[Addiction-related clinical practice in hospital setting : from specialization to responsibilization]. / La clinique des addictions en milieu hospitalier : entre spécialisation et responsabilisation.

Over the past two years, the Swiss Institute for Postgraduate and Further Education in Medicine has implemented a new certification in addiction medicine and an in-depth training in addiction psychiatry and psychotherapy. These developments contribute to the recognition of a specialty and the training of a new generation of specialized clinicians. This context leads to the question of the role and the skills to be passed on to non-specialists when taking care of drug addiction. This article focuses on the importance of preparing non-specialized clinicians in the hospital setting and presents two prerequisites for improving their training: to explore clinicians' field experience and to make the individual and institutional actors aware of their responsibility.

Au cours des deux dernières années, l'ISFM (Institut suisse pour la formation médicale postgraduée et continue) a établi le cadre d'une nouvelle certification en médecine de l'addiction et d'une formation approfondie en psychiatrie et psychothérapie des addictions. Ces développements contribuent à la reconnaissance d'une spécialité et à la formation d'une nouvelle génération de cliniciens spécialistes. Dans ce contexte, se pose la question du rôle et des compétences à transmettre aux non-spécialistes, notamment à l'hôpital, pièce maîtresse de la prise en charge des personnes souffrant d'un problème d'addiction aux substances. Cet article décrit l'importance de préparer les cliniciens non spécialistes sur le terrain hospitalier et évoque deux prérequis à l'amélioration de leur préparation : explorer les expériences de terrain et responsabiliser les acteurs.

[Assertive community treatment: promoting engagement with care of people suffering severe addiction]. / Suivi intensif dans la communauté pour faciliter l'accès aux soins des personnes avec des problèmes d'addiction.

Despite the increasing number of specialized addiction services and the constant deployment of health care resources, a coordinated needs-based treatment is not always available for people with severe drugs and/or alcohol problems. Too often the involved health care professionals feel helpless and overwhelmed by the complexity of the situation. In order to promote the treatment engagement of the hard-to-reach substance users, a multidisciplinary mobile team project for addiction (SIMA) was developed in Lausanne, Switzerland, in 20174. This paper describes the model of intervention, the profile of the population followed during the first year of intervention and illustrates, through two clinical cases, the advantages of this approach.

[Implementation of psychiatric involuntary outpatient treatment in canton de Vaud]. / Introduction des mesures ambulatoires (traitements psychiatriques contraints) dans le canton de Vaud.

Civil involuntary outpatient treatment authorises the provision to unwilling psychiatric patients of continuing ambulatory treatment. There is an absence of convincing international evidence for their effectiveness. From 2013 and after the Swiss Civil Code was amended, all cantonal governments enacted legislation for this new form of coercion. In canton Vaud, a working group including jurists, psychiatrists and civil judges has been set up by the Department of health in order to propose involuntary outpatient treatments respectful of patients' rights and proportional to patients' and network's needs. This article describes how involuntary outpatient treatments are locally implemented and assessed in the context of a pilot project limited to one year.

Caring for patients with substance use disorders: a qualitative investigation of difficulties encountered by hospital-based clinicians.

Background: Caring for patients with substance use disorders (SUD) is held in low regard and many clinicians resist treating them. To address this situation, numerous research projects assessed training program gaps and professional attitudes. In contrast, this study explored the actual clinical difficulties that a variety of hospital-based professionals encounter when treating patients with SUD. Methods: Qualitative multiple method design including: (1) individual semi-structured interviews with SUD experts and educators; (2) video-elicited, cross self-confrontation interviews with clinicians working in a specialist addiction unit; (3) paired semi-structured interviews with clinicians working in non-specialist units. Participants were recruited within one university hospital. Data collected at stages (1) and (3) relied on an interview guide and were analyzed using conventional content analyses. Data collected at stage (2) consisted of discussions of video recorded clinical interviews and were analyzed based on a participatory approach. Results: Twenty-three clinicians from seven hospital units participated. Forty-four difficulties were reported that we classified into six categories: knowledge-based; moral; technical; relational; identity-related; institutional. We identified seven cross-category themes as key features of SUD clinical complexity: exacerbation of patient characteristics; multiplication of medical issues; hybridity and specificity of medical discipline; experiences of stalemate, adversity, and role reversal. Conclusions: Our study, providing a comprehensive analysis of the difficulties of caring for patients with SUD, reveals a highly challenging clinical practice for a diversity of healthcare providers. They represent a complementary approach to addressing resistance as an important feature of a complex clinical system, and valuable material to discussing professional preparedness.

Usefulness of methadone plasma concentration measurement in patients receiving nevirapine or efavirenz.

OBJECTIVE: To determine methadone plasma trough and peak concentrations in patients presenting opiate withdrawal symptoms after introduction of nevirapine or efavirenz. To describe the disappearance of these symptoms after methadone titration based on plasma concentrations rather than on the symptoms. METHODS: Nine patients undergoing highly active antiretroviral therapy (HAART) and either nevirapine or efavirenz treatment were monitored daily for opiate withdrawal in a specialized drug addiction center. Methadone dose was titrated daily, and plasma concentrations were measured. The data are retrospective (case series). RESULTS: Several patients complained of symptoms such as nausea, vomiting, accelerated intestinal transit, or insomnia. Even after methadone titration based on clinical symptoms, patients and health-care providers trained in infectious disease did not classify these as withdrawal symptoms and considered them as the side effects of HAART or anxiety. Methadone plasma trough concentration showed low levels of (R)- and (R,S)-methadone. Further methadone dose adjustment according to plasma level resulted in the disappearance of these withdrawal symptoms. The daily methadone dose was split when the peak/trough (R)-methadone ratio was more than 2. CONCLUSIONS: When introducing efavirenz or nevirapine to patients undergoing methadone treatment, withdrawal symptoms should be monitored, especially those such as insomnia, vomiting, or nausea. Methadone plasma trough and peak measurements can be of value in preventing unnecessary side effects of HAART.

Exploring Clinical Practice and Developing Clinician Self-Reflection Through Cross Self-Confrontation Methodology: An Application Within an Addiction Medicine Unit.

Use of the methodology of cross self-confrontation (CSC) is limited in the field of healthcare and in the context of clinical practice. We applied this methodology within an addiction medicine unit of a university hospital, as part of an exploration of addiction-related clinical difficulties. Cross self-confrontation was used according to a 3-phase design based on video recorded clinical interviews with pairs of nurses and medical doctors. The article reports and discusses the application of CSC in a specific clinical context and illustrates the methodological process through one result. Findings suggest two major strengths of CSC in the context of clinical practice research and education: (1) the capacity to elicit tacit knowledge from daily clinical practice and (2) the ability to enhance self-reflection by questioning professionals both individually and collectively. Further use of CSC in nursing surroundings and clinical settings should be encouraged.

[Addiction]. / Dépendances.

The 2009 news in medicine regarding dependence confirm the bio-psycho-social field of addiction medicine and psychiatry. First a statement is made about the risk of cardiac arythmy in opioid substitution treatments. Then a review of the treatment of C hepatitis shows its importance in an addicted population. In the field of cognitive neuroscience, progress has been made in the knowledge of "craving" and of its endophenotypical components. Electronic medias related disorders are on the border of addiction: a case study is exploring this new domain. At last, recent datas are presented on the relationship between cannabis and psychosis.

[Risk reduction among cocaine users: a motivational approach in the GP's office]. / Reduction des risques au cabinet du généraliste chez les consommateurs de cocaine: une perspective motivationnelle.

Today, cocaine use is a public health issue. Cocaine is a powerfully addictive stimulant drug which use is increasing among some part of the population. After a brief description of the physical and psychological effects of cocaine use, the article presents a motivational way for general practitioners to deal with risk-reduction issues. Based on the Transtheoretical Model of human behavior change and providing clinical examples, the article focuses particularly on the two earliest stages of change: "pre-contemplation" and "contemplation".

Association of dopamine and opioid receptor genetic polymorphisms with response to methadone maintenance treatment.

BACKGROUND: Genetic variations of the dopamine and opioid receptors could influence the response to methadone maintenance treatment (MMT). METHODS: We included 238 MMT patients according to their response to treatment and methadone dosing, along with 217 subjects without substance dependence. All were genotyped for polymorphisms of the dopamine D1, D2, micro-opioid and delta-opioid receptor genes. RESULTS: The polymorphisms of the micro-opioid (118A>G), delta-opioid (921T>C), dopamine D1 (DdeI) and D2 (TaqI A) receptor genes were not associated with response to MMT and methadone dosing, whereas an association was found with the dopamine D2 receptor (DRD2) 957C>T polymorphism. The 957CC carriers were more frequently non-responders to treatment (OR=2.4; p=0.02) and presented a fourfold shorter period of negative urine screening (p=0.02). No significant differences in allele frequencies were observed between the MMT patients and the control group, suggesting no association of the analyzed polymorphisms with opioid dependence. CONCLUSIONS: These results suggest that DRD2 genotype may contribute to the understanding of the interindividual variability to the response to MMT.

Swiss multicenter study evaluating the efficacy, feasibility and safety of peginterferon-alfa-2a and ribavirin in patients with chronic hepatitis C in official opiate substitution programs.

BACKGROUND: Though patients in opiate substitution programs are commonly infected with HCV, due to safety and efficacy concerns, they are rarely treated with interferon and ribavirin. METHODS: In a multicenter study, HCV-infected patients in opiate maintenance treatment programs received 180 microg pegylated interferon-alfa-2a once weekly, plus daily ribavirin for 24 weeks (genotypes 2, 3), or 48 weeks (genotypes 1, 4). RESULTS: Of the 67 patients enrolled, 31 (46%) had HCV genotypes 1 or 4, and 36 (54%) had genotypes 2 or 3. Intent-to-treat analysis showed end-of-treatment virologic response in 75% of patients (81% of genotypes 2 or 3; 65% of genotypes 1 or 4), and a sustained virologic response in 61% of patients (72% of genotypes 2 or 3; 48% of genotypes 1 or 4). Fifteen patients (22%) did not complete the study, in 5 (8%) cases because of severe adverse events. CONCLUSIONS: Drug users with chronic HCV infection, regularly attending an opiate maintenance program in which close collaboration between hepatologists/internists and addiction specialists is assured, can be treated effectively and safely with pegylated interferon-alfa-2a and ribavirin. Treatment results are very similar to those in other patient groups, and thus therapy should also be considered for this population.

Could pharmacogenetic data explain part of the interindividual sensitivity to methadone-induced respiratory depression?

In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected.

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment.

BACKGROUND AND OBJECTIVE: Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment. METHODS: We included 209 patients in methadone maintenance treatment on the basis of their response to treatment and their daily methadone dose. Patients were genotyped for CYP2B6, CYP2C9, and CYP2C19. Steady-state trough and peak (R)-, (S)-, and (R,S)-plasma levels and peak-to-trough plasma level ratios were measured. RESULTS: CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng . kg/mL . mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004). CYP2C9 and CYP2C19 genotypes do not influence methadone plasma levels. Lower peak and trough plasma levels of methadone and higher peak-to-trough ratios were measured in patients considered as nonresponders [median (R,S)-methadone trough plasma levels of 183 and 249 ng . kg/mL . mg (P = .0004) and median peak-to-trough ratios of 1.82 and 1.58 for high-dose nonresponders and high-dose responders, respectively (P = .0003)]. CONCLUSION: Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study. Lower plasma levels of methadone in nonresponders, suggesting a higher clearance, and higher peak-to-trough ratios, suggesting a shorter elimination half-life, are in agreement with the usual clinical measures taken for such patients, which are to increase methadone dosages and to split the daily dose into several intakes.

HIV-1 co/super-infection in intravenous drug users.

BACKGROUND: The frequency of HIV-1 co/super-infection is unknown despite their implications for public health and vaccine development. This issue was addressed during an epidemic of both CRF11 and B subtype among intravenous drug users (IVDUs). METHODS: Bulk sequencing of reverse transcriptase, protease and C2V3 regions and subtype-specific nested polymerase chain reaction (PCR) in plasma and proviral DNA were performed using baseline and follow-up samples collected in recently infected IVDUs between 1998-2002 and in IVDUs with chronic infection living in the same area and presenting an unexpected rise of viremia (> 1 log10). RESULTS: In 58 recently infected patients, three B/CRF-11 co-infections, 25 B, 28 CRF-11 and two other subtypes were detected at baseline. In the three co-infected patients, both CRF-11 and B were detected in plasma and proviral DNA and persisted during follow-up. B- and CFR-11-specific PCR performed on follow-up samples of 40 of 58 recently infected patients (median follow-up, 14.5 months) revealed a transient B super-infection in a patient initially infected by CRF-11. Five of 156 chronic IVDUs (total follow-up: 346 years) had an unexpected rise of viremia. In two of them, aviremic without treatment for years after an initial B infection, a symptomatic CRF-11 super-infection occurred and was associated with high viral load and a fall of CD4 cell count. CONCLUSIONS: In recently infected IVDUs, co-infection B/CRF-11 is relatively frequent (5%). In chronically infected IVDUs super-infection may be transient and may occur in patients controlling efficiently HIV infection by the initial strain.

Treatment of hepatitis C in HCV mono-infected and in HIV-HCV co-infected patients: an open-labelled comparison study.

BACKGROUND/AIMS: Treatment of chronic HCV infection has become a priority in HIV+ patients, given the faster progression to end-stage liver disease. The primary endpoint of this study was to evaluate and compare antiviral efficacy of Peginterferon alpha 2a plus ribavirin in HIV-HCV co-infected and HCV mono-infected patients, and to examine whether 6 months of therapy would have the same efficacy in HIV patients with favourable genotypes 2 and 3 as in mono-infected patients, to minimise HCV-therapy-related toxicities. Secondary endpoints were to evaluate predictors of sustained virological response (SVR) and frequency of side-effects. METHODS: Patients with genotypes 1 and 4 were treated for 48 weeks with Pegasys 180 microg/week plus Copegus 1000-1200 mg/day according to body weight; patients with genotypes 2 and 3 for 24 weeks with Pegasys 180 microg/week plus Copegus 800 mg/day. RESULTS: 132 patients were enrolled in the study: 85 HCV mono-infected (38: genotypes 1 and 4; 47: genotypes 2 and 3), 47 HIV-HCV co-infected patients (23: genotypes 1 and 4; 24: genotypes 2 and 3). In an intention-to-treat analysis, SVR for genotypes 1 and 4 was observed in 58% of HCV mono-infected and in 13% of HIV-HCV co-infected patients (P = 0.001). For genotypes 2 and 3, SVR was observed in 70% of HCV mono-infected and in 67% of HIV-HCV co-infected patients (P = 0.973). Undetectable HCV-RNA at week 4 had a positive predictive value for SVR for mono-infected patients with genotypes 1 and 4 of 0.78 (95% CI: 0.54-0.93) and of 0.81 (95% CI: 0.64-0.92) for genotypes 2 and 3. For co-infected patients with genotypes 2 and 3, the positive predictive value of SVR of undetectable HCV-RNA at week 4 was 0.76 (95%CI, 0.50-0.93). Study not completed by 22 patients (36%): genotypes 1 and 4 and by 12 patients (17%): genotypes 2 and 3. CONCLUSION: Genotypes 2 or 3 predict the likelihood of SVR in HCV mono-infected and in HIV-HCV co-infected patients. A 6-month treatment with Peginterferon alpha 2a plus ribavirin has the same efficacy in HIV-HCV co-infected patients with genotypes 2 and 3 as in mono-infected patients. HCV-RNA negativity at 4 weeks has a positive predictive value for SVR. Aggressive treatment of adverse effects to avoid dose reduction, consent withdrawal or drop-out is crucial to increase the rate of SVR, especially when duration of treatment is 48 weeks. Sixty-one percent of HIV-HCV co-infected patients with genotypes 1 and 4 did not complete the study against 4% with genotypes 2 and 3.

Polyfunctional HCV-specific T-cell responses are associated with effective control of HCV replication.

HCV infection has a severe course of disease in HIV/HCV co-infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV-specific T-cell responses in 86 HCV mono-infected patients, 48 HIV/HCV co-infected patients and 42 liver transplant recipients. IFN-gamma and IL-2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCV-derived peptides. We observed that HCV-specific T-cell responses were polyfunctional in HCV mono-infected patients, with presence of proliferating single IL-2-, dual IL-2/IFN-gamma and single IFN-gamma-producing CD4+ and dual IL-2/IFN-gamma and single IFN-gamma-producing CD8+ cells. In contrast, HCV-specific T-cell responses had an effector profile in HIV/HCV co-infected individuals and liver transplant recipients with absence of single IL-2-producing HCV-specific CD4+ and dual IL-2/IFN-gamma-producing CD8+ T cells. In addition, HCV-specific proliferation of CD4+ and CD8+ T cells was severely impaired in HIV/HCV co-infected patients and liver transplant recipients. Importantly, "only effector" T-cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores. Therefore, the present results suggest that immune-based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV-1 co-infection and liver transplantation.

Topiramate in benzodiazepine withdrawal.

There is an increasing interest in anticonvulsants for the treatment of benzodiazepine withdrawal symptoms. The new anticonvulsant compound topiramate seems to be an especially promising drug for this indication. It acts, among others, as an AMPA antagonist, which may be responsible in part for its anticonvulsant efficacy, but may also modulate the withdrawal-induced activation of noradrenergic neurons in the locus coeruleus, which are related to some behavioural effects of benzodiazepine withdrawal. A case is presented of a rapid benzodiazepine-withdrawal treated successfully with topiramate.