Supports and modified nano-particles for designing model catalysts.

In order to design catalytic materials, we need to understand the essential causes for material properties resulting from its composite nature. In this paper we discuss two, at first sight, diverse aspects: (a) the effect of the oxide-metal interface on metal nanoparticle properties and (b) the consequences of metal particle modification after activation on the selectivity of hydrogenation reactions. However, these two aspects are intimately linked. The metal nanoparticle's electronic structure changes at the interface as a catalyst is brought to different reaction temperatures due to morphological modifications in the metal and, as we will discuss, these changes in the chemistry lead to changes in the reaction path. As the morphology of the particle varies, facets of different orientations and sizes are exposed, which may lead to a change in the surface chemistry as well. We use two specific reactions to address these issues in some detail. To the best of our knowledge, the present paper reports the first observations of this kind for well-defined model systems. The changes in the electronic structure of Au nanoparticles due to their size and interaction with a supporting oxide are revealed as a function of temperature using CO2 activation as a probe. The presence of spectator species (oxopropyl), formed during an activation step of acrolein hydrogenation, strongly controls the selectivity of the reaction towards hydrogenation of the unsaturated C[double bond, length as m-dash]O bond vs. the C[double bond, length as m-dash]C bond on Pd(111) when compared with oxide-supported Pd nanoparticles.

A range of research-based pharmacotherapies for addiction.

Modern approaches to the treatment of addiction have been influenced by several important factors. These include advances in our understanding of the nature of addiction based on longitudinal studies, and progress in elucidating the biological underpinnings of addictive behavior. In addition, changes in the system for delivery of services have begun to shape the way that addiction is treated.

Conditioned narcotic withdrawal in humans.

Subjective and physiological manifestations of the narcotic withdrawal syndrome were produced as a conditioned response. Withdrawal reactions precipitated by the narcotic antagonist naloxone in methadone-dependent volunteers were the unconditioned response. These data support clinical anecdotes of withdrawal symptoms occurring in former addicts when they return to their drug-related environment.

Desipramine treatment of cocaine dependence in methadone-maintained patients.

We performed a double-blind, placebo-controlled, randomized 12-week trial of desipramine hydrochloride treatment of cocaine dependence among methadone-maintained patients. Fifty-nine patients completed the 12-week medication trial (36 received desipramine and 23 received placebo), and 94% were recontacted 1, 3, and 6 months after treatment. There were significantly more dropouts in the desipramine than in the placebo group. Baseline to 12-week comparisons of Addiction Severity Index interview data indicated that both groups showed improvements. At 12 weeks, the desipramine group showed significantly better psychiatric status than the placebo group but did not differ from the placebo group on any of 21 other outcome measures, including cocaine use. During the 12-week medication phase and at the 1-month follow-up evaluation, urine toxicology screenings showed no significant difference between groups, but the placebo group had significantly less cocaine use at both the 3- and 6-month follow-up points. We conclude that desipramine has few benefits with regard to control of cocaine use in this population.

Propoxyphene form maintenance treatment of narcotic addiction.

Two studies compared propoxyphene napsylate (Darvon-N) with methadone hydrochloride as maintenance treatment for narcotic addicts. Most measures indicated that methadone was more effective than propoxyphene as a maintenance drug. Patients receiving propoxyphene reported more withdrawal-related symptoms early in treatment, tended to drop out sooner than patients receiving methadone, and were more likely to abuse heroin. Nevertheless, follow-up interviews at one and six months after treatment indicated no between-group differences in adjustment.

Use of disulfiram for alcoholics in methadone maintenance programs. A Veterans Administration Cooperative Study.

A multicentered clinical trial studied the efficacy and safety of disulfiram in controlling heavy alcohol consumption by patients on methadone maintenance regimens. The trial was stopped when sample size targets were not achieved. Efficacy comparisons were based on 82 patients who started the study; safety comparisons were based on 35 patients who completed 12 weeks of study. Patients received either disulfiram and methadone or placebo and methadone. Disulfiram was administered at a dosage of 125 mg/day for seven days and 250 mg/day thereafter for 36 weeks. No significant differences between the disulfiram and placebo groups were observed in either the retention in study or any other important end point. Both groups showed improvement in control of drinking during the study. There were no serious adverse reactions that could be attributed to the combined use of the two drugs.

Problem-service 'matching' in addiction treatment. A prospective study in 4 programs.

BACKGROUND: Our initial attempts to "match" substance-abuse patients from an employee assistance program to an optimal setting or program failed. Scientifically, we found no differential predictors of better outcomes by setting or program. From a practical perspective, it was impossible to place patients in the intended programs. This led to a second study, designed to identify specific patient problems and match professional services to those problems within each of the 4 programs. METHODS: Ninety-four new patients admitted to 4 substance-abuse treatment programs were randomly assigned to standard treatment and treated in the usual manner or were assigned to "matched" services, in which patients received at least 3 professional sessions directed at their important employment, family, or psychiatric problems. RESULTS: Matched patients stayed in treatment longer, were more likely to complete treatment, and had better posttreatment outcomes than did the standard patients treated in the same programs. CONCLUSIONS: For logistical, financial, and clinical reasons, it is improbable that patients will be matched to specific types of programs. However, within any program, it is possible and practical to match appropriate services to patients' specific treatment problems. This strategy was clinically and administratively practical, attractive to patients, and responsible for a 20% to 30% increase in the effectiveness of this substance-abuse treatment system.

Predicting response to alcohol and drug abuse treatments. Role of psychiatric severity.

Male alcoholics (n = 460) and drug addicts (n = 282) were evaluated at six-month follow-up after treatment in six rehabilitation programs. Initial analyses of the unstratified samples showed significant patient improvement, but no evidence of differential effectiveness from different treatments or from "matching" patients to treatments. The two samples were then divided into groups based on the number, duration, and intensity of their psychiatric symptoms at admission, ie, their overall "psychiatric severity." Patients with low psychiatric severity improved in every treatment program. Patients with high psychiatric severity showed virtually no improvement in any treatment. Patients with midrange psychiatric severity (60% of the samples) showed outcome differences from different treatments and especially from specific patient-program matches. These findings support the effectiveness and specificity of different substance abuse treatments, suggest methodologic reasons for the lack of similar findings in previous studies, and demonstrate the importance of psychiatric factors in substance abuse treatment.

Sociopathy and psychotherapy outcome.

One hundred ten nonpsychotic opiate addicts were randomly assigned to receive paraprofessional drug counseling alone or counseling plus professional psychotherapy. The outcomes of patients who received psychotherapy were examined in terms of their DSM-III diagnoses. Four groups were compared: those with opiate dependence alone (N = 16); opiate dependence plus depression (N = 16); opiate dependence plus depression plus antisocial personality disorder (N = 17); and opiate dependence plus antisocial personality disorder (N = 13). Those with opiate dependence plus antisocial personality disorder alone improved only on ratings of drug use. Patients with opiate dependence alone or with opiate dependence plus depression improved significantly and in many areas. Opiate-dependent patients with antisocial personality plus depression responded almost as well as those with only depression. Antisocial personality disorder alone is a negative predictor of psychotherapy outcome, but the presence of depression appears to be a condition that allows the patient to be amenable to psychotherapy, even though the behavioral manifestations of sociopathy are present.

Therapist success and its determinants.

This study examined the relatively unexplored contribution of the therapist's performance in determining outcomes of treatment. Nine therapists were studied: three performed supportive-expressive psychotherapy; three, cognitive-behavioral psychotherapy; and three, drug counseling. Profound differences were discovered in the therapists' success with the patients in their case loads. Four potential determinants of these differences were explored: patient factors; therapist factors; patient-therapist relationship factors; and therapy factors. Results showed that patient characteristics within each case load (after random assignments) were similar and disclosed no differences that would have explained the differences in success; therapist's personal qualities were correlated with outcomes but not significantly (mean r = .32); an early-in-treatment measure of the patient-therapist relationship, the Helping Alliance Questionnaire, yielded significant correlations with outcomes (mean r = .65); among the therapy techniques, "purity" provided significant correlations with outcomes (mean r = .44), both across therapists and within each therapist's case load. The three therapist-related factors were moderately associated with each other.

Naltrexone in the treatment of alcohol dependence.

Seventy male alcohol-dependent patients participated in a 12-week, double-blind, placebo-controlled trial of naltrexone hydrochloride (50 mg/d) as an adjunct to treatment following alcohol detoxification. Subjects taking naltrexone reported significantly less alcohol craving and days in which any alcohol was consumed. During the 12-week study, only 23% of the naltrexone-treated subjects met the criteria for a relapse, whereas 54.3% of the placebo-treated subjects relapsed. The primary effect of naltrexone was seen in patients who drank any alcohol while attending outpatient treatment. Nineteen (95%) of the 20 placebo-treated patients relapsed after they sampled alcohol, while only eight (50%) of 16 naltrexone-treated patients exposed to alcohol met relapse criteria. Naltrexone was not associated with mood changes or other psychiatric symptoms. Significant side effects (nausea) occurred in two naltrexone-treated subjects, and one naltrexone-treated subject complained of increased pain from arthritis. These results suggest that naltrexone may be a safe and effective adjunct to treatment in alcohol-dependent subjects, particularly in preventing alcohol relapse.

Predicting the outcome of psychotherapy. findings of the Penn Psychotherapy Project.

Our study of predictability of outcomes of psychotherapy used predictions of two kinds: (1) direct predictions by patients, therapists, and clinical observers; and (2) predictive measures derived from the same sources. Seventy-three nonpsychotic patients were treated in psychoanalytically oriented psychotherapy (mean, 44 sessions). Two thirds of the therapists were residents in psychiatry; one third were more experienced. The two main composite outcome measures, measured at termination, were Raw Gain (residualized) and Rated Benefits, which intercorrelated at .76. Most patients improved and showed a considerable range of benefits. The clinical observers' direct predictions of Rated Benefits were highest (.27, P less than 905). The success of the predictive measures were generally insignificant, and the best of them were in the .2 to .3 range meaning that only 5% to 10% of the outcome variance was predicted. The Prognostic Index Interview variables did the best (eg, emotional freedom composite, .30; a crossvalidation for 30 patients was .39 (P less than .05). Neither the therapist measures nor the early psychotherapy session measures predicted significantly. Reanalysis of the similar Chicago Counseling Center study, in our terms, showed a similar low level of prediction success, eg, adequacy of functioning, marital status match, and length of treatment predicted significantly in both studies.

Naltrexone and alcohol dependence. Role of subject compliance.

BACKGROUND: Two previous double-blind, placebo-controlled studies demonstrated that naltrexone (50 mg/d) reduces alcohol drinking in alcohol-dependent subjects. In both studies, treatment compliance was excellent. However, a robust treatment effect size for naltrexone relative to placebo has been shown for compliant subjects but not for subjects who missed research visits. The goal of this study was to determine the effectiveness of naltrexone in subjects who received psychosocial treatment in a more naturalistic setting with respect to the role of treatment attendance and medication compliance. METHODS: Ninety-seven alcohol-dependent subjects were randomly assigned to receive either naltrexone (n = 48) or matching placebo (n = 49) for 12 weeks. All subjects received individual counseling (twice per week for the first month followed by once per week). RESULTS: Overall, naltrexone showed only modest effects in reducing alcohol drinking for the 12 weeks of treatment. However, naltrexone treatment efficacy improved across a variety of outcome measures for subjects who completed treatment and were highly compliant with taking medication. CONCLUSIONS: Naltrexone is clinically effective relative to placebo in individuals who comply with the treatment protocol and take medication. The modest treatment effects in the entire sample suggest that the clinical efficacy of naltrexone could be improved by enhancing treatment compliance.

Psychotherapy for opiate addicts. Does it help?

Opiate addicts beginning a new treatment episode on a methadone maintenance program were offered random assignment to drug counseling alone or to counseling plus six months of either supportive-expressive psychotherapy or cognitive-behavioral psychotherapy. Sixty percent of patients meeting the study criteria expressed an interest and 60% of these actually became engaged. One hundred ten subjects completed the study intake procedure and kept three or more appointments within the first six weeks of the project. Measures including standardized psychological tests, independent observer ratings, and continuous records of licit and illicit drug use were done at baseline and seven-month follow-up. All three treatment groups showed significant improvement, but patients receiving the additional psychotherapies showed improvement in more areas and to a greater degree than those who received counseling alone, and with less use of medication. More than a third of opiate addicts in our treatment program thus both were interested in professional psychotherapy and apparently benefitted from it. Certain administrative procedures appear necessary to maximize the chances that psychotherapy can be used effectively with drug-addicted patients.

Attenuation of the euphoric effects of cocaine by the dopamine D1/D5 antagonist ecopipam (SCH 39166)

BACKGROUND: The subjective and reinforcing effects of cocaine in humans are associated with the enhancement of endogenous dopamine function in the mesolimbic system. This study examined the role of dopamine D1-like receptors in the behavioral and mood effects of cocaine by evaluating the effects of the selective D1/D5 antagonist ecopipam (SCH 39166) on subjective responses to intravenous cocaine in 11 subjects with cocaine dependence as defined by DSM-IV. METHODS: Subjects were pretreated in a randomized double-blind fashion with either placebo or 10 mg, 25 mg, or 100 mg of ecopipam orally on 4 separate occasions. Two hours later a single intravenous injection of 30 mg of cocaine was administered. Subjective and cardiovascular responses were measured and blood samples for pharmacokinetic evaluation were obtained prior to cocaine dosing and at various times after dosing. RESULTS: The euphoric (P = .004) and stimulating (P = .03) effects of cocaine were attenuated in a dose-dependent manner by ecopipam, while ratings of desire to take cocaine were diminished (P = .02). Ecopipam in combination with cocaine was safe and well tolerated. CONCLUSION: These data indicate a potentially important role for D1-like receptors in the acute mood-altering and rewarding effects of cocaine in humans.

Neural correlates of adherence to extended-release naltrexone pharmacotherapy in heroin dependence.

Injectable extended-release naltrexone (XRNTX) presents an effective therapeutic strategy for opioid addiction, however its utility could be hampered by poor adherence. To gain a better insight into this phenomenon, we utilized blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in conjunction with a validated cue-induced craving procedure to examine neural correlates of XRNTX adherence. We operationalized treatment adherence as the number of monthly XRNTX injections (range: 0-3) administered to a group of fully detoxified heroin-dependent subjects (n=32). Additional outcomes included urine toxicology screening and self-reported tobacco use. The presented heroin-related visual cues reliably elicited heroin craving in all tested subjects. Nine, five, three and 15 of the participants, respectively, received zero, one, two and three XRNTX injections, predicted by the individual baseline fMRI signal change in response to the cues in the medial prefrontal cortex, a brain region involved in inhibitory self-control and emotional appraisal. The incidence of opioid-positive urines during the XRNTX therapy was low and remained about half the pre-treatment rate after the XRNTX ended. During the treatment, cigarette smoking behaviors followed patterns of opioid use, while cocaine consumption was increased with reductions in opioid use. The present data support the hypothesis that medial prefrontal cortex functions are involved in adherence to opioid antagonist therapy. A potential role of concurrent non-opioid addictive substances consumption during the XRNTX pharmacotherapy warrants further investigation. Our findings set the stage for further bio-behavioral investigations of the mechanisms of relapse prevention in opioid dependence.

Endogenous opioids in cerebrospinal fluid of opioid-dependent humans.

Endogenous opioid systems may be altered as a consequence of addiction, but evidence to support this idea is meager so far. We obtained 136 cerebrospinal fluid (CSF) samples from 72 opioid addicts during four distinct states: methadone maintenance, detoxification from methadone, opioid antagonist treatment, and drug-free status. CSF endorphins were measured in 86 patients samples using a radioreceptor assay (RRA), and beta-endorphin levels were measured in 85 patient samples using a radioimmuno assay (RIA). During detoxification, both RRA fraction I and beta-endorphin showed a generally similar pattern of changes. Both were lowest when measured 40-50 hr after the last opioid dose, and both showed an apparent rebound to higher than methadone maintenance values at 60-70 hr following the last dose. During methadone maintenance and drug-free states, the addicts' levels of fraction I RRA endorphins in the CSF were higher than levels found in a normal control group. Fraction II endorphins were also elevated in the addicts who were drug free. In contrast, CSF beta-endorphin during both methadone maintenance and drug-free states was lower in the addicts as compared to the normal, drug-naive group. Except for the pattern found during detoxification, there were no consistent changes in endorphin levels across different states of addiction.

Do caffeine-containing analgesics promote dependence? A review and evaluation.

OBJECTIVE: Debates about the suspected association between kidney disease and use of analgesics have led to concern about whether caffeine could stimulate an undesirable overuse of phenacetin-free combined analgesics. A committee was asked to critically review the pertinent literature and to suggest guides for clinical practice and for consideration of international regulatory authorities. PARTICIPANTS: A group of international scientists, jointly selected by the regulatory authorities of Germany, Switzerland, and Austria and the pharmaceutical industry. EVIDENCE: All invited experts evaluated relevant literature and reports and added further information and comments. CONCLUSIONS: Caffeine has a synergistic effectiveness with analgesics. Although caffeine has a dependence potential, the potential is low. Experimental data regarding dependence potential for caffeine alone may not correspond to the conditions in patients with pain. Withdrawal is not likely to cause stimulation or sustainment of analgesic intake. For drug-induced headache, no single or combined analgesic was consistently identified as causative, and no evidence exists for a special role of caffeine. Strong dependence behavior was observed only in patients using phenacetin-containing preparations, coformulated with antipyretics/analgesics and caffeine. This finding may have led to the impression that caffeine stimulates overuse of analgesics. SUMMARY: Although more experimental and long-term data would be desirable to show possible mechanisms of dependence and to offer unequivocal proof of safety, the committee concluded that the available evidence does not support the claim that analgesics coformulated with caffeine, in the absence of phenacetin, stimulate or sustain overuse.

Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene.

Plasma concentrations of propoxyphene (P) and its pharmacologically active metabolite norpropoxyphene (NP) were determined in normal subjects after single 130-mg oral doses and during and after 13 consecutive oral doses of 130 mg P, and in former heroin addicts who were maintained on 900 to 1200 mg of P per day. The data were analyzed using a first-pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5 to 7 times those after the first dose. In contrast, "maintenance" patients exhibited steady-state trough plasma NP cumulation that exceeded that of P by a factor of 13. Several changes in P and NP kinetics occurred during repeated dosing with P to the normal subjects: P clearance decreased from 994 to 508 ml/min, NP clearance decreased from 454 to 2210 ml/min, P half-life (t 1/2) increased from 3.3 to 11.8 hr, NP t 1/2 increased from 6.1 to 39.2 hr, and area under the concentration time curves for P and NP were doubled. These changes in kinetics during repeated dosing resulted in more extensive cumulation of P and NP than would be predicted from the single-dose kinetic profile. Changes in the extent of first-pass elimination of P result in variability in plasma P and NP that may contribute to P-induced toxicity.