Peter Krajci

Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid Dependence: A Randomized Clinical Noninferiority Trial

Importance To date, extended-release naltrexone hydrochloride has not previously been compared directly with opioid medication treatment (OMT), currently the most commonly prescribed treatment for opioid dependence. Objective To determine whether treatment with extended-release naltrexone will be as effective as daily buprenorphine hydrochloride with naloxone hydrochloride in maintaining abstinence from heroin and other illicit substances in newly detoxified individuals. Design, Setting and Participants A 12-week, multicenter, outpatient, open-label randomized clinical trial was conducted at 5 urban addiction clinics in Norway between November 1, 2012, and December 23, 2015; the last follow-up was performed on October 23, 2015. A total of 232 adult opioid-dependent (per DSM-IV criteria) individuals were recruited from outpatient addiction clinics and detoxification units and assessed for eligibility. Intention-to-treat analyses of efficacy end points were performed with all randomized participants. Interventions Randomization to either daily oral flexible dose buprenorphine-naloxone, 4 to 24 mg/d, or extended-release naltrexone hydrochloride, 380 mg, administered intramuscularly every fourth week for 12 weeks. Main Outcomes and Measures Primary end points (protocol) were the randomized clinical trial completion rate, the proportion of opioid-negative urine drug tests, and number of days of use of heroin and other illicit opioids. Secondary end points included number of days of use of other illicit substances. Safety was assessed by adverse event reporting. Results Of 159 participants, mean (SD) age was 36 (8.6) years and 44 (27.7%) were women. Eighty individuals were randomized to extended-release naltrexone and 79 to buprenorphine-naloxone; 105 (66.0%) completed the trial. Retention in the extended-release naltrexone group was noninferior to the buprenorphine-naloxone group (difference, −0.1; with 95% CI, −0.2 to 0.1; Pu2009=u2009.04), with mean (SD) time of 69.3 (25.9) and 63.7 (29.9) days, correspondingly (Pu2009=u2009.33, log-rank test). Treatment with extended-release naltrexone showed noninferiority to buprenorphine-naloxone on group proportion of total number of opioid-negative urine drug tests (mean [SD], 0.9 [0.3] and 0.8 [0.4], respectively, difference, 0.1 with 95% CI, −0.04 to 0.2; Pu2009<u2009.001) and use of heroin (mean difference, −3.2 with 95% CI, −4.9 to −1.5; Pu2009<u2009.001) and other illicit opioids (mean difference, −2.7 with 95% CI, −4.6 to −0.9; Pu2009<u2009.001). Superiority analysis showed significantly lower use of heroin and other illicit opioids in the extended-release naltrexone group. No significant differences were found between the treatment groups regarding most other illicit substance use. Conclusions and Relevance Extended-release naltrexone was as effective as buprenorphine-naloxone in maintaining short-term abstinence from heroin and other illicit substances and should be considered as a treatment option for opioid-dependent individuals. Trial Registration clinicaltrials.gov Identifier: NCT01717963

Buprenorphine dosing choices in specific populations: review of expert opinion.

ABSTRACT Introduction: Treatment of opioid dependence with buprenorphine improves outcomes. Typical dosing ranges for all patients from clinical evidence and as defined in the product information are wide. For specific groups with complex clinical scenarios, there is no clear consensus on dosing choices to achieve best possible outcomes. Areas covered: The doses of buprenorphine used in 6 European countries was reviewed. A review of published evidence supported rapid induction with buprenorphine and the benefits of higher doses but did not identify clearly useful guidance on dosing choices for groups with complex clinical scenarios. An expert group of physicians with experience in addiction care participated in a discussion meeting to share clinical practice experience and develop a consensus on dosing choices. Expert opinion: There was general agreement that treatment outcomes can be improved by optimising buprenorphine doses in specific subgroups. Specific groups in whom buprenorphine doses may be too low and who could have better outcomes with optimised dosing were identified on the basis of clinical practice experience. These groups include people with severe addiction, high tolerance to opioids, and psychiatric comorbidities. In these groups it is recommended to review dosing choices to ensure buprenorphine dosing is sufficient.

The Impact of Misuse and Diversion of Opioid Substitution Treatment Medicines: Evidence Review and Expert Consensus.

Background/Aims: Opioid substitution treatment (OST) improves outcomes in opioid dependence. However, controlled drugs used in treatment may be misused or diverted, resulting in negative treatment outcomes. This review defines a framework to assess the impact of misuse and diversion. Methods: A systematic review of published studies of misuse and diversion of OST medicines was completed; this evidence was paired with expert real-world experience to better understand the impact of misuse and diversion on the individual and on society. Results: Direct impact to the individual includes failure to progress in recovery and negative effects on health (overdose, health risks associated with injecting behaviour). Diversion of OST has impacts on a community that is beyond the intended OST recipient. The direct impact includes risk to others (unsupervised use; unintended exposure of children to diverted medication) and drug-related criminal behavior. The indirect impact includes the economic costs of untreated opioid dependence, crime and loss of productivity. Conclusion: While treatment for opioid dependence is essential and must be supported, it is vital to reduce misuse and diversion while ensuring the best possible care. Understanding the impact of OST misuse and diversion is key to defining strategies to address these issues.

Effects of Hemodialysis on Methadone Pharmacokinetics and QTc

PURPOSEnEffects of hemodialysis on pharmacokinetic properties and QTc were studied in 4 patients taking daily methadone dose of 100 mg (range, 60-120 mg).nnnMETHODSnMethadone in serum, dialysate, and urine were measured by LC-MS/MS. QTc was calculated with Bazetts formula.nnnFINDINGSnThe serum Cmin methadone level was 1124 nmol/L (range, 547-1581 nmol/L). Methadone dialysate clearance was 17.1 mL/min (range, 13.7-20.6 mL/min). Total loss in dialysate was 2.30% (range, 1,25-3,70%) of daily methadone intake. QTc increased from 391 msec (range, 369-406 msec) to 445 msec (range, 407-479 msec), independently of serum methadone level, which may be explained by normalization of serum electrolytes.nnnIMPLICATIONSnMethadone dose adjustment is not needed because of hemodialysis.

Effectiveness, safety and feasibility of extended-release naltrexone for opioid dependence: a 9-month follow-up to a 3-month randomized trial: Extended-release naltrexone

BACKGROUND AND AIMnThis is a follow-up study of a previously published randomized clinical trial conducted in Norway that compared extended-release naltrexone (XR-NTX) to buprenorphine-naloxone (BP-NLX) over 3xa0months. At the conclusion of the trial, participants were offered their choice of study medication for an additional 9xa0months. While BP-NLX was available at no cost through opioid maintenance treatment programmes, XR-NTX was available only through study participation, accounting for why almost all participants chose XR-NTX in the follow-up. The aim of this follow-up study was to compare differences in outcome between adults with opioid dependence continuing XR-NTX and those inducted on XR-NTX for a 9-month period, on measures of effectiveness, safety and feasibility.nnnDESIGNnIn this prospective cohort study, participants were either continuing XR-NTX, changed from BP-NLX to XR-NTX or re-included into the study and inducted on XR-NTX treatment.nnnSETTINGnFive urban, out-patient addiction clinics in Norway.nnnPARTICIPANTSnOpioid-dependent adults continuing (nxa0=xa054) or inducted on (nxa0=xa063) XR-NTX.nnnINTERVENTIONnXR-NTX administrated as intramuscular injections (380xa0mg) every fourth week.nnnMEASUREMENTSnData on retention, use of heroin and other illicit substances, opioid craving, treatment satisfaction, addiction-related problems and adverse events were reported every fourth week.nnnFINDINGSnNine-month follow-up completion rates were 51.9% among participants continuing XR-NTX in the follow-up and 47.6% among those inducted on XR-NTX. Opioid abstinence rates were, respectively, 53.7 and 44.4%. No significant group differences were found in use of heroin and other opioids.nnnCONCLUSIONSnOpioid-dependent individuals who elect to switch from buprenorphine-naltrexone treatment after 3xa0months to extended-release naltrexone treatment for 9xa0months appear to experience similar treatment completion and abstinence rates and similar adverse event profiles to individuals who had been on extended-release naltrexone from the start of treatment.

Are we ready to treat hepatitis C virus in individuals with opioid use disorder: assessment of readiness in European countries on the basis of an expert-generated model

Individuals with a history of injecting drugs have a high prevalence of chronic hepatitis C (HCV) infection. Many have a history of opioid use disorder (OUD). Despite novel treatments with improved efficacy and tolerability, treatment is limited in the group. A faculty of experts shared insights from clinical practice to develop an HCV care-readiness model. Evidence and expert knowledge was collected. Ten experts developed a model of three factors (with measures): ‘healthcare engagement’, ‘guidance’ and ‘place’. Overall, 40–90% of individuals with OUD engage with drug treatment services. Ten of 12 HCV guidelines provided specific advice for the OUD population. Ten of 12 OUD care guidelines provided useful HCV care advice. In 11 of 12 cases, location of HCV/drug treatment care was in different places. This readiness assessment shows that there are important limitations to successful HCV care in OUD. Specific actions should be taken: maintain/increase access to OUD treatment services/opioid agonist therapy, updating HCV guidance, locate care in the same place and allow wider prescribing of anti HCV medicines.