METODO, a prospective observational study to assess the efficacy and tolerability of methadone in heroin-addicted patients undergoing a methadone maintenance treatment: preliminary results at baseline evaluation.

METODO (methadone efficacy therapy optimization dosage on-going) is a prospective observational study to assess the efficacy and tolerability of methadone in 500 heroin-addicted patients taking a methadone maintenance treatment, enrolled through 2010 to 2011 in five Italian sites, observed over 2 years. The Opiate Dosage Adequacy Scale has been used for the evaluation of the "adequacy" of the methadone dosage and to stratify patients in adequate and not adequate groups. The treatment efficacy has been evaluated in correlation to the dosage adequacy during the visits. Moreover, patients have been evaluated according to the retention rate and duration of retention in treatment and a series of questionnaires.

New frontiers in alcoholism and addiction treatment.

Drug addiction and alcoholism are behavioural disorders characterized by a profound alteration of several brain circuits induced by chronic drug use. Their treatment is yet based on empiricism and today only few pharmacological strategies are fully effective to control both drug use and relapse. The present paper reviews the most updated pharmacotherapies able to contrast both alcoholism and drug addiction including the new patented drugs and the future therapeutic trends.

Opioid maintenance therapy suppresses alcohol intake in heroin addicts with alcohol dependence: preliminary results of an open randomized study.

An open randomized study lasting 12 months was performed to evaluate the efficacy of methadone or buprenorphine to suppress alcohol use in two hundred and eighteen heroin addicts with alcohol dependence. Daily maintenance doses of methadone were 80, 120, 160, and 200 mg/day, while doses of buprenorphine were 8, 16, 24, and 32 mg/day. As expected, both treatments were able to reduce both heroin use and addiction severity (measured with ASI interview). However, although both medications were able to suppress alcohol use, the highest dose of buprenorphine was better than the highest dose of methadone, in reducing alcohol craving, ethanol intake (measured as daily number of drinks), and the ASI subscale of alcohol use. The mechanism underlying the effects of the opioid maintenance therapy on the reduction of alcohol intake is still unclear. The results of the present study may represent the first clinical evidence of the potential effective use of the highest doses of buprenorphine for the suppression of ethanol intake in heroin addicts with alcohol dependence.

Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolism in severe abstinent alcoholics: an open study vs. diazepam.

In 42 alcoholic inpatients we performed an open randomized study to compare the effects of diazepam and gamma-hydroxybutyrate (GHB) on the suppression of severe alcohol withdrawal syndrome and hypercortisolism. Both diazepam (.5 mg/kg bodyweight, q.i.d.) and GHB (50 mg/kg bodyweight, q.i.d.) were orally administered for three weeks. During all study period, GHB was more able than diazepam in reducing both withdrawal syndrome and hypercortisolism. These effects were evident during the first week of treatment and persisted throughout the study period. The results confirm a strict correlation between high levels of plasma cortisol and alcohol withdrawal symptoms and they show a slight superiority of GHB over diazepam in the suppression of both ethanol withdrawal and hypercortisolism. Taken together, our data suggest that GHB may act as potent anti-withdrawal agent in severe abstinent alcoholics.

Combination of olanzapine with opioid-agonists in the treatment of heroin-addicted patients affected by comorbid schizophrenia spectrum disorders.

The objective of this study was to evaluate the efficacy of olanzapine (OLA) in heroin-dependent patients affected by comorbid schizophrenia spectrum disorders (SSD). Sixty-one patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for heroin dependence and the criteria for SSD (schizophrenia and schizotypal and schizoaffective-bipolar disorders) were treated in a 12-week prospective observational trial of substitution treatment in combination with OLA or typical antipsychotic haloperidol. Patients were included into 2 subgroups, in relationship with treatment, for the evaluation of the end points at week 12: group 1, SSD treated with OLA (35 patients); group 2, SSD treated with haloperidol (26 patients). Efficacy measures were retention in treatment, Symptoms Checklist-90 score changes, negative urinalyses results, and craving reduction. The rate of patients who remained in treatment at week 12 in group 1 SSD, treated with OLA, was significantly higher (32[91.4%]) than that of group 2 SSD (13 [50%]), treated with the typical antipsychotic (P < 0.001). The decrease in Symptoms Checklist-90 total scores from baseline, as expression of an improvement in comorbid psychopathology in the patients who completed the treatment, was significantly more consistent in group 1 than in group 2 patients (P < 0.01). Among the patients who remained in treatment, 64.4% achieved early full substance abuse remission, whereas 35.6% achieved partial substance abuse remission, with a significant difference between 1 (78.13%) and 2 (46.1%) treatment subgroups (P = 0.04). Although obtained by an observational-open clinical study with multiple limitations, our findings suggest that OLA may be able to increase retention and negative urinalyses rates during opioid agonist maintenance treatment in the patients with SSD and to improve psychopathology symptoms and tolerability in these dually diagnosed heroin addicts. Preliminary accurate diagnostic assessment and appropriate psychoactive medication in addicted patients affected by schizophrenia and schizotypal and schizoaffective-bipolar disorders seem to obtain less adverse effects and a more successful outcome of drug dependence treatment.

Chronic cannabis use does not affect the normalization of hypothalamic-pituitary-adrenal (HPA) axis induced by methadone in heroin addicts.

The hypothalamic-pituitary-adrenal (HPA) axis activity is usually altered by heroin use. In the present study we evaluated in one hundred twenty-one heroin addicts the effects of marijuana smoking on the normalization of HPA axis upon methadone treatment. The study showed that in heroin addicts who are chronic cannabis smokers a treatment with methadone lasting 12 months was able to normalize both plasma corticotropin (ACTH) and cortisol levels, as well as to control both heroin withdrawal symptoms and opioid craving. As expected in the same group of patients marijuana smoking and its craving were not reduced by methadone treatment. Our data confirm that methadone treatment outcomes are not modified by cannabis use and they add in the literature the evidence that chronic cannabis use is not able to affect the normalization of HPA axis upon methadone treatment in heroin addicts.

Comparing treatments of alcoholism on craving and biochemical measures of alcohol consumptionst.

An open randomized study was conducted to compare different treatments of alcoholism on ethanol intake, craving, and on biochemical measures of alcohol consumptions. Eighty-six alcoholics were abstinent for a mean of two weeks prior to random assignment to g-hydroxybutyrate (GHB, 50 mg/kg of body weight t.i.d), naltrexone (NTX, 50 mg/day) or disulfiram (DSF, 200 mg/ day) treatment for 12 months. All treatments were equally effective in reducing alcohol intake and in maintaining abstinence. In all patients, the treatments were able to reduce both craving and the altered biological markers of alcohol abuse. The maximum effects were observed in GHB-treated patients. The results of the present study suggest that GHB might act both as anticraving and cellular protector agent.

Relationship between plasma cortisol levels, withdrawal symptoms and craving in abstinent and treated heroin addicts.

Twelve-month treatment of heroin addicts with methadone or buprenorphine normalized plasma cortisol levels, and controlled withdrawal symptoms as well as craving. During treatment, the time course of plasma cortisol levels and craving was not strictly correlated: heroin craving was more elevated at 12 than at 3 months. The results suggest a correlation between hypercortisolism, withdrawal symptoms and heroin use and suppose a more complex role for craving and its components in drug-taking behaviour. The main goal of the pharmacological treatment of opioid-dependence should be addressed at the normalization of hypothalamic-pituitary-adrenocortical (HPA) axis more than at the control of craving.

Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: A retrospective study.

The present study compared retrospectively in a clinical non-experimental setting the efficacy of buprenorphine (BUP) in different subgroups of dually diagnosed and non-dually diagnosed opioid-dependent patients: all the subjects included in the study showed severe long-lasting heroin addiction and 68.4% were affected by psychiatric comorbidity. Participants (206) (mean age 32.2+/-8.9, 177 males-29 females) were applicants to a long-term buprenorphine treatment program (mean doses 7.9+/-0.42 mg). Aim of the study was to evaluate dual diagnosis variables possibly influencing retention rate and abstinence from illicit drugs. The patients were divided into 5 subgroups on the basis of dual diagnosis: group 1: major depression (MD) 29.61%; group 2: generalized anxiety (GAD) (11.2%); group 3: personality disorders (PD), antisocial-borderline (21.84%); group 4: schizophrenia (SC)(6.3%); group 5: substance use disorder without overt psychiatric comorbidity (SUD) (31.1%). Group 1 patients affected by MD showed the highest retention rate at 12 months (72.1%) in comparison with the other groups of patients: group 2 GAD (39.1%), group 3 PD (17.8%), group 4 SC (7.7%) and group 5 SUD, without comorbidity (45.3%) (p=0.006, p<0.001, p<0.001, p=0.002). Similarly, at 12 months, the patients affected by MD showed less risk of illicit opioid use (16.4%) than those affected by GAD (34.8%), PD (42.2%), SC (53.8%) and SUD without comorbidity (34.4%) (p=0.06, p=0.003, p=0.008, p=0.017). When evaluated on the whole sample, retention rate was not influenced by dose. In contrast, the higher BUP doses were associated with less risk of illicit opioid use, than lower doses (p<0.001). Multivariate analysis and factor analysis showed a greater association of outcome measures (retention rate and negative urines rate) with comorbid diagnosis (depression) (respectively 0.64) than with buprenorphine doses (respectively 0.54). Our data need to be interpreted with caution because of the retrospective methodology applied to a clinical non-experimental setting. BUP seems to be more effective in opioid-dependent patients affected by depression, probably due to the kappa opioid-receptors antagonist action, counteracting dysphoria, negativism and anxiety. High doses of BUP appear to predict a better outcome, in terms of negative urines, but not in terms of retention.

Good safety profile and efficacy of leucocyte interferon-alpha in combination with oral ribavirin in treatment-naive patients with chronic hepatitis C: a multicentre, randomised, controlled study.

BACKGROUND: The differential tolerability profile of various interferon (IFN)-alpha preparations used in combination with ribavirin for the treatment of chronic hepatitis C needs to be elucidated. Approximately 8% of patients receiving recombinant IFNalpha-2b plus ribavirin discontinue treatment because of adverse events. Human leucocyte IFNalpha is deemed to have a better safety profile than recombinant IFNalpha. We therefore compared the safety profile and efficacy of ribavirin combined with leucocyte IFNalpha or with recombinant IFNalpha-2b in treatment-naive patients with chronic hepatitis C. STUDY DESIGN: We randomised 423 patients to either leucocyte IFNalpha 3MU three times weekly plus ribavirin (210 patients) or the same dose of recombinant IFNalpha-2b plus ribavirin (213 patients). Patients were treated for 24 weeks and followed-up for a further 48 weeks. The primary endpoint was the safety profile of the two therapies; the secondary endpoint was the rate of sustained response. RESULTS: In patients receiving leucocyte IFNalpha, the total number of adverse events was lower than in the group receiving recombinant IFNalpha (259 vs 441 patients), and the percentage of patients discontinuing treatment because of adverse events or laboratory abnormalities was significantly reduced (4% vs 11%; p = 0.013). Sustained response was observed in 47% of patients receiving leucocyte IFNalpha plus ribavirin and in 44% of patients receiving IFNalpha-2b plus ribavirin. CONCLUSIONS: Both therapeutic regimens were effective in inducing a sustained response in naive patients. However, the safety profile of leucocyte IFNalpha plus ribavirin was more favourable than that observed with the administration of recombinant IFNalpha-2b plus ribavirin, suggesting that leucocyte IFNalpha may be an alternative option in patients with reduced tolerability to other IFNs.

An open-label, prospective, observational study of the incidence of coronary artery disease in patients with HIV infection receiving highly active antiretroviral therapy.

BACKGROUND: The association of highly active antiretroviral therapy (HAART) regimens that include protease inhibitors (PIs) with metabolic and somatic disorders has raised concerns about the possibility of an increased risk of coronary artery disease (CAD) in patients with HIV infection. OBJECTIVE: The aim of this study was to assess the incidence of CAD in previously untreated HIV infected outpatients who received reverse transcriptase inhibitors with or without PIs. METHODS: In this open-label, multicenter, prospective, observational trial, previously untreated and asymptomatic HIV-infected Italian patients were followed to assess the incidence of CAD (primary end point) according to the HAART regimen they received: 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) in combination with PIs (group PI+) or 1 non-nucleoside reverse transcriptase inhibitor in combination with 2 NRTIs (group PI-). Patients underwent clinical examination and laboratory testing every 4 months. RESULTS: A total of 1551 HIV-infected patients (994 [64%] men; median age, 35 years; range, 22-50 years) were followed for a median 36 months (range, 34-42 months). The cumulative annual incidence of CAD-related events was 9.8/1000 in group PI+ and 0.8/1000 in group PI- (P < 0.001). The annual incidence of myocardial infarction was 5.1/1000 in group PI+ and 0.4/1000 in group PI- (P < 0.001). Independent of patient age, the incidence of CAD was greater among men (P < 0.001) and patients who smoked >20 cigarettes per day (P < 0.001). Lipodystrophy and metabolic alterations were observed in 62% of patients in group PI+ and in 4% of patients in group PI- (P < 0.001). Of 23 patients receiving PIs who developed CAD, 17 (73.9%) had lipodystrophy and all 23 had hypertriglyceridemia and hypercholesterolemia. CONCLUSIONS: According to our findings, HAART that includes PIs may accelerate the onset of CAD-related events in young, male, heavy smokers who develop metabolic disorders and lipodystrophy during therapy. Patients with increased coronary risk should receive careful cardiac monitoring if treated with PIs.