Effects of Opioid Withdrawal on Psychobiology in People Living with HIV.

OBJECTIVE: Many persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood. METHOD AND PARTICIPANTS: Study participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation. Participants were examined at admission, at the anticipated peak of withdrawal 3 to 7 days after the last day of a clonidine-based withdrawal process lasting 7 to 14 days, and 3 to 4 weeks after completing withdrawal. At these times, participants received medical exams and were evaluated for symptoms of withdrawal, as well as cognition and mood. Viral load, plasma cortisol, DHEA sulfate ester (DHEA-S), interleukin-6 (IL-6), and soluble CD14 (sCD14) were determined. Multivariable models examined the relationships between markers of HPA activation and the other parameters over time. RESULTS: HPA activation as indexed by cortisol/DHEA-S ratio increased during withdrawal, as did markers of immune activation, IL-6 and sCD14. There were no significant associations between viral load and indicators of HPA activation. In longitudinal analyses, higher cortisol/DHEA sulfate was related to worse cognition overall, and more mood disturbance. Increase in IL-6 was associated with worse cognitive performance on a learning task. There were no significant associations with sCD14. CONCLUSIONS: Worsening of cognition and measures of mood disturbance during withdrawal were associated with activation of the HPA axis and some measures of inflammation. Whether repeated episodes of opioid withdrawal have a cumulative impact on long-term HIV outcomes and neurocognition is a topic for further investigation.

Determinants of health-related quality of life among individuals with opioid use disorder, recently released from incarceration.

BACKGROUND\OBJECTIVES: Concomitant with low rates of pharmacotherapy for incarcerated individuals with OUD, there is a high rate of opioid overdose following re-entry into the community. Our research objective was to develop a better understanding of the factors that influence health-related quality-of-life (HRQoL) among this population during the high-risk transition period from incarceration to community. Few studies have assessed health-related quality-of-life (HRQoL) among individuals with OUD who are involved with the criminal-legal system, let alone over the period directly surrounding release from incarceration. METHODS: Secondary longitudinal analysis of data from a clinical trial where participants were randomized 1:1 to pre-release extended-release naltrexone (XR-NTX) + referral to community XR-NTX, vs. referral only. We conducted individual, multivariable regressions of EQ-5D domains (mobility, pain/discomfort, anxiety/depression; usual activities and self-care were excluded due to insufficient variation in scores), and the overall preference/utility score. HRQoL data were subset to timepoints immediately before release (baseline) and 12 weeks post-release; treatment groups were collapsed across condition. Multiple imputation by chained equations was conducted to handle missing 3-month data in the dependent variables and covariates, ad hoc. RESULTS: Greater severity in the psychiatric composite score was associated with substantially lower HRQoL, across all measures, following release from incarceration. Greater severity in the medical composite score was associated with lower pain/discomfort-related HRQoL. CONCLUSIONS: Our findings highlight the importance of ensuring individuals with OUD are linked not only to MOUD, but also treatment for their comorbid conditions upon release from incarceration.

Cost-effectiveness of extended-release injectable naltrexone among incarcerated persons with opioid use disorder before release from prison versus after release.

INTRODUCTION: Opioid use disorder (OUD) is highly prevalent among incarcerated populations, and the risk of fatal overdose following release from prison is substantial. Despite efficacy, few correctional facilities provide evidence-based addiction treatment. Extended-release injectable naltrexone (XR-NTX) administered prior to release from incarceration may improve health and economic outcomes. METHODS: We conducted an economic evaluation alongside a randomized controlled trial testing the effectiveness of XR-NTX before release from prison (n = 38) vs. XR-NTX referral after release (n = 48) of incarcerated participants with OUD, both groups continuing treatment at a community addiction treatment center. The incremental cost-effectiveness ratio (ICER) assessed the cost-effectiveness of XR-NTX before release compared to referral after release for three stakeholder perspectives at 12- and 24-week periods: state policymaker, health care sector, and societal. Effectiveness measures included quality-adjusted life-years (QALYs) and abstinent years from opioids. In addition, we categorized resources as OUD-related and non-OUD-related medical care, state transfer payments, and other societal costs (productivity, criminal justice resources, etc.). RESULTS: Results showed an association between XR-NTX and greater OUD-related costs and total costs from the state policymaker perspective. QALYs gained were positive but statistically insignificant between arms; however, results showed XR-NTX had an estimated 15.5 more days of opioid abstinence over 24 weeks and statistically significant at a 95 % confidence level based on the distribution of bootstrapped samples. We found that estimated ICERs to be > $500,000 per QALY for all stakeholder perspectives. For the abstinent-year effectiveness measure, we found XR-NTX before release to be cost-effective at a 95 % confidence level for willingness-to-pay values >$49,000 per abstinent-year, across all perspectives. CONCLUSIONS: XR-NTX administered to persons who are incarcerated with OUD before release may provide value for stakeholders and bridge a well-known treatment gap for this vulnerable population. Lower than expected participant engagement and missing data limit our results, and study outcomes may be sensitive to methods that address missing data if replicated.

Identifying Clinically Relevant Drug-Drug Interactions With Methadone and Buprenorphine: A Translational Approach to Signal Detection.

Methadone and buprenorphine have pharmacologic properties that are concerning for a high risk of drug-drug interactions (DDIs). We performed high-throughput screening for clinically relevant DDIs with methadone or buprenorphine by combining pharmacoepidemiologic and pharmacokinetic approaches. We conducted pharmacoepidemiologic screening via a series of self-controlled case series studies (SCCS) in Optum claims data from 2000 to 2019. We included persons 18 years or older who experienced an outcome of interest during target drug treatment. Exposures were all overlapping medications (i.e., the candidate precipitants) during target drug treatment. Outcomes were opioid overdose, non-overdose adverse effects, and cardiac arrest. We used conditional Poisson regression to calculate rate ratios, accounting for multiple comparisons with semi-Bayes shrinkage. We explored the impact of key study design choices in analyses that varied the exposure definitions of the target drugs and the candidate precipitant drugs. Pharmacokinetic screening was conducted by incorporating published data on CYP enzyme metabolism into an equation-based static model. In SCCS analysis, 1,432 events were included from 248,069 new users of methadone or buprenorphine. In the primary analysis, statistically significant DDIs included gabapentinoids with either methadone or buprenorphine; baclofen with methadone; and benzodiazepines with methadone. In sensitivity analysis, additional statistically significant DDIs included methocarbamol, quetiapine, or simvastatin with methadone. Pharmacokinetic screening identified two moderate-to-strong potential DDIs (clonidine and fluconazole with buprenorphine). The combination of clonidine and buprenorphine was also associated with a significantly increased risk of opioid overdose in pharmacoepidemiologic screening. These DDI signals may be the most important targets for future confirmation studies.

Burden of Chronic Conditions Among Persons with HIV/AIDS and Psychiatric Comorbidity.

BACKGROUND: Improved survivorship among persons living with HIV translates into a higher risk of medical comorbidities. OBJECTIVES: We assessed the association between the intersection of physical (HIV) and mental health (psychiatric) conditions and intermediate outcomes. METHODS: This was a cross-sectional study of the Medical Expenditure Panel Survey (MEPS)- Household Component between 1996 and 2016. We created four groups for persons aged ≥18: (1) HIV + psychiatric comorbidity, (2) HIV, (3) psychiatric comorbidity, and (4) no-HIV/no-psychiatric comorbidity. We compared the burden of medical comorbidities (metabolic disorders, cardiovascular disease, cancers, infectious diseases, pain, and substance use) among groups using chisquare tests. We used logistic regression to determine the association between group status and medical comorbidity. RESULTS: Of 218,133,630 (weighted) persons aged ≥18, 0.18% were HIV-positive. Forty-three percent of the HIV group and 19% of the no-HIV group had psychiatric comorbidities. Half of the HIV+ psychiatric disorder group had at least one medical comorbidity. Compared to the no- HIV/no-psychiatric comorbidity group, the HIV + psychiatric comorbidity group had the highest odds of medical comorbidity (OR= 3.69, 95% CI = 2.99, 4.52). CONCLUSION: Persons presenting with HIV + psychiatric comorbidity had higher odds of medical comorbidities of pain, cancer, cardiovascular disease, substance use, metabolic disorders and infectious diseases, beyond that experienced by persons with HIV infection or psychiatric disorders, independently. Future research will focus on the mediating effects of social determinants and biological factors on outcomes such as the quality of life, cost and mortality. This will facilitate a shift away from the single-disease framework and compress morbidity of the aging cohort of HIV-infected persons.

Extended release injectable naltrexone before vs. after release: A randomized trial of opioid addicted persons who are in prison.

BACKGROUND: Usual treatment for persons with opioid use disorders who are in prison is detoxification with referral to treatment after release but failure to engage in treatment and relapse is common. Starting medication treatment before release might improve outcomes. OBJECTIVES: Determine if administering extended-release injectable naltrexone (XR-NTX) before release (BR) from prison results in less relapse within the first three months after release than when offered by referral after release (AR). METHODS: The study randomized 1:1 persons who had an OUD, expressed interest in XR-NTX, and met study admission criteria to receive XR-NTX BR or at a local program AR, with continued medication and counseling available at that program. RESULTS: Four-hundred and two persons expressed interest in the study, 222 consented, and the study randomized 146. Uncertainty about release dates resulted in a time lag between randomization and final disposition during which 60 of the randomized patients were sentenced to other facilities, withdrew consent, or became otherwise unavailable for study treatment, leaving 86 for outcome analyses (38, BR; 48 AR). Missed follow-up appointments on the remaining 86 led to development of a phone-based questionnaire to determine presence/absence of relapse. Using it to supplement other data, we were able to confirm relapse or nonrelapse for 63 of the 86 (73%). All BR and a third of the AR patients received their first XR-NTX dose, however dropout was high and nonrelapse by month three was not significantly different between BR (39.5%) and AR (25%) (Chisq (2) = 3.23, p = 0.20). CONCLUSIONS: BR patients were much more likely to receive medication and its extended relapse and overdose protection effects in the first weeks after release. Dropout was high and the study detected no significant difference in relapse by month 3; however, the less-than-planned number of patients and missing data make this finding inconclusive.

Health and economic outcomes of treatment with extended-release naltrexone among pre-release prisoners with opioid use disorder (HOPPER): protocol for an evaluation of two randomized effectiveness trials.

BACKGROUND: Persons with an opioid use disorder (OUD) who were incarcerated face many challenges to remaining abstinent; concomitantly, opioid-overdose is the leading cause of death among this population, with the initial weeks following release proving especially fatal. Extended-release naltrexone (XR-NTX) is the most widely-accepted, evidence-based OUD pharmacotherapy in criminal justice settings, and ensures approximately 30 days of protection from opioid overdose. The high cost of XR-NTX serves as a barrier to uptake by many prison/jail systems; however, the cost of the medication should not be viewed in isolation. Prison/jail healthcare budgets are ultimately determined by policymakers, and the benefits/cost-offsets associated with effective OUD treatment will directly and indirectly affect their overall budgets, and society as a whole. METHODS: This protocol describes a study funded by the National Institute of Drug Abuse (NIDA) to: evaluate changes in healthcare utilization, health-related quality-of-life, and other resources associated with different strategies of XR-NTX delivery to persons with OUD being released from incarceration; and estimate the relative "value" of each strategy. Data from two ongoing, publicly-funded, randomized-controlled trials will be used to evaluate these questions. In Study A, (XR-NTX Before vs. After Reentry), participants are randomized to receive their first XR-NTX dose before release, or at a nearby program post-release. In Study B, (enhanced XR-NTX vs. XR-NTX), both arms receive XR-NTX prior to release; the enhanced arm receives mobile medical (place of residence) XR-NTX treatment post-release, and the XR-NTX arm receives referral to a community treatment program post-release. The economic data collection instruments required to evaluate outcomes of interest were incorporated into both studies from baseline. Moreover, because the same instruments are being used in both trials on comparable populations, we have the opportunity to not only assess differences in outcomes between study arms within each trial, but also to merge the data sets and test for differences across trials. DISCUSSION: Initiating XR-NTX for OUD prior to release from incarceration may improve patient health and well-being, while also producing downstream cost-offsets. This study offers the unique opportunity to assess the effectiveness and cost-effectiveness of multiple strategies, according to different stakeholder perspectives.

Slow-release naltrexone implant versus oral naltrexone for improving treatment outcomes in people with HIV who are addicted to opioids: a double-blind, placebo-controlled, randomised trial.

BACKGROUND: Untreated opioid addiction in people with HIV is associated with poor HIV treatment outcomes. Slow-release, long-acting, implantable naltrexone might improve these outcomes. Here, we present results of a study aimed to test this hypothesis. METHODS: We did a 48 week double-blind, double-dummy, placebo-controlled, phase 3, randomised trial with men and women addicted to opioids who were starting antiretroviral therapy (ART) for HIV and whose viral loads were higher than 1000 copies per mL. Participants were seeking treatment at two HIV and two narcology programme centres in Saint Petersburg, Russia, and the surrounding Leningrad region. The Pavlov statistical department created a table with stratification on gender distribution, viral load, and CD4 cell count. We stratified participants according to gender, viral load, and CD4 cells per µL, and randomly assigned (1:1) them to addiction treatment with a naltrexone implant and oral naltrexone placebo (implant group) or oral naltrexone and placebo implant (oral group). The primary outcome was plasma viral load of less than 400 copies per mL at 24 weeks and 48 weeks. We included all randomly assigned participants in outcome analyses (intention to treat). Treatment staff and patients were masked to group assignment. The study is complete and registered at ClinicalTrials.gov, NCT01101815. FINDINGS: Between July 14, 2011, and April 14, 2014, 238 potential participants were recruited and screened, 35 were excluded for not meeting inclusion criteria, three declined to participate, and 200 were randomly assigned to treatment (100 to each group). At week 24, 38 (38) participants in the implant group and 35 (35%) in the oral group had viral loads less than 400 copies per mL (risk ratio 1·1, 95% CI 0·76-1·56; p=0·77). At week 48, 66 participants in the implant group and 50 in the oral group had viral loads less than 400 copies per mL (risk ratio 1·32, 95% CI 1·04-1·68; p=0·045). There were seven serious adverse events: three deaths in the implant group (one due to heart disease, one trauma, and one AIDS), and four in the oral group (two overdoses, one pancreatic cancer, and one AIDS). The overdose deaths occurred 9-10 months after the last naltrexone dose. INTERPRETATION: The longer the blockade of opioid effects, the more protection an individual gets from missed ART doses and impulsive behaviours that lead to relapse and poor, even fatal, outcomes. Commercial development of implants could result in a meaningful addition to addiction treatment options. FUNDING: National Institutes of Health, National Institute on Drug Abuse, Penn Centre for AIDS Research, and Penn Mental Health AIDS Research Centre.

Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies.

BACKGROUND AND OBJECTIVES: Opioid use disorder (OUD) is a chronic condition with potentially severe health and social consequences. Many who develop moderate to severe OUD will repeatedly seek treatment or interact with medical care via emergency department visits or hospitalizations. Thus, there is an urgent need to develop feasible and effective approaches to help persons with OUD achieve and maintain abstinence from opioids. Treatment that includes one of the three FDA-approved medications is an evidence-based strategy to manage OUD. The purpose of this review is to address practices for managing persons with moderate to severe OUD with a focus on opioid withdrawal and naltrexone-based relapse-prevention treatment. METHODS: Literature available on PubMed was used to review the evolution of treatment strategies from the 1960s onward to manage opioid withdrawal and initiate treatment with naltrexone. RESULTS: Emerging practices for extended-release naltrexone induction include the use of agonist tapers and adjuvant medications. Clinical challenges frequently encountered when initiating this therapy include managing withdrawal and ongoing opioid use during treatment. Clinical factors may inform decisions regarding patient selection and length of naltrexone treatment, such as recent opioid use and patient preferences. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Treatment strategies to manage opioid withdrawal have evolved, but many patients with OUD do not receive medication for the prevention of relapse. Clinical strategies for induction onto extended-release naltrexone are now available and can be safely and effectively implemented in specialty and select primary care settings. (© 2018 The Authors. The American Journal on Addictions Published by Wiley Periodicals, Inc. on behalf of The American Academy of Addiction Psychiatry (AAAP);27:177-187).

Extended-Release Injectable Naltrexone (XR-NTX) With Intensive Psychosocial Therapy for Amphetamine-Dependent Persons Seeking Treatment: A Placebo-Controlled Trial.

OBJECTIVE: Explore the efficacy of extended-release injectable naltrexone (XR-NTX) for preventing relapse to amphetamine use. METHOD: Clinical trial of 100 amphetamine-dependent, treatment-seeking patients who were randomized to 6 monthly 380 mg doses of XR-NTX or matching placebo before entering intensive outpatient after varying lengths of inpatient treatment in Reykjavik, Iceland. Weekly urine drug tests, retention, and standardized instruments assessed efficacy. RESULTS: Of 169 approached, 100 were randomized. Although amphetamine dependence was the main reason for seeking treatment, three-quarters or more of participants had 1 or more other substance dependencies. Of 51 randomized to XR-NTX, 20 received 4 or more injections; of 49 assigned to placebo, 26 received 4 or more injections. Of the planned 2400 weekly urine drug tests, 1247 were collected (52%); 4% of these were positive for amphetamine, 8% for benzodiazepine, 7% for marijuana, 1% for cocaine, and 1% for opioid. XR-NTX had no effect on amphetamine-positive tests, retention, or other outcomes. Those providing half or more of their tests attended more weeks of treatment than those providing less than half of their tests (m = 10.76 vs 3.31; t (92) = 5.91, P < 0.0001), and 92 participants provided at least 1 test. CONCLUSIONS: Adding XR-NTX to the usual combination of inpatient and intensive outpatient treatment did not reduce amphetamine use. The low prevalence of substance use among collected urine samples, and the association between collected samples and weeks in treatment, was consistent with other studies showing that staying in treatment is associated with better outcomes.

Causes of death and expected years of life lost among treated opioid-dependent individuals in the United States and Taiwan.

AIMS: This study compared the cause-specific standardized mortality ratios (SMRs) and expected years of life lost (EYLL) among opioid-dependent individuals in the United States and Taiwan. METHODS: Survival data came from two cohorts followed until 2014: The U.S. data were based on a randomized trial of 1267 opioid-dependent participants enrolled between 2006 and 2009; the Taiwan data were from a study of 983 individuals that began in 2006, when opioid agonist treatment (OAT) was implemented in Taiwan. SMRs were calculated for each national cohort and compared. Kaplan-Meier estimation was performed on the survival data, then lifespans were extrapolated to 70 years (840 months) to estimate life expectancy using a semi-parametric method. EYLLs for both cohorts were estimated by subtracting their life expectancies from the age- and gender-matched referents within the general population of their respective country. RESULTS: Compared with age- and gender-matched referents, the SMRs were 3.2 for the U.S. sample and 7.8 for the Taiwan sample; the EYLLs were 7.7 and 16.4 years, respectively. Half of decedents died of unnatural causes in both cohorts; overdose deaths predominated in the U.S. and suicide in Taiwan. CONCLUSIONS: Our study identified differences by country in EYLL and causes of deaths. These findings suggest that intervention strategies to reduce mortality risk by overdose (particularly in the U.S.) and suicide (particularly in Taiwan) are urgently needed in these countries.

Advances in the treatment of opioid use disorders.

The development of medications for treating persons with opioid use disorders has expanded the number of evidence-based treatment options, particularly for persons with the most severe disorders. It has also improved outcomes compared to psychosocial treatment alone and expanded treatment availability by increasing the number of physicians involved in treatment and the settings where patients can be treated. The medications include methadone, buprenorphine, buprenorphine/naloxone, and extended-release injectable naltrexone. Studies have shown that they are most effective when used over an extended, but as-yet-unspecified, period of time and with counseling and other services, particularly for the many with psychosocial problems. Though controversial in some cultures, well-designed studies in Switzerland, the Netherlands, Germany, and Canada have demonstrated the efficacy of supervised heroin injecting for persons who responded poorly to other treatments, and this treatment option has been approved by Switzerland and a few other E.U. countries. The degree to which medication-assisted therapies are available is dependent on many variables, including national and local regulations, preferences of individual providers and their geographical location, treatment costs, and insurance policies. Greater availability of medication-assisted therapies has become a major focus in the U.S. and Canada, where there has been a marked increase in deaths associated with heroin and prescription opioid use. This paper provides a brief summary of these developments.

Distinctive Trajectories of Opioid Use Over an Extended Follow-up of Patients in a Multisite Trial on Buprenorphine + Naloxone and Methadone.

OBJECTIVES: Uncovering heterogeneities in longitudinal patterns (trajectories) of opioid use among individuals with opioid use disorder can increase our understanding of disease progression and treatment responses to improve care. The present study aims to identify distinctive opioid use trajectories and factors associated with these patterns among participants randomized to treatment with methadone (MET) or buprenorphine + naloxone (BUP). METHODS: Growth mixture modeling was applied to identify distinctive opioid use trajectories among 795 opioid users after their enrollment in a multisite trial during 2006 to 2009, with follow-up interviews conducted during 2011 to 2014. RESULTS: Four distinctive trajectories were identified based on opioid use over the follow-up period: low use (42.0%), high use (22.3%), increasing use (17.1%), and decreasing use (18.6%). Greater odds of being in the high use group (relative to low use) was associated with Hispanics (relative to African American, odds ratio [OR] 3.21), injection drug use (OR 2.12), higher mental health functioning at baseline (OR 1.23), location on the West Coast (vs East Coast, OR 2.15), and randomization to BUP (relative to MET, OR 1.53). High use and increasing use groups had greater severity in problems related to drug, employment, legal, and social/family relationships, and worsened mental health functioning at follow-up. Participation in treatment significantly accounted for both within and between-group differences in opioid use. CONCLUSIONS: Continued treatment is necessary to reduce risk for opioid use and related adverse consequences, particularly among individuals (eg, injecting drug) at risk for consistently high level of opioid use.

Anhedonia, depression, anxiety, and craving in opiate dependent patients stabilized on oral naltrexone or an extended release naltrexone implant.

BACKGROUND: Naltrexone is a µ-opioid receptor antagonist that blocks opioid effects. Craving, depression, anxiety, and anhedonia are common among opioid dependent individuals and concerns have been raised that naltrexone increases them due to blocking endogenous opioids. Here, we present data that address these concerns. OBJECTIVE: Assess the relationship between affective responses and naltrexone treatment. METHODS: Opioid dependent patients (N = 306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Test, and the Ferguson and Chapman Anhedonia Scales. Between-group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the Tukey test for those who remained and treatment and did not relapse, and between the last measure before dropout with the same measure for those remaining in treatment. RESULTS: Depression, anxiety, and anhedonia were elevated at baseline but reduced to normal within the first 1-2 months for patients who remained in treatment and did not relapse. Other than a slight increase in two anxiety measures at week two, there were no significant between-group differences prior to treatment dropout. CONCLUSION: These data do not support concerns that naltrexone treatment of opioid dependence increases craving, depression, anxiety or anhedonia.