Prazosin and cyproheptadine in combination in the treatment of alcohol use disorder: A randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: Pre-clinical studies suggest that the simultaneous blockade of the α1b and 5HT2A receptors may be effective in reducing alcohol consumption. This study aimed to assess the efficacy and safety of prazosin (α1b blocker) and cyproheptadine (5HT2A blocker) combination in decreasing total alcohol consumption (TAC) in alcohol use disorder (AUD). DESIGN, SETTING AND PARTICIPANTS: This was a double-blind, parallel group, placebo-controlled, Phase 2, randomized clinical trial conducted in 32 addiction treatment centres in France. A total of 108 men and 46 women with severe AUD took part. INTERVENTION: Participants were randomly assigned to one of the following 3-month treatments: (1) low-dose group (LDG) receiving 8 mg cyproheptadine and 5 mg prazosin extended-release (ER) formulation daily; (2) high-dose group (HDG) receiving 12 mg cyproheptadine and 10 mg prazosin ER daily; and (3) placebo group (PG) receiving placebo of cyproheptadine and prazosin ER. A total of 154 patients were randomized: 54 in the PG, 54 in the LDG and 46 in the HDG. MEASUREMENTS: The primary outcome was TAC change from baseline to month 3. FINDINGS: A significant main treatment effect in the change in TAC was found in the intent-to-treat population (P = 0.039). The HDG and LDG showed a benefit in the change in TAC from baseline to month 3 compared with PG: -23.6 g/day, P = 0.016, Cohen's d = -0.44; -18.4 g/day, P = 0.048 (Bonferroni correction P < 0.025), Cohen's d = -0.36. In a subgroup of very high-risk drinking-level participants (> 100 g/day of pure alcohol for men and > 60 g/day for women), the difference between the HDG and the PG in the primary outcome was -29.8 g/day (P = 0.031, Cohen's d = -0.51). The high and low doses were well-tolerated with a similar safety profile. CONCLUSIONS: A randomized controlled trial of treatment of severe alcohol use disorder with a cyproheptadine-prazosin combination for 3 months reduced drinking by more than 23 g per day compared with placebo. A higher dose combination was associated with a larger magnitude of drinking reduction than a lower dose combination while showing similar safety profile.

Determinants of interest in extended-released buprenorphine: A survey among 366 French patients treated with buprenorphine or methadone.

AIM: To explore the factors determining the interest in extended-release buprenorphine (XR-BUP) injections among patients receiving opioid agonist treatment (OAT) in France. METHODS: 366 patients receiving OAT for opioid use disorder, recruited in 66 French centers, were interviewed from 12/2018 to 05/2019. A structured questionnaire assessed their interest in XR-BUP using a [1-10] Likert scale. 'More' vs. 'less' interested groups were defined using the median score of interest, and their characteristics were explored using adjusted odds ratios (aORs) and 95 % confidence interval (95 %CI). Independent variables were as follows: sociodemographic characteristics, OAT-related features (e.g., type of OAT and prescriber, dosing, or duration of treatment), OAT representations, and personal objectives of treatment. RESULTS: The median interest in XR-BUP was 7 (interquartile range: 3-9) out of 10. The participants who were 'more interested' (i.e. those scoring ≥7) showed no substantial difference in sociodemographic characteristics, relative to the 'less interested' participants. However, they more frequently reported forgetting to take their OAT (OR = 1.81; CI95 % = 1.06-3.10) or reported experiencing situations where taking their OAT was impractical (aOR = 1.69; CI95 % = 1.05-2.73). Their treatment objective was more focused on stopping illicit drugs (aOR = 1.67; 95 %CI = 1.02-2.70), reducing health risks (aOR = 3.57; 95 %CI = 1.67-7.69) and craving (aOR = 2.38; 95 %CI = 1.39-4.02) or improving family (aOR = 1.81; 95 %CI = 1.03-3.13) or professional (aOR = 2.22; 95 %CI = 1.43-3.85) recovery. CONCLUSIONS: In France, where the access to OAT is relatively unrestricted, the majority of participants were interested in XR-BUP formulations. Being interested was associated with treatment objectives focused on abstinence and recovery, and with experiencing constraints in taking a daily oral OAT.

Factors of Interest in Extended-Release Buprenorphine: Comparisons Between Incarcerated and Non-Incarcerated Patients with Opioid Use Disorder.

PURPOSE: Extended-release buprenorphine (XR-BUP) covers a range of formulations of buprenorphine-based treatments for opioid use disorder (OUD) that release the medication over a period of one week, one month, or six months. OUD is particularly prevalent among incarcerated populations, and previous findings have shown that incarcerated subjects were not less interested in XR-BUP than non-incarcerated subjects. However, no study has ever investigated whether the factors of interest in XR-BUP were similar in incarcerated and non-incarcerated populations. PATIENTS AND METHODS: We carried out post-hoc analyses using data from the "AMBRE" survey, which was conducted among 366 individuals with OUD, that were recruited in 68 French addiction settings, including six prison medical centers. The reasons for interest in XR-BUP were compared between incarcerated and non-incarcerated interviewees, using logistic regressions models, which provided raw and adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Adjustment variables were gender, age category, level of education, and type of current medication for OUD, respectively. RESULTS: Data from 317 participants (ie, 221 non-incarcerated, and 96 incarcerated individuals) were included in the analyses. Adjusted comparisons found that "no longer taking a daily treatment" (aOR= 2.91; 95% CI= 1.21-6.98) and "having a more discreet medication" (aOR= 1.76; 95% CI= 1.01-3.10) were reasons that appealed more to incarcerated participants than to non-incarcerated ones. On the other hand, the potential reduction of withdrawal symptoms (aOR= 0.54; 95% CI= 0.29-0.99) or the risk of misuse (aOR= 0.56; 95% CI= 0.34-0.94) associated with XR-BUP treatment were considered more important by non-incarcerated individuals than by incarcerated ones. CONCLUSION: Incarcerated interviewees were interested in XR-BUP for different reasons than those outside prison. In particular, incarcerated patients were more interested in practicability and discretion features, and less in improving recovery or reducing misuse than non-incarcerated patients.

[Prolonged-release buprenorphine formulations: Perspectives for clinical practice]. / Buprénorphine d'action prolongée : quelles perspectives pour la pratique clinique ?

Buprenorphine and methadone are the two main opioids agonist treatments approved for opioid use disorder. Buprenorphine is a partial agonist of the mu-opioid receptors, which has been merely available through sublingual form until now. In practice, the use of buprenorphine is smoother than that of methadone, and it induces reduced risks of overdose. However, sublingual buprenorphine also exposes to risks (e.g., withdrawal, misuse) and constraints (e.g., daily intake). Three new galenic formulations of prolonged-release buprenorphine (PRB) are being commercialized and should allow some improvements in patients' comfort and safety. This narrative review aims to describe the main technical features and efficacy and safety data of these PRBs, as well as patients' and professionals' expectancies and concerns, using data of the scientific literature and the regulatory texts. PRBs consist of one subcutaneous implant and two subcutaneous injection depots. Sixmo®/Probuphine® is a six-month-long implant which needs to be surgically placed and removed and is approved for subjects previously treated with a maximum daily dose of 8mg of sublingual buprenorphine, and can be used only for two successive periods of six months before the subject needs to be switched back to sublingual form. Sublocade® is a one-month-long depot formulation that is indicated in switch from sublingual buprenorphine, and which proposes only two dose schemes, i.e., 100 and 300mg monthly. Buvidal®/Brixadi® is a one-week- or one-month-long depot formulation with multiple dosages, which can be used in initiation or in switched from sublingual formulations. While opioid users report some concerns with a risk of coercive use of long-acting forms of buprenorphine, both users and professionals deem that these new specialties could be particularly appreciated in stabilized patients bothered with the daily intake of the treatments, or specific situations at risk of treatment dropout (e.g., following hospital discharge or prison release).

Prolonged-release buprenorphine formulations: Perspectives for clinical practice.

Buprenorphine and methadone are the two main opioid agonist treatments approved for opioid use disorder. Buprenorphine is a partial agonist of the mu opioid receptors, which has been merely available through sublingual form until now. In practice, the use of buprenorphine is smoother than that of methadone, and it induces reduced risks of overdose. However, sublingual buprenorphine also exposes to risks (e.g., withdrawal, misuse) and constraints (e.g., daily intake). Three new galenic formulations of prolonged-release buprenorphine (PRB) are being commercialized and should allow some improvements in patients' comfort and safety. This narrative review aims to describe the main technical features and efficacy and safety data of these PRBs, as well as patients' and professionals' expectancies and concerns, using data of the scientific literature and the regulatory texts. PRBs consist of one subcutaneous implant and two subcutaneous injection depots. Sixmo®/Probuphine® is a six-month-long implant which needs to be surgically placed and removed and is approved for subjects previously treated with a maximum daily dose of 8mg of sublingual buprenorphine, and can be used only for two successive periods of six months before the subject needs to be switched back to sublingual form. Sublocade® is a one-month-long depot formulation that is indicated in switch from sublingual buprenorphine, and which proposes only two dose schemes, i.e., 100 and 300mg monthly. Buvidal®/Brixadi® is a one-week- or one-month-long depot formulation with multiple dosages, which can be used in initiation or in switched from sublingual formulations. While opioid users report some concerns with a risk of coercive use of long-acting forms of buprenorphine, both users and professionals deem that these new specialties could be particularly appreciated in stabilized patients bothered with the daily intake of the treatments, or specific situations at risk of treatment dropout (e.g., following hospital discharge or prison release).

Addendum: Brousse, G.; et al. Alcohol risk reduction in France: a modernised approach related to alcohol misuse disorders. Int. J. Environ. Res. Public health 2014, 11, 11664-11675.

The author would like to update "Conflicts of Interest" section of their previous publication [1] as follows: Conflicts of Interest Georges Brousse has received sponsorship to attend scientific meetings, speaker honoraria, and consultancy fees from Lundbeck and Merck-Lipha. Patrick Bendimerad received honoraria and travel reimbursements for conferences and consultancy by Lundbeck Laboratory and participated as a coinvestigator.in the multicenter investigational drug studies of Lundbeck. [...].

Alcoholism risk reduction in France: a modernised approach related to alcohol misuse disorders.

During many years in France, risk reduction strategies for substance abuse concerned prevention strategies in the general population or interventions near users of illicit substances. In this spirit, the reduction of consumption only concerned opiate addicts. With regard to alcohol, the prevention messages relative to controlled consumption were difficult to transmit because of the importance of this product in the culture of the country. In addition, methods of treatment of alcoholism rested on the dogma of abstinence. Several factors have recently led to an evolution in the treatment of alcohol use disorders integrating the reduction of consumption in strategies. Strategies for reducing consumption should aim for consumption below recommended thresholds (two drinks per day for women, three for the men) or, at least, in that direction. It must also be supported by pharmacotherapy and psychotherapy, which offer possibilities. Failure to manage reduction will allow the goals to be revisited and to reconsider abstinence. Finally this evolution or revolution is a new paradigm carried in particular by a pragmatic approach of the disease and new treatments. The aims of this article are to give elements of comprehension relating to the evolution of the practices in France in prevention and treatment of alcohol use disorders and in particular with regard to the reduction of consumption.