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).

Proactive coping and spirituality among patients who left or remained in antiretroviral treatment in St Petersburg, Russian Federation.

Positive Psychology, the study of "positive" factors or strengths and evidence-based interventions to increase them, is a rapidly developing field that is beginning to be applied to HIV care. Proactive coping and spirituality are two positive characteristics that have been examined in multiple chronic serious health conditions. In the present study, lost-to-care (LTCs; did not attend treatment for ≥12 months; n = 120) and engaged-in-care HIV clinic patients (EICs; attended treatment for ≥12 months and adherent with antiretrovirals; n = 120) in Leningrad Oblast, Russian Federation were compared on the Proactive Coping Inventory and View of God Scale. EICs had higher scores in proactive coping [t(229) = 3.69; p = .001] and instrumental [t(232) = 2.17; p = .03] and emotional [t(233) = 2.33; p = .02] support, indicating that they engage in autonomous goal setting and self-regulate their thoughts and behaviors; obtain advice and support from their social network; and cope with emotional distress by turning to others. LTCs had higher scores in avoidance coping [t(236) = -2.31; p = .02]. More EICs were spiritual, religious, or both [ χ(2)(1, N = 239) = 7.49, p = .006]. EICs were more likely to believe in God/Higher Power [χ(2)(1, N = 239 = 8.89, p = .002] and an afterlife [ χ(2)(1, N = 236) = 5.11, p = .024]; have a relationship with God/Higher Power [ χ(2)(1, N = 237) = 12.76, p = .000]; and call on God/Higher Power for help, healing, or protection [ χ(2)(1, N = 239) = 9.61]. EICs had more positive [t(238) = 2.78; p = .006] and less negative [t(236) = -2.38; p = .002] views of God. Similar proportions, but slightly more EICs than LTCs were members of a faith community; members of a12-step group; or attended religious or spiritual services, meetings, or activities. More EICs than LTCs engaged in private spiritual or religious activities, such as prayer or meditation [ χ(2)(1, N = 239) = 9.226, p = .002].

Depression, substance use, viral load, and CD4+ count among patients who continued or left antiretroviral therapy for HIV in St. Petersburg, Russian Federation.

Antiretroviral therapy (ART) became more widely available in the Russian Federation in 2006 when the Global Fund made a contribution to purchase ART with a mandate to increase numbers of patients receiving it. Funds were distributed to AIDS Centers and selected hospitals, and numbers quickly increased. Though ART is highly effective for adherent patients, dropout has been a problem; thus understanding characteristics of patients who remain on ART vs. those who leave treatment may provide information to facilitate engagement. We retrospectively assessed depression, hopelessness, substance use, viral load, and CD4+ counts of 120 patients who dropped out of ART for ≥12 months (Lost-to-Care, LTCs) and 120 who continued for ≥12 months (Engaged-in-Care, EICs). As expected, LTCs had higher viral loads and depression, lower CD4+ counts, more alcohol, heroin, and injection drug use in the past 30 days. A binary logistic regression with Center for Epidemiologic Studies Depression score, Beck Hopelessness score, whether drugs/alcohol had ever prevented them from taking ART, and past 30 days' alcohol use [χ(2)(4) = 64.27, p = .0.000] correctly classified 74.5% of participants as LTC or EIC, suggesting that integrated treatment for substance use, psychiatric, and HIV could reduce dropout and improve outcomes.

Antagonist models for treating persons with substance use disorders.

This paper provides an overview on the status of antagonist models for treating patients with substance use disorders. It begins with an overview describing the ambivalence about stopping or not stopping substance use and how antagonist approaches, combined with psychosocial treatment, are aimed to address it. It then goes on to review data on disulfiram and acamprosate treatment of alcohol dependence and naltrexone treatment of opioid and alcohol dependence. The superior results achieved by extended release formulations are emphasized. The mixed findings on naltrexone treatment for amphetamine dependence are presented and the chapter ends with a brief review of vaccine development for treatment of substance use disorders. Overall conclusions are that the strongest treatment effects are with extended release naltrexone with opioid dependence. Disulfiram treatment of alcohol dependence also has strong effects but is not widely used due to low levels of patient acceptance and concerns about its potential for serious adverse events. Less robust but clinically meaningful effects are seen with naltrexone or acamprosate treatment of alcohol dependence. Vaccines are a very interesting and promising new development but many challenges and hurdles must be overcome before they are ready for clinical use.

Progress in addiction treatment: from one-size-fits-all to medications and treatment matching.

This paper briefly reviews the development of treatment for substance use disorders over the last 100 years from the perspective of the author, who has participated in treatment outcome studies since the mid-1970s. It includes some personal events that contributed to the author's involvement in addiction treatment and research, and describes the gradual evolution of an approach that began with a focus on detoxification and psychosocial treatment to one that involves blending psychosocial treatments with use of Food and Drug Administration (FDA)-approved medications and adding treatments for psychiatric and medical disorders when necessary based on patient assessments. It ends with comments on the gap between what is known and the degree to which existing knowledge is applied, and how the Affordable Care Act holds promise for bridging that gap.

Factors contributing to dropping out from and returning to HIV treatment in an inner city primary care HIV clinic in the United States.

Although advances in pharmacotherapy have enabled people living with HIV/AIDS to live longer, fuller lives, some leave medical care, resulting in sub-optimal treatment and increased health risk to themselves and others. Forty-one patients who dropped out of an urban, publically funded primary care HIV clinic were contacted and encouraged by outreach staff to return. Participants were interviewed within two weeks of returning, and themes associated with dropping out and returning were elicited and content analyzed. Dropping out was associated with drug/alcohol use, unstable housing/homelessness, psychiatric disorders, incarceration, problems with HIV medications, inability to accept the diagnosis, relocation, stigma, problems with the clinic, and forgetfulness. Returning was associated with health concerns, substance abuse treatment/recovery, stable housing, incarceration/release, positive feelings about the clinic, spirituality, and assistance from family/relocation. Because a large number of patients reported substance abuse, depression, and past suicide attempts. Clinic staff should assess substance use, depression, and suicidal ideation at each primary care visit and encourage patients to obtain substance abuse treatment and mental health care. Future interventions could include providing SBIRT and/or onsite mental health and substance abuse treatment, all of which may boost retention.

Compensation effects on clinical trial data collection in opioid-dependent young adults.

BACKGROUND: Attrition in studies of substance use disorder treatment is problematic, potentially introducing bias into data analysis. OBJECTIVES: This study aimed to determine the effect of participant compensation amounts on rates of missing data and observed rates of drug use. METHODS: We performed a secondary analysis of a clinical trial of buprenorphine/naloxone among 152 treatment-seeking opioid-dependent subjects aged 15-21 during participation in a randomized trial. Subjects were randomized to a 2-week detoxification with buprenorphine/naloxone (DETOX; N = 78) or 12 weeks buprenorphine/naloxone (BUP; N = 74). Participants were compensated $5 for weekly urine drug screens and self-reported drug use information and $75 for more extensive assessments at weeks 4, 8, and 12. RESULTS: Though BUP assignment decreased the likelihood of missing data, there were significantly less missing data at 4, 8, and 12 weeks than other weeks, and the effect of compensation on the probability of urine screens being positive was more pronounced in DETOX subjects. CONCLUSION: These findings suggest that variations in the amount of compensation for completing assessments can differentially affect outcome measurements, depending on treatment group assignment. SCIENTIFIC SIGNIFICANCE: Adequate financial compensation may minimize bias when treatment condition is associated with differential dropout and may be a cost-effective way to reduce attrition. Moreover, active users may be more likely than non-active users to drop out if compensation is inadequate, especially in control groups or in groups who are not receiving active treatment.

The science and practice of medication-assisted treatments for opioid dependence.

This paper briefly reviews the evolution of opioid addiction treatment from humanitarian to scientific and evidence-based, the evidence bases supporting major medication-assisted treatments and adjunctive psychosocial techniques, as well as challenges faced by clinicians and treatment providers seeking to provide those treatments. Attitudes, politics, policy, and financial issues are discussed.

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.

NIDA's Clinical Trials Network: an opportunity for HIV research in community substance abuse treatment programs.

BACKGROUND/OBJECTIVES: HIV continues to be a significant problem among substance users and their sexual partners in the United States. The National Drug Abuse Treatment Clinical Trials Network (CTN) offers a national platform for effectiveness trials of HIV interventions in community substance abuse treatment programs. This article presents the HIV activities of the CTN during its first 10 years. RESULTS: While emphasizing CTN HIV protocols, this article reviews the (1) HIV context for this work; (2) the collaborative process among providers, researchers, and National Institute on Drug Abuse CTN staff, on which CTN HIV work was based; (3) results of CTN HIV protocols and HIV secondary analyses in CTN non-HIV protocols; and (4) implications for future HIV intervention effectiveness research in community substance abuse treatment programs. CONCLUSION/SIGNIFICANCE: While the feasibility of engaging frontline providers in this research is highlighted, the limitations of small to medium effect sizes and weak adoption and sustainability in everyday practice are also discussed.

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.

Penn/VA center for studies of addiction.

The Penn/VA Center was founded in 1971 because of great concern over the number of Vietnam veterans returning home addicted to heroin. At that time little was known about the science of addiction, so our program from the very beginning was designed to gather data about the nature of addiction and measure the effects of available treatments. In other words, the goals were always a combination of treatment and research. This combination has continued to the present day. A human laboratory for the study of addiction phenomena such as conditioned responses was also founded in 1971. The key clinician investigators in this group have remained in the Center since the 1970s with most of the research staff continuing to work together. Important new investigators have been added over the years. Treatment was empirically based with randomized, controlled clinical trials as the gold standard for determining evidence-based treatment. The patients coming to treatment do not distinguish between abuse of alcohol and other drugs, so the treatment and research programs have always focused on all drugs including ethyl alcohol and the combination of ethyl alcohol with other drugs such as cocaine and opioids. Most of the patients coming for treatment also suffered from additional psychiatric disorders such as depression, anxiety, bipolar disorder or schizophrenia. Thus, the addiction treatment program in 1980 absorbed the rest of the VA Psychiatry Service into the Substance Abuse Program forming a new Behavioral Health Service with responsibility for over 9000 patients. The integration of substance abuse treatment with overall mental health care was the most efficient way to handle patients with complicated combinations of disorders. While this continues to be the best way to treat patients, it has proven difficult in practice. The main reason for this difficulty is that most mental health therapists whether they are psychiatrists, psychologists or social workers feel very inadequate to handle substance abuse problems. Unless they have had specialized training in addictive disorders, therapists are likely to be uncomfortable if substance abuse is one of the diagnoses while they may be quite comfortable treating other complex disorders such as schizophrenia. This lack of education of clinicians remains a major problem for our field. Some of the findings that came out of both the Penn/VA laboratory and clinical studies are now widely accepted and form the basis of standard clinical practice. These concepts and evidence will be briefly reviewed below.

Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial.

CONTEXT: The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful. OBJECTIVE: To evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth. DESIGN, SETTING, AND PATIENTS: Clinical trial at 6 community programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone or a 14-day taper (detox). INTERVENTIONS: Patients in the 12-week buprenorphine-naloxone group were prescribed up to 24 mg per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg per day and then tapered to day 14. All were offered weekly individual and group counseling. MAIN OUTCOME MEASURE: Opioid-positive urine test result at weeks 4, 8, and 12. RESULTS: The number of patients younger than 18 years was too small to analyze separately, but overall, patients in the detox group had higher proportions of opioid-positive urine test results at weeks 4 and 8 but not at week 12 (chi(2)(2) = 4.93, P = .09). At week 4, 59 detox patients had positive results (61%; 95% confidence interval [CI] = 47%-75%) vs 58 12-week buprenorphine-naloxone patients (26%; 95% CI = 14%-38%). At week 8, 53 detox patients had positive results (54%; 95% CI = 38%-70%) vs 52 12-week buprenorphine-naloxone patients (23%; 95% CI = 11%-35%). At week 12, 53 detox patients had positive results (51%; 95% CI = 35%-67%) vs 49 12-week buprenorphine-naloxone patients (43%; 95% CI = 29%-57%). By week 12, 16 of 78 detox patients (20.5%) remained in treatment vs 52 of 74 12-week buprenorphine-naloxone patients (70%; chi(2)(1) = 32.90, P < .001). During weeks 1 through 12, patients in the 12-week buprenorphine-naloxone group reported less opioid use (chi(2)(1) = 18.45, P < .001), less injecting (chi(2)(1) = 6.00, P = .01), and less nonstudy addiction treatment (chi(2)(1) = 25.82, P < .001). High levels of opioid use occurred in both groups at follow-up. Four of 83 patients who tested negative for hepatitis C at baseline were positive for hepatitis C at week 12. CONCLUSIONS: Continuing treatment with buprenorphine-naloxone improved outcome compared with short-term detoxification. Further research is necessary to assess the efficacy and safety of longer-term treatment with buprenorphine for young individuals with opioid dependence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00078130.

Prescription OxyContin abuse among patients entering addiction treatment.

OBJECTIVE: OxyContin and other pharmaceutical opioids have been given special attention in the media, who frequently describe problematic users of the drug as previously drug-naive individuals who become addicted following legitimate prescriptions for medical reasons. The purpose of this study was to characterize the nature and origins of pharmaceutical opioid addiction among patients presenting at substance abuse treatment programs. METHOD: The authors evaluated the prevalence and correlates of OxyContin use and abuse among a population of 27,816 subjects admitted to 157 addiction treatment programs in the United States from 2001-2004. The data collected included the lifetime and past 30-day use of OxyContin and other drugs prior to admission to addiction treatment, source of drug supply, and prior treatment history. RESULTS: Approximately 5% of all subjects who were admitted to the 157 addiction treatment programs reported prior use of OxyContin. Of those subjects, 4.5% reported using the drug on a regular basis for at least 1 year, and 2% reported use of the drug during the 30 days prior to admission. Seventy-eight percent of subjects who reported OxyContin use also reported that the drug had not been prescribed to them for any medical reason, 86% reported use of the drug to "get high or get a buzz," and 78% reported receiving prior treatment for a substance use disorder. CONCLUSIONS: The patients in this sample did not include individuals from private therapists or pain clinics. However, among treatment-seeking individuals who use OxyContin, the drug is most frequently obtained from nonmedical sources as part of a broader and longer-term pattern of multiple substance abuse.

Site matters: multisite randomized trial of motivational enhancement therapy in community drug abuse clinics.

The effectiveness of motivational enhancement therapy (MET) in comparison with counseling as usual (CAU) for increasing retention and reducing substance use was evaluated in a multisite randomized clinical trial. Participants were 461 outpatients treated by 31 therapists within 1 of 5 outpatient substance abuse programs. There were no retention differences between the 2 brief intervention conditions. Although both 3-session interventions resulted in reductions in substance use during the 4-week therapy phase, MET resulted in sustained reductions during the subsequent 12 weeks whereas CAU was associated with significant increases in substance use over this follow-up period. This finding was complicated by program site main effects and higher level interactions. MET resulted in more sustained substance use reductions than CAU among primary alcohol users, but no difference was found for primary drug users. An independent evaluation of session audiotapes indicated that MET and CAU were highly and comparably discriminable across sites.

Abuse of buprenorphine in the United States: 2003-2005.

This study examines trends in the reported abuse of two sublingual buprenorphine products, Subutex and Suboxone, in the United States. Quarterly counts of abuse cases were obtained from 18 regional poison control centers (PCCS) for 2003-2005. Seventy-seven abuse cases were reported, of which 7.8 percent involved Subutex and 92.2 percent involved Suboxone. The average quarterly ratio of abuse cases per 1,000 prescriptions dispensed was 0.08 (SD +/- 0.09) for Subutex, and 0.16 (SD +/- 0.08) for Suboxone. Findings suggest that these sublingual buprenorphine formulations have a low rate of abuse based on toxico-surveillance data.

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.