Effect on QTc interval by switching from methadone to equipotent R-methadone dose in methadone maintenance treatment patients.

Methadone (R,S-methadone) can prolong the QT interval. R-methadone inhibits cardiac potassium channel function less than S-methadone. We tested if switching from methadone to R-methadone would reduce corrected QT (QTc) intervals in methadone maintenance treatment (MMT) patients. Nine patients, with automatically read QTc intervals ≥450 ms, were required to detect a 20 ms (clinically relevant) reduction in QTc intervals with 15 ms standard deviation (SD) and 90% power. Nine stabilized MMT patients, using median (range) 70 (40-120) mg methadone, were included. Data (ECG recordings, serum samples, and withdrawal symptoms) were collected both before drug intake (Cmin ) and at 3 h after drug intake (Cmax ), and were collected on the day before the switch from methadone to equipotent R-methadone dose and at 14 and 28 days after the switch. A cardiologist calculated QTc intervals retrospectively. Serum electrolytes and methadone concentrations were measured. Mean QTc intervals at Cmin were 472 ms and 422 ms on methadone (automatically and manually read) and 414 ms on R-methadone (manually read). Mean (SD) change in QTc intervals was -8 (10) ms (p = 0.047) at Cmin but non-significant at Cmax . R-methadone showed a concentration-dependent relationship with QTc intervals. Switching to R-methadone reduced QTc intervals, but far less than the 20 ms considered clinically relevant.

Concentrations of psychoactive substances in blood samples from non-fatal and fatal opioid overdoses.

AIM: The primary aim was to compare concentrations of psychoactive substances in blood in non-fatal and fatal opioid overdoses. The secondary aim was to assess the concentration levels of naloxone in blood in non-fatal overdoses and the association between naloxone findings and concomitantly detected drugs. METHOD DESIGN: Case-control study. SETTING: Norway. Fatal overdoses from 2017 and non-fatal overdoses from February 2018 to September 2019. CASES: Thirty-one non-fatal and 160 fatal opioid overdose cases. Data from the non-fatal overdoses were collected from hospital records and blood samples, and data from the fatal overdoses were collected from autopsy reports. Concentrations of psychoactive substances (including ethanol) in blood samples were collected at the time of hospital admission for the non-fatal overdoses and during autopsy for the fatal overdoses. RESULTS: The median number of different substances detected was four for fatal and five for non-fatal overdoses. The fatal overdoses had higher pooled concentrations of opioids (188 vs 57.2 ng/mL, P < .001), benzodiazepines (5467 vs 2051 ng/mL, P = .005) and amphetamines (581 vs 121 ng/mL, P < .001) than the non-fatal overdoses. A linear relationship between naloxone and concomitant pooled opioid concentrations was found (95% confidence interval = 0.002-0.135, P < .05). CONCLUSION: The total load of drug concentrations was associated with the fatal outcome of an overdose, while the number of drugs used, to a lesser extent, differentiated between those who survived and those who died from an overdose. Higher opioid concentrations were associated with treatment with higher naloxone doses.

Adapting treatment length to opioid-dependent individuals' needs and preferences: A 2-year follow-up to a 1-year study of extended-release naltrexone.

BACKGROUND AND AIM: Extended-release naltrexone (XR-NTX) is an underused treatment option for opioid dependence, today only available in a few countries in the world. Although effective, safe and feasible in short-term treatment, long-term data are scarce and there is no recommendation for required treatment length. The aims of the study were to determine the perceived need of long-term XR-NTX treatment and to examine long-term treatment outcomes. DESIGN: In this prospective cohort study, following a parent 1-year study of XR-NTX, participants received treatment with XR-NTX at their own discretion for a maximum of 104 weeks. SETTING: Five urban, outpatient addiction clinics in Norway. PARTICIPANTS: Opioid-dependent adults 18-60 years old (n=50) already participating in the parent study. INTERVENTION: XR-NTX administrated as intra-muscular injections (380 mg) every 4 weeks. MEASUREMENTS: Time in the study, use of opioids and other illicit substances, opioid craving, and treatment satisfaction reported every 4 weeks. FINDINGS: Among 58 participants who completed the 1-year parent study, 50 chose to continue the treatment with XR-NTX. Median prolonged treatment time was 44.0 weeks (95% CI: 25.5-62.5), ranging from 8 to 104 weeks. Most participants (35, 70%) reported no relapse to opioid use during treatment while a subgroup (15, 30%) reported relapses to opioids during the study. Scores for mean treatment satisfaction and recommending treatment to others were very high (>9) and mean opioid craving score was very low (<1) on a scale ranging from 0 to 10. CONCLUSIONS: Extended-release naltrexone (XR-NTX) was well tolerated in long-term treatment of opioid dependent individuals in Norway already in XR-NTX treatment. On average, the participants chose to continue treatment for almost 1 year beyond the initial 9 to 12 months of treatment. Participants reported high treatment satisfaction and 70% showed no relapse to opioids during the treatment period.

Unrestricted use of polymer-free sirolimus eluting stents in routine clinical practice.

Stent designs with ultrathin struts may further increase the procedural success of challenging lesion subsets. The objective of this study was to assess the safety and efficacy of ultrathin strut, polymer-free sirolimus eluting stent (PF-SES) implantations in a large scale, unselected patient population.Adult patients underwent percutaneous coronary interventions (PCI) with a thin-strut PF-SES. Data from two all-comers observational studies having the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were pooled. The accumulated target lesion revascularization (TLR) rate at 9-12 months was the primary endpoint. All dual antiplatelet therapy strategies according to the applicable guidelines were permissible.In total, 7243 patients were prospectively enrolled for PCI with PF-SES in stable coronary artery disease or acute coronary syndrome (ACS). Major risk factors in the overall cohort were diabetes (37.3%), ST elevation myocardial infarction (18.1%) and non-ST myocardial infarction (24.6%). The follow-up rate was 88.6% in the overall population. The TLR rate in the overall cohort was 2.2% whereas definite/probable stent thrombosis (ST) occurred in 0.7%. In patients with in-stent restenosis lesions, the major adverse cardiac events rate was 6.4% whereas the corresponding rate for isolated left main coronary artery (LMCA) disease was highest with 6.7% followed by patients with culprit lesions in vein bypasses (VB, 7.1%). The mortality rate in patients treated in VB lesions was highest with 5.4%, followed by the isolated LMCA subgroup (3.4%) and ACS (2.6%).PCI with PF-SES in an unselected patient population, is associated with low clinical event and ST rates. Furthermore, PF-SES angioplasty in niche indications demonstrated favorable safety and efficacy outcomes with high procedural success rates.

Polymer-free sirolimus-eluting stent use in Europe and Asia: Ethnic differences in demographics and clinical outcomes.

BACKGROUND: The objective of this study was to assess regional and ethnic differences in an unselected patient population treated with polymer-free sirolimus-eluting stents (PF-SES) in Asia and Europe. METHODS: Two all-comers observational studies based on the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were combined for data analysis to assure sufficient statistical power. The primary endpoint was the accumulated target lesion revascularization (TLR) rate at 9-12 months. RESULTS: Of the total population of 7243 patients, 44.0% (3186) were recruited in the Mediterranean region and 32.0% (2317) in central Europe. The most prominent Asian region was South Korea (17.6%, 1274) followed by Malaysia (5.7%, 413). Major cardiovascular risk factors varied significantly across regions. The overall rates for accumulated TLR and MACE were low with 2.2% (140/6374) and 4.4% (279/6374), respectively. In ACS patients, there were no differences in terms of MACE, TLR, MI and accumulated mortality between the investigated regions. Moreover, dual antiplatelet therapy (DAPT) regimens were substantially longer in Asian countries even in patients with stable coronary artery disease as compared to those in Europe. CONCLUSIONS: PF-SES angioplasty is associated with low clinical event rates in all regions. Further reductions in clinical event rates seem to be associated with longer DAPT regimens.

Availability of Extended-Release Naltrexone May Increase the Number of Opioid-Dependent Individuals in Treatment: Extension of a Randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: Opioid maintenance treatment (OMT) is highly available in Norway, but only 50% of opioid-dependent individuals are enrolled in such programs. This study was aimed at examining if availability of extended-release naltrexone (XR-NTX) could attract individuals who for different reasons were not enrolled in an OMT program. METHODS: In a Norwegian clinical study, n = 117 opioid-dependent adults volunteered to receive XR-NTX in a 9-month period, as an extension of a previous randomized clinical trial. RESULTS: Before study inclusion, 40.2% (n = 47) of the study participants were not enrolled in OMT while the remainder were recruited from OMT. Participants not enrolled in OMT displayed more ongoing severe addiction-related problems such as heroin use (p = 0.002), but displayed a higher retention in treatment in the 9-month extension study (p = 0.048 for log-rank test) than participants enrolled in OMT. CONCLUSION: Availability of XR-NTX attracted opioid-dependent individuals not previously enrolled in OMT. While OMT may be perceived as a burden with regard to daily intake and control measures, one-monthly injections with XR-NTX may be perceived favourable, offering more freedom to the patients, not having addictive properties, and potentially reducing heroin craving. We suggest that an introduction of XR-NTX in Europe may increase the number of opioid-dependent individuals in treatment.

No increased pain among opioid-dependent individuals treated with extended-release naltrexone or buprenorphine-naloxone: A 3-month randomized study and 9-month open-treatment follow-up study.

BACKGROUND AND OBJECTIVES: It is presently unclear whether extended-release naltrexone hydrochloride treatment induces pain or aggravates existing pain among individuals with opioid use disorders. We assessed changes in pain among individuals receiving treatment with either extended-release naltrexone hydrochloride or buprenorphine-naloxone hydrochloride. METHODS: This randomized prospective open-label clinical study included 143 participants (aged 18-60 years) with opioid dependencies, recruited from outpatient addiction clinics at five urban hospitals in Norway. After in-patient detoxification from opioids, patients were randomized to 12-week treatment with either long-acting naltrexone (380 mg intramuscularly injected every four weeks) or buprenorphine-naloxone (flexible 4-16 mg sublingual doses daily). This phase was followed by a 9-month open-treatment study with the participant's choice of either naltrexone or buprenorphine-naloxone. Changes in pain were assessed every 4 weeks using the Norwegian Short-Form of McGill Pain Questionnaire. RESULTS: Throughout the study period, we found no increase in mean sensory pain, affective pain, or present pain intensity on the McGill Pain Questionnaire, in either treatment group, including the subgroups of participants with chronic pain. Participants who switched from buprenorphine-naloxone to extended-release naltrexone treatment after week 12 reported no increase in pain intensity during longer-term treatment. Women experienced significantly more affective pain symptoms than men (p = .01). DISCUSSION AND CONCLUSIONS: Among individuals with opioid use disorder, switching from daily opioid use to long-acting naltrexone did not induce pain, or aggravate mild-to-moderate chronic pain. SCIENTIFIC SIGNIFICANCE: In opioid-dependent individuals, mild-to-moderate chronic pain was not influenced by opioid agonist or antagonist treatment. TRIAL REGISTRATION: Clinicaltrials.gov #NCT01717963, first registered: Oct 28, 2012. Protocol version # 3C, June 12th 2012. (Am J Addict 2018;XX:1-9).

Anxiety, Depression, and Insomnia Among Adults With Opioid Dependence Treated With Extended-Release Naltrexone vs Buprenorphine-Naloxone: A Randomized Clinical Trial and Follow-up Study.

Importance: Extended-release naltrexone (XR-NTX) is a promising alternative treatment of opioid addiction but has never been compared with opioid agonist treatment for effects on symptoms of anxiety, depression, and insomnia. Objective: To investigate whether XR-NTX unmasks or reinforces current comorbid symptoms of anxiety, depression, or insomnia compared with opioid agonist treatment. Design, Setting, and Participants: In this prospective randomized clinical trial, 159 men and women aged 18 to 60 years with opioid dependence were randomized to 12 weeks of treatment with either XR-NTX or combined buprenorphine-naloxone (BP-NLX) followed by a 9-month, open-label treatment study with participant choice of 1 of these 2 drugs. The study was conducted at outpatient addiction clinics in 5 urban hospitals in Norway, with the clinical trial performed from November 1, 2012, to October 23, 2015, and the follow-up study completed on July 23, 2016. All analyses were conducted using an intention-to-treat sample. Interventions: Extended-release naltrexone hydrochloride, 380 mg, administered as an injection every 4 weeks or flexible doses (4-24 mg; target dosage 16 mg/d) of daily oral combined BP-NLX. Main Outcomes and Measures: Every 4 weeks, symptoms of anxiety and depression were assessed using the 25-item Hopkins Symptom Checklist, and symptoms of insomnia were assessed using the Insomnia Severity Index. Results: In total, 159 participants were randomized to treatment with either XR-NTX (n = 80) or BP-NLX (n = 79), and 105 participants (66.0%) completed the trial. The treatment groups showed similar distributions of age (mean [SD], 36.4 [8.8] vs 35.7 [8.5] years), sex (61 [76.3%] women and 54 [68.4%] men), and duration of heroin use (mean [SD], 6.9 [5.8] vs 6.7 [5.2] years). For the clinical trial period, no overall differences were detected between treatment groups for anxiety (effect size [95% CI], -0.14 [-0.47 to 0.19]) or depression (effect size [95% CI], -0.12 [-0.45 to 0.21]) scores, but the insomnia score was significantly lower in the XR-NTX group (effect size [95% CI], -0.32 [-0.61 to -0.02]; P = .008). In the follow-up period, no overall differences could be detected in the effect size [95% CI] of scores for anxiety (0.04 [-0.34 to 0.42]), depression (-0.04 [-0.42 to 0.33]), or insomnia (0.04 [-0.33 to 0.42]) between participants continuing with and participants switching to XR-NTX. No significant sex differences between the 2 treatment groups were detected. Conclusions and Relevance: Comorbid symptoms of anxiety, depression, or insomnia in abstinence-motivated persons with opioid dependence should not prevent switching from treatment with an opioid agonist to treatment with XR-NTX. Trial Registration: ClinicalTrials.gov Identifier: NCT01717963.

The LASSO Program in Oslo: Harm Reduction Using Buprenorphine-Naloxone (Suboxone®) in a Low Threshold Setting.

BACKGROUND: This is a 6-year retrospective quality control study of the LASSO Program (Low Threshold Substitution Treatment in Oslo), using exclusively Suboxone® (buprenorphine-naloxone [BPNX]) in out-patient settings. Adequate abstinence prior to induction is necessary to avoid acute onset opioid withdrawal symptoms; thus, its use in low threshold settings is far less common than methadone. OBJECTIVES: The aim of this study was to determine if BPNX is a safe and feasible medication to use in a low threshold setting. METHODS: The analysis is based on daily supervised BPNX medication. The standardized induction regime started with 4-mg BPNX increasing by 4 mg daily until 16 mg, with individual adjustments based on clinical status. Treatment effect was evaluated by the number of medication induction attempts, treatment length and lag time between initial contact and medication start. Statistical computations were performed with SPSS®. RESULTS: There were 331 out of 394 registered patient inquires that started on BPNX. Two hundred fifty-three patients (76.4%) completed induction on first attempt with 95% Wilson score CIs of (0.716-0.807). The accumulated percentage increased to 85.2% during successive inductions. No significant association was found between lag time and (i) the number of days on medication during the first induction; or (ii) total treatment length. Patients had a median lag time of 5 days, remained in treatment a median of 52.0 days with an average of 3.9 inductions. There were no cases of severe precipitated withdrawal and only 2 cases of adverse reactions among the 1,293 inductions and 25,544 administered dosages. CONCLUSION: This study shows that BPNX is highly effective in treating marginalized heroin addicts in low threshold settings. Even during their first attempt, 76.4% completed induction. There were no cases of severe precipitated withdrawal. Prolonged lag time affected neither the length of first treatment nor the total treatment length. Individualized induction readiness approach and motivation were central to the above results.

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

BACKGROUND AND AIM: This 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 3 months. At the conclusion of the trial, participants were offered their choice of study medication for an additional 9 months. 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. DESIGN: In 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. SETTING: Five urban, out-patient addiction clinics in Norway. PARTICIPANTS: Opioid-dependent adults continuing (n = 54) or inducted on (n = 63) XR-NTX. INTERVENTION: XR-NTX administrated as intramuscular injections (380 mg) every fourth week. MEASUREMENTS: Data on retention, use of heroin and other illicit substances, opioid craving, treatment satisfaction, addiction-related problems and adverse events were reported every fourth week. FINDINGS: Nine-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. CONCLUSIONS: Opioid-dependent individuals who elect to switch from buprenorphine-naltrexone treatment after 3 months to extended-release naltrexone treatment for 9 months 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.

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; P = .04), with mean (SD) time of 69.3 (25.9) and 63.7 (29.9) days, correspondingly (P = .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; P < .001) and use of heroin (mean difference, -3.2 with 95% CI, -4.9 to -1.5; P < .001) and other illicit opioids (mean difference, -2.7 with 95% CI, -4.6 to -0.9; P < .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.

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.

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

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.

Addressing misuse and diversion of opioid substitution medication: guidance based on systematic evidence review and real-world experience.

BACKGROUND: Opioid dependence treatment, comprising opioid substitution treatment (OST) and psychosocial intervention, is accepted to improve outcomes in opioid addiction for both the individual and public health. OST medication such as methadone or buprenorphine may be misused or diverted. This results in failure to recover from addiction, increased crime and the spread of blood-borne viruses. Worldwide, attempts to address misuse and diversion have been proposed and implemented with varying impact. METHODS: A structured, expert-led process recommended the most impact. As an initial step, a broad range of strategies were defined, and a systematic review of published literature identified 37 highly relevant sources of evidence. Experts reviewed this evidence and ranked the list of strategies for effectiveness and ease of implementation, based on their clinical experience. RESULTS/CONCLUSIONS: Three groups of strategies to address misuse or diversion are defined, depending on impact (effectiveness and ease of implementation). Preferred strategies include the promotion of access to treatment and the use of product formulations less likely to be misused. However, additional data and innovative approaches to address this complex problem are needed.

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.

PURPOSE: Effects of hemodialysis on pharmacokinetic properties and QTc were studied in 4 patients taking daily methadone dose of 100 mg (range, 60-120 mg). METHODS: Methadone in serum, dialysate, and urine were measured by LC-MS/MS. QTc was calculated with Bazett's formula. FINDINGS: The 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. IMPLICATIONS: Methadone dose adjustment is not needed because of hemodialysis.

Histopathological grading of laryngectomy specimens.

A material comprising 118 laryngectomy specimens, prepared by whole organ serial sectioning, was analyzed to determine the prognostic significance of histopathological tumor grading. No statistically significant association could be demonstrated between grading and a number of clinical and histopathological variables, including pathological staging, lymph node metastases or recurrence rate. The study supports the contention that the prognostic value of histopathological grading of laryngeal squamous cell carcinoma remains uncertain and unproven. Serial sections of the whole organ, processed by routine laboratory techniques, remain important for studying tumor extension but do not contribute to establishing histopathological grading as a significant prognostic parameter.

Laryngectomy whole organ serial sections--histological parameters correlated with recurrence rate.

Whole organ sections of laryngectomy specimens, collected over a 10-year period (1976-1985) from 118 patients with carcinoma of the larynx, were reviewed. The aim of the investigation was to compare the histopathological data with the rate of recurrence to evaluate which factors were most significant in predicting recurrence. Epitome chi2 analysis of frequency tables using corrected Yates' values revealed significant association between the recurrence rate and the depth of tumor infiltration, the presence of tumor cells at the surgical margins and the pathological TNM (tumor, nodes, metastases) stage. Multiple regression analysis identified perineural and thyroid gland tumor infiltration, anatomical location of the primary tumor and depth of tumor infiltration as independent predictors of recurrence. The greater the number of poor prognostic factors, the higher the risk for recurrence. Exact histopathological investigations integrated with clinical examinations and close patient follow-up are important and should be supported by statistical analysis to give a prognostic basis for the selection and evaluation of the treatment.

The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.

BACKGROUND: The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival. METHODS: Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index. RESULTS: Three gene-expression subgroups--germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma--were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators. CONCLUSIONS: DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for diffuse large-B-cell lymphoma.