Long-Acting Buprenorphine Formulations as a New Strategy for the Treatment of Opioid Use Disorder.

Long-acting buprenorphine formulations have been recently marketed for the Opioid Agonist Treatment (OAT) of opioid use disorder (OUD) associated with medical, social, and psychological support. Their duration of action ranges from one week up to 6 months. The non-medical use of opioids is increasing with a parallel rise in lethal overdoses. Methadone and buprenorphine are the standard treatment for opioid dependence. Methadone Maintenance Treatment (MMT) is widely recognized as one of the most effective ways of reducing the risks of overdose, crime, and transmission of HIV (Human Immunodeficiency Virus) in people who use opioids; however, its effectiveness has been hindered by low rates of uptake and retention in treatment. Furthermore, both methadone and buprenorphine are widely diverted and misused. Thus, a crucial aspect of treating OUD is facilitating patients' access to treatment while minimizing substance-related harm and improving quality of life. The newly developed long-acting buprenorphine formulations represent a significant change in the paradigm of OUD treatment, allowing an approach individualized to patients' needs. Strengths of this individualized approach are improved adherence (lack of peaks and troughs in blood concentrations) and a reduced stigma since the patient doesn't need to attend their clinic daily or nearly daily, thus facilitating social and occupational integrations as the quality of life. However, less frequent attendance at the clinic should not affect the patient-physician relationship. Therefore, teleconsulting or digital therapeutic services should be developed in parallel. In addition, diversion and intravenous misuse of buprenorphine are unlikely due to the characteristics of these formulations. These features make this approach of interest for treating OUD in particular settings, such as subjects staying or when released from prison or those receiving long-term residential treatment for OUD in the therapeutic communities. The long-lasting formulations of buprenorphine can positively impact the OUD treatment and suggest future medical and logistic developments to maximize their personalized management and impact.

Hepatitis C virus: Current steps toward elimination in Germany and barriers to reaching the 2030 goal.

Hepatitis C virus (HCV) affects over 70 million people globally, with an estimated 399 000 HCV-related deaths in 2016. The World Health Organization (WHO) has set a goal to eliminate HCV by 2030. Despite the availability of direct-acting antivirals-highly effective and well-tolerated therapies for HCV-many patients infected with HCV in Germany have not initiated treatment, including a majority of those who are aware of their positive diagnosis. Barriers to screening, diagnosis, and treatment are major factors taking many countries off track for HCV elimination by 2030. Identifying country-specific barriers and challenges, particularly in at-risk populations such as people who inject drugs or men who have sex with men, has the potential to create tailored programs and strategies to increase access to screening or treatment and engage at-risk populations. This review aims to report the current steps toward HCV elimination in Germany, the country-specific barriers and challenges that will potentially prevent reaching the 2030 HCV elimination goal and describe good practice examples to overcome these barriers.

Substitution treatment for opioid dependence with slow-release oral morphine: Retention rate, health status, and substance use after switching to morphine.

INTRODUCTION: Since April 2015, slow-release oral morphine (SROM) has been approved for opioid agonist treatment (OAT) in Germany. Experimental studies show that benefits of SROM over methadone include less heroin craving, better tolerability, and higher patient satisfaction and mental stability. The SROMOS study (Efficacy and Tolerability of Slow-Release Oral Morphine in Opioid Substitution Treatment) aims to investigate the long-term effects (effectiveness and safety) of morphine substitution under routine care in Germany. MATERIAL AND METHODS: This is a prospective, noninterventional, naturalistic, observational study. Between July 2016 and November 2017, this study recruited patients in OAT who decided to switch to SROM from 23 outpatient addiction treatment centers in Germany. The study collected data on mental health (Brief Symptom Inventory - BSI-18), substance use, somatic health (Opiate Treatment Index Health-Symptoms-Scale - OTI-HSS), opioid craving (visual analogue scale), and withdrawal symptoms (Short Opiate Withdrawal Scale) at baseline (t0) and after 3 (t3), 6 (t6) and 12 (t12) months. Physicians documented side effects as adverse events (AEs) and adverse drug reactions (ADRs). RESULTS: Three-quarters of the enrolled study participants (N = 180) were male. The average age was 44.4 years. Patients were opioid-dependent for 23 years and had been in OAT for almost seven years on average. After 12 months, 60.6% were still being treated with SROM. Mental health improved significantly under SROM treatment between t0 and t12. The intention-to-treat (ITT), as well as the per-protocol (PP) analysis, shows a statistically significant improvement of the mean Global Severity Index (GSI) of the BSI-18 value of 20% (ITT) and 24% (PP). Physical health also improved significantly under SROM treatment. There were no statistically significant changes in the use of cannabis, cocaine, amphetamines, and tranquillizers in the past 30 days, but heroin use, intravenous consumption, and the number of drinking days significantly decreased. CONCLUSIONS: This study provides some of the first long-term data on OAT with SROM under routine care conditions. SROM treatment is an effective alternative for a subgroup of opioid-dependent patients with an unsatisfactory course of OAT or in cases where undesirable side effects due to alternative substances have occurred. ETHICAL STATEMENT: The study protocol was approved by the Ethics Committee of the Chamber of Physicians in Hamburg in March 2016 (No. PV5222). The study was conducted by following the Declaration of Helsinki and is registered with the German Register of Clinical Trials (DRKS, ID: DRKS00010712).

Perceived barriers related to testing, management and treatment of HCV infection among physicians prescribing opioid agonist therapy: The C-SCOPE Study.

The aim of this analysis was to evaluate perceived barriers related to HCV testing, management and treatment among physicians practicing in clinics offering opioid agonist treatment (OAT). C-SCOPE was a study consisting of a self-administered survey among physicians practicing at clinics providing OAT in Australia, Canada, Europe and the United States between April and May 2017. A 5-point Likert scale (1 = not a barrier, 3 = moderate barrier, 5 = extreme barrier) was used to measure responses to perceived barriers for HCV testing, evaluation and treatment across the domains of the health system, clinic and patient. Among the 203 physicians enrolled (40% USA, 45% Europe, 14% Australia/Canada), 21% were addiction medicine specialists, 29% psychiatrists and 69% were metro/urban. OAT physicians in this study reported poor access to on-site venepuncture (35%), point-of-care HCV testing (16%), and noninvasive liver disease assessment (25%). Only 30% of OAT physicians reported personally treating HCV infection. Major perceived health system barriers to HCV management included the lack of funding for noninvasive liver disease testing, long wait times to see an HCV specialist, lack of funding for new HCV therapies, and reimbursement restrictions based on drug/alcohol use. Major perceived clinic barriers included the lack of peer support programmes and/or HCV case managers to facilitate linkage to care, the need to refer people off-site for noninvasive liver disease staging, the lack of support for on-site phlebotomy and the lack of on-site delivery of HCV therapy. This study highlights several important modifiable barriers to enhance HCV testing, evaluation and treatment among PWID attending OAT clinics.

Perceptions and self-reported competency related to testing, management and treatment of hepatitis C virus infection among physicians prescribing opioid agonist treatment: The C-SCOPE study.

BACKGROUND: This study evaluated competency related to HCV testing, management and treatment among physicians practicing in clinics offering opioid agonist treatment (OAT). METHODS: C-SCOPE is a study consisting of a self-administered survey among physicians practicing at clinics providing OAT in Australia, Canada, Europe and USA between April-May 2017. A 7-point scale was used to measure < average competence (score >4 of 7) related to HCV testing, management and treatment. RESULTS: Among 203 physicians (40% USA, 45% Europe, 14% Australia/Canada) 21% were addiction medicine specialists, 29% psychiatrists, and 70% were metro/urban [mean PWID managed, 51; years of experience, 11]. The majority perceived HCV testing (82%) and treatment (85%) among PWID as important. The minority reported < average competence with respect to regular screening (12%) and interpretation of HCV test results (14%), while greater proportions reported < average competence in advising patients about new HCV therapies (28%), knowledge of new treatments (37%), and treatment/management of HCV (40%). In adjusted analysis, factors independently associated with < average self-reported competency related to the ability to treat HCV and manage side effects included fewer years in medical practice, fewer numbers of patients treated for HCV infection in the past six months, not having obtained information on screening, diagnosing or treatment of HCV, not having attended any training on HCV in the past year, and not having read or consulted AASLD/IDSA, EASL or other guidelines for HCV. CONCLUSION: Physicians treating HCV infection among PWID attending OAT clinics recognized the importance of HCV testing and treatment. However, self-perceived competency related to HCV management and treatment was low, highlighting the importance of improved HCV education and training among physicians practicing in clinics offering OAT.

Recommendations for buprenorphine and methadone therapy in opioid use disorder: a European consensus.

INTRODUCTION: Management of patients with opioid use disorder (OUD) commonly includes opioid agonist therapy (OAT) as a part of an integrated treatment plan. These interventions are associated with proven benefits to the individual and society. Areas covered: The use of methadone and buprenorphine within an integrated treatment plan in the management of patients with OUD: this work provides consensus recommendation on pharmacotherapy in OUD to assist clinicians with practical decision making in this field. Expert opinion: Pharmacotherapy is recommended as part of an integrated OUD treatment approach with psychosocial interventions, with the goal of reducing risks of illicit opioid use, overdose mortality, infection with HIV or HCV, improving health, psychological and social outcomes. Access to OAT should be prioritised in the treatment of OUD. Treatment choices in OUD pharmacotherapy should be based on the needs of the individual and characteristics of medications. Recommendations for choices of OAT are based on clinical efficacy, safety, patient preference, side effects, pharmacological interactions, quality of life, dose titration potential and outcomes (control craving, ongoing opioids consumption or other drugs, and potentially psychiatric comorbidities). Special groups, pregnant women, prisoners, patients with mental health problems have specific needs which must be addressed with expert input.

High Concomitant Misuse of Fentanyl in Subjects on Opioid Maintenance Treatment.

BACKGROUND: Concomitant opioid misuse is an increasing problem in opioid maintenance treatment as it interferes with treatment success. OBJECTIVE: Therefore, the rates of concomitant fentanyl misuse in opioid maintained patients were investigated. METHODS: We conducted a cross-sectional study which consisted in collecting data via urine samples and questionnaires in Germany. Urine samples of patients on opioid maintenance treatment were gathered and fentanyl concentrations were measured from 2008 to 2012. An anonymous questionnaire provided data on the consumption of fentanyl as concomitant drug. Data were analyzed with descriptive statistics and group differences were calculated using the Chi-Square test. RESULTS: Among the total sample (urine probes of 960 patients), 6.8% opioid maintained patients had positive urine samples for fentanyl and 37.9% reported concomitant fentanyl misuse (401 of these patients filled out the questionnaire). A significant age-related association of concomitant fentanyl misuse was identified in the urine analyses (χ2 = 7.489; p = .024) and also in the questionnaire data (χ2 = 11.899, p = .003), indicating that young age increased the probability of fentanyl consumption. Patients receiving methadone had the highest rates of concomitant fentanyl misuse with 18.4% according to urine analysis. In addition, the results show that patients who are on diamorphine are significantly less likely to misuse fentanyl. CONCLUSIONS: Fentanyl is a frequently used concomitant drug. Especially young patients and patients taking methadone are at high risk. Because of the life-threatening consequences of fentanyl overdose, patients taking fentanyl should be intensively medically surveilled.

The opiate dosage adequacy scale for identification of the right methadone dose--a prospective cohort study.

BACKGROUND: Opioid maintenance treatment with methadone is regarded as gold standard in the therapy of opioid dependence. Identification of the 'right' methadone dose, however, remains challenging. We wanted to explore if the Opiate Dosage Adequacy Scale (ODAS) is a helpful instrument in methadone titration. METHODS: Within this 12-months prospective naturalistic cohort study patients in stable maintenance treatment with methadone (Eptadone®) were included. Sociodemographic and clinical data were gathered at baseline, and months 3, 6, and 12. At the same points in time, the instruments ODAS, European Addiction Severity Index (EuropASI), and Derogatis Interview for Sexual Functioning-Self Report (DISF-SR) were applied. RESULTS: Five hundred fifteen patients were enrolled, 129 patients prematurely terminated substitution treatment (treatment failure), in 108 patients substitution medication was changed, likely due to bitter taste of Eptadone®. Complete longitudinal ODAS and EuropASI data sets were available for 229 patients. The frequency of adequate methadone doses (ODAS) increased (60.9 % at baseline, 85.3 % at month 12) as well as the average daily methadone dose (63.8 (±30.8) mg/day at baseline to 69.6 (±36.0) mg/day at month 12). Inadequacy of methadone dose was not associated with treatment failure (RR 1.019; CI 95 % 0.756-1.374). Addiction severity decreased statistically significantly. Compared to adequately dosed patients, inadequately dosed patients benefited more, in that they showed greater improvements in ODAS scores, had higher increases in methadone dose, and partially experienced more advanced sexual functioning. CONCLUSION: Application of ODAS was associated with improved methadone dose adequacy and addiction severity parameters as well as increased methadone doses. Its usefulness should be corroborated in a controlled trial.

When higher doses in opioid replacement treatment are still inadequate - association to multidimensional illness severity: a cohort study.

BACKGROUND: Opioid replacement treatment (ORT) with methadone is regarded as gold standard in the treatment of opioid addiction. Treatment doses of 60 mg methadone per day and above are associated with better treatment retention and reduction in the use of heroin and cocaine. However, an absolute dose level cannot function as parameter for adequate dosing. This study aims to determine dose adequacy in a sample of patients on stable methadone treatment, and to relate dose adequacy to disease severity. METHODS: This study was designed as open prospective cohort study over 12 months, with baseline data reported here. Patients on stable substitution treatment with methadone (Eptadone®) were consecutively included. Medical and socio-demographic data were gathered and the instruments Opiate Dosage Adequacy Scale (ODAS), European Addiction Severity Index (EuropASI) and the Derogatis Interview for Sexual Functioning - Self Report (DISF-SR) were applied. RESULTS: Five hundred and sixteen subjects, who received on average 60.3 (±30.4) mg methadone per day, were included. According to ODAS, 40.6% suffered from an inadequate dosing, and 59.4% had an adequate dose. Patients with an adequate dose received on average 57.8 (±27.5) mg methadone per day, whilst patients with an inadequate dose received on average 70.6 (±33.0) mg per day. The frequencies of patients with methadone doses of less than 60 mg per were 45.4% in the inadequate and 60.6% in the adequate group. The inadequate group suffered from a statistically significant higher burden of addiction related problems in all EuropASI domains. Sexual functioning did not differ by adequacy group, but women suffered from more pronounced sexual dysfunction as compared to men. CONCLUSION: A high frequency of inadequate dosing was found in this sample of patients on ORT. Higher disease severity should alert for possible need of even higher methadone doses. The tendency to low methadone doses warrants further research in the treatment system. Higher methadone doses are not related to increased sexual dysfunction. Sexual dysfunction, especially in women, should be considered in treatment.

Maintenance treatment for opioid dependence with slow-release oral morphine: a randomized cross-over, non-inferiority study versus methadone.

AIMS: To compare the efficacy of slow-release oral morphine (SROM) and methadone as maintenance medication for opioid dependence in patients previously treated with methadone. DESIGN: Prospective, multiple-dose, open label, randomized, non-inferiority, cross-over study over two 11-week periods. Methadone treatment was switched to SROM with flexible dosing and vice versa according to period and sequence of treatment. SETTING: Fourteen out-patient addiction treatment centres in Switzerland and Germany. PARTICIPANTS: Adults with opioid dependence in methadone maintenance programmes (dose ≥50 mg/day) for ≥26 weeks. MEASUREMENTS: The efficacy end-point was the proportion of heroin-positive urine samples per patient and period of treatment. Each week, two urine samples were collected, randomly selected and analysed for 6-monoacetyl-morphine and 6-acetylcodeine. Non-inferiority was concluded if the two-sided 95% confidence interval (CI) in the difference of proportions of positive urine samples was below the predefined boundary of 10%. FINDINGS: One hundred and fifty-seven patients fulfilled criteria to form the per protocol population. The proportion of heroin-positive urine samples under SROM treatment (0.20) was non-inferior to the proportion under methadone treatment (0.15) (least-squares mean difference 0.05; 95% CI = 0.02, 0.08; P > 0.01). The 95% CI fell within the 10% non-inferiority margin, confirming the non-inferiority of SROM to methadone. A dose-dependent effect was shown for SROM (i.e. decreasing proportions of heroin-positive urine samples with increasing SROM doses). Retention in treatment showed no significant differences between treatments (period 1/period 2: SROM: 88.7%/82.1%, methadone: 91.1%/88.0%; period 1: P = 0.50, period 2: P = 0.19). Overall, safety outcomes were similar between the two groups. CONCLUSIONS: Slow-release oral morphine appears to be at least as effective as methadone in treating people with opioid use disorder.