol without loss of control. Side effects, mainly extrapyramidal in nature, were readily alleviated with benztropine mesylate. Penfluridol, administered orally once a week, appeared to be well tolerated; it was comparable to daily chlorpromazine in treating and maintaining schizophrenic patients.

The oral analgesic efficacy of bicifadine hydrochloride in postoperative pain.

The analgesic efficacy of 75 and 150 mg bicifadine hydrochloride was compared to 650 mg aspirin and placebo in a double-blind, single-dose study. Oral doses were administered to 100 patients suffering from moderate to severe postoperative pain. Significant analgesic activity was demonstrated with 650 mg aspirin and 150 mg bicifadine as compared to 75 mg bicifadine or placebo. No significant treatment difference was found between 75 mg bicifadine and placebo. Side effects were minor and did not interfere with the course of therapy.