Hilary S. Connery

Medication-assisted Treatment of Opioid Use Disorder: Review of the Evidence and Future Directions

Learning ObjectiveAfter participating in this activity, learners should be better able to: Evaluate the rationale for and current evidence supporting medication-assisted treatment of opioid use disorder. AbstractMedication-assisted treatment of opioid use disorder with physiological dependence at least doubles rates of opioid-abstinence outcomes in randomized, controlled trials comparing psychosocial treatment of opioid use disorder with medication versus with placebo or no medication. This article reviews the current evidence for medication-assisted treatment of opioid use disorder and also presents clinical practice imperatives for preventing opioid overdose and the transmission of infectious disease. The evidence strongly supports the use of agonist therapies to reduce opioid use and to retain patients in treatment, with methadone maintenance remaining the gold standard of care. Combined buprenorphine/naloxone, however, also demonstrates significant efficacy and favorable safety and tolerability in multiple populations, including youth and prescription opioid–dependent individuals, as does buprenorphine monotherapy in pregnant women. The evidence for antagonist therapies is weak. Oral naltrexone demonstrates poor adherence and increased mortality rates, although the early evidence looks more favorable for extended-release naltrexone, which has the advantages that it is not subject to misuse or diversion and that it does not present a risk of overdose on its own. Two perspectives—individualized treatment and population management—are presented for selecting among the three available Food and Drug Administration–approved maintenance therapies for opioid use disorder. The currently unmet challenges in treating opioid use disorder are discussed, as are the directions for future research.

Gender differences in a clinical trial for prescription opioid dependence

Although gender differences in substance use disorders have been identified, few studies have examined gender differences in prescription drug dependence. The aim of this study was to examine gender differences in clinical characteristics and treatment outcomes in a large clinical trial for prescription opioid dependence. Despite no pre-treatment differences in opioid dependence severity, women reported significantly greater functional impairment, greater psychiatric severity, and higher likelihood of using opioids to cope with negative affect and pain than men. Women were also more likely than men to have first obtained opioids via a legitimate prescription and to use opioids via the intended route of administration. Men reported significantly more alcohol problems than women. There were no significant gender differences in medication dose, treatment retention, or opioid outcomes. Thus, despite the presence of pre-treatment gender differences in this population, once the study treatment was initiated, women and men exhibited similar opioid use outcomes.

A multi-site, two-phase, Prescription Opioid Addiction Treatment Study (POATS): rationale, design, and methodology.

The National Institute on Drug Abuse Clinical Trials Network launched the Prescription Opioid Addiction Treatment Study (POATS) in response to rising rates of prescription opioid dependence and gaps in understanding the optimal course of treatment for this population. POATS employed a multi-site, two-phase adaptive, sequential treatment design to approximate clinical practice. The study took place at 10 community treatment programs around the United States. Participants included men and women age > or =18 who met Diagnostic and Statistical Manual, 4th Edition criteria for dependence upon prescription opioids, with physiologic features; those with a prominent history of heroin use (according to pre-specified criteria) were excluded. All participants received buprenorphine/naloxone (bup/nx). Phase 1 consisted of 4 weeks of bup/nx treatment, including a 14-day dose taper, with 8 weeks of follow-up. Phase 1 participants were monitored for treatment response during these 12 weeks. Those who relapsed to opioid use, as defined by pre-specified criteria, were invited to enter Phase 2; Phase 2 consisted of 12 weeks of bup/nx stabilization treatment, followed by a 4-week taper and 8 weeks of post-treatment follow-up. Participants were randomized at the beginning of Phase 1 to receive bup/nx, paired with either Standard Medical Management (SMM) or Enhanced Medical Management (EMM; defined as SMM plus individual drug counseling). Eligible participants entering Phase 2 were re-randomized to either EMM or SMM. POATS was developed to determine what benefit, if any, EMM offers over SMM in short-term and longer-term treatment paradigm. This paper describes the rationale and design of the study.

It’s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system

Opioids selective for the G protein-coupled mu opioid receptor (MOR) produce potent analgesia and euphoria. Heroin, a synthetic opioid, is considered one of the most addictive substances, and the recent exponential rise in opioid addiction and overdose deaths has made treatment development a national public health priority. Existing medications (methadone, buprenorphine, and naltrexone), when combined with psychosocial therapies, have proven efficacy in reducing aspects of opioid addiction. Unfortunately, these medications have critical limitations including those associated with opioid agonist therapies (e.g., sustained physiological dependence and opioid withdrawal leading to high relapse rates upon discontinuation), non-adherence to daily dosing, and non-renewal of monthly injection with extended-release naltrexone. Furthermore, current medications fail to ameliorate key aspects of addiction such as powerful conditioned associations that trigger relapse (e.g., cues, stress, the drug itself). Thus, there is a need for developing novel treatments that target neural processes corrupted with chronic opioid use. This requires a basic understanding of molecular and cellular mechanisms underlying effects of opioids on synaptic transmission and plasticity within reward-related neural circuits. The focus of this review is to discuss how crosstalk between MOR-associated G protein signaling and glutamatergic neurotransmission leads to immediate and long-term effects on emotional states (e.g., euphoria, depression) and motivated behavior (e.g., drug-seeking, relapse). Our goal is to integrate findings on how opioids modulate synaptic release of glutamate and postsynaptic transmission via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors in the nucleus accumbens and ventral tegmental area with the clinical (neurobehavioral) progression of opioid dependence, as well as to identify gaps in knowledge that can be addressed in future studies.

Integrated Management of Physician-delivered Alcohol Care for Tuberculosis Patients: Design and Implementation.

BACKGROUND While the integration of alcohol screening, treatment, and referral in primary care and other medical settings in the U.S. and worldwide has been recognized as a key health care priority, it is not routinely done. In spite of the high co-occurrence and excess mortality associated with alcohol use disorders (AUDs) among individuals with tuberculosis (TB), there are no studies evaluating effectiveness of integrating alcohol care into routine treatment for this disorder. METHODS We designed and implemented a randomized controlled trial (RCT) to determine the effectiveness of integrating pharmacotherapy and behavioral treatments for AUDs into routine medical care for TB in the Tomsk Oblast Tuberculosis Service (TOTBS) in Tomsk, Russia. Eligible patients are diagnosed with alcohol abuse or dependence, are newly diagnosed with TB, and initiating treatment in the TOTBS with Directly Observed Therapy-Short Course (DOTS) for TB. Utilizing a factorial design, the Integrated Management of Physician-delivered Alcohol Care for Tuberculosis Patients (IMPACT) study randomizes eligible patients who sign informed consent into 1 of 4 study arms: (1) Oral Naltrexone + Brief Behavioral Compliance Enhancement Therapy (BBCET) + treatment as usual (TAU), (2) Brief Counseling Intervention (BCI) + TAU, (3) Naltrexone + BBCET + BCI + TAU, or (4) TAU alone. RESULTS Utilizing an iterative, collaborative approach, a multi-disciplinary U.S. and Russian team has implemented a model of alcohol management that is culturally appropriate to the patient and TB physician community in Russia. Implementation to date has achieved the integration of routine alcohol screening into TB care in Tomsk; an ethnographic assessment of knowledge, attitudes, and practices of AUD management among TB physicians in Tomsk; translation and cultural adaptation of the BCI to Russia and the TB setting; and training and certification of TB physicians to deliver oral naltrexone and brief counseling interventions for alcohol abuse and dependence as part of routine TB care. The study is successfully enrolling eligible subjects in the RCT to evaluate the relationship of integrating effective pharmacotherapy and brief behavioral intervention on TB and alcohol outcomes, as well as reduction in HIV risk behaviors. CONCLUSIONS The IMPACT study utilizes an innovative approach to adapt 2 effective therapies for treatment of alcohol use disorders to the TB clinical services setting in the Tomsk Oblast, Siberia, Russia, and to train TB physicians to deliver state of the art alcohol pharmacotherapy and behavioral treatments as an integrated part of routine TB care. The proposed treatment strategy could be applied elsewhere in Russia and in other settings where TB control is jeopardized by AUDs. If demonstrated to be effective, this model of integrating alcohol interventions into routine TB care has the potential for expanded applicability to other chronic co-occurring infectious and other medical conditions seen in medical care settings.

The Relationship of Self-Esteem and Self-Efficacy to Treatment Outcomes of Alcohol-Dependent Men and Women

This study investigates whether self-esteem is associated with clinical and demographic characteristics, self-efficacy expectancies, and post-treatment drinking outcomes. Forty-one (40.6%) women and 60 (59.4%) men were recruited during inpatient alcohol dependence treatment. At baseline, lower self-esteem was significantly associated with current depression and other psychiatric disorders. Self-esteem was not related to gender, relapse, other one-year drinking outcomes, or self-efficacy. Age and psychiatric disorders were strong predictors of self-esteem at follow-up. This study suggests that different perceptions of the self have unique roles in recovery from alcohol use disorders.

Who benefits from additional drug counseling among prescription opioid dependent patients receiving buprenorphine-naloxone and standard medical management?

BACKGROUND In the multi-site Prescription Opioid Addiction Treatment Study (POATS), conducted within the National Drug Abuse Clinical Trials Network, participants randomly assigned to receive individual drug counseling in addition to buprenorphine-naloxone and medical management did not have superior opioid use outcomes. However, research with other substance-dependent populations shows that subgroups of participants may benefit from a treatment although the entire population does not. METHOD We conducted a secondary analysis of POATS data to determine whether a subgroup of participants benefited from drug counseling in addition to buprenorphine-naloxone and medical management, either due to greater problem severity or more exposure to counseling as a result of greater treatment adherence. Problem severity was measured by a history of heroin use, higher Addiction Severity Index drug composite score, and chronic pain. Adequate treatment adherence was defined a priori as attending at least 60% of all offered sessions. RESULTS Patients who had ever used heroin and received drug counseling were more likely to be successful (i.e., abstinent or nearly abstinent from opioids) than heroin users who received medical management alone, but only if they were adherent to treatment and thus received adequate exposure to counseling (OR=3.7, 95% CI=1.1-11.8, p=0.03). The association between severity and outcome did not vary by treatment condition for chronic pain or ASI drug severity score. CONCLUSIONS These findings emphasize the importance of treatment adherence, and suggest that patients with prescription opioid dependence are a heterogeneous group, with different optimal treatment strategies for different subgroups.

HIV risk behavior in treatment-seeking opioid-dependent youth: Results from a NIDA clinical trials network multisite study

Objective:To assess baseline rates of and changes in HIV drug and sexual risk behavior as a function of gender and treatment in opioid-dependent youth. Methods:One hundred fifty participants were randomly assigned to extended buprenorphine/naloxone therapy (BUP) for 12 weeks or detoxification for 2 weeks; all received drug counseling for 12 weeks. HIV risk was assessed at baseline and 4-week, 8-week, and 12-week follow-ups. Behavioral change was examined using generalized estimating equations. Results:Baseline rates of past-month HIV risk for females/males were 51%/45% for injection drug use (IDU) (ns), 77%/35% for injection risk (P < 0.001), 82%/74% for sexual activity (ns), 14%/24% for multiple partners (ns), and 68%/65% for unprotected intercourse (ns). IDU decreased over time (P < 0.001), with greater decreases in BUP versus detoxification (P < 0.001) and females versus males in BUP (P < 0.05). Injection risk did not change for persistent injectors. Sexual activity decreased in both genders and conditions (P < 0.01), but sexual risk did not. Conclusions:Overall, IDU and sexual activity decreased markedly, particularly in BUP patients and females, but injection and sexual risk behaviors persisted. Although extended BUP seems to have favorable effects on HIV risk behavior in opioid-dependent youth, risk reduction counseling may be necessary to extend its benefits.

Adolescent Substance Use and Unplanned Pregnancy: Strategies for Risk Reduction

Substance use among adolescents increases the risk of unplanned pregnancies, which then increases the risk of fetal exposure to addictive, teratogenic substances. Specific interventions are necessary to target pregnancy planning and contraception among reproductive-age substance users. Screening for substance use using the CRAFFT is recommended in all health care settings treating adolescent patients. Screening for tobacco and nicotine use is also recommended along with the provision of smoking cessation interventions. Using motivational interviewing style and strategies is recommended to engage adolescents in discussions related to reducing substance use, risky sexual behavior, and probability of unplanned pregnancy or late-detection pregnancy.

Association of Cannabis Use with Opioid Outcomes among Opioid-Dependent Youth

OBJECTIVE Cannabis use is common among opioid-dependent patients, but studies of its association with treatment outcome are mixed. In this secondary analysis, the association of cannabis use with opioid treatment outcome is assessed. METHODS In the main study, participants (n=152) aged 15-21 years were randomized to receive psychosocial treatments and either a 12-week course of buprenorphine-naloxone with a dose taper to zero in weeks 9-12, or a 2-week detoxification with buprenorphine-naloxone. Drug use was assessed by self-report and urine drug screen at baseline and during study weeks 1-12. The association between cannabis and opioid use at weeks 4, 8, and 12 was examined using logistic regression models. RESULTS Participants reported a median of 3.0 days (range=0-30) cannabis use in the past month; half (50.3%; n=77) reported occasional use, one-third reported no use (33.1%; n=50), and one-sixth reported daily cannabis use (16.6%; n=25). Median lifetime cannabis use was 4.0 years (range=0-11) and median age of initiation of use was 15.0 years (range 9-21). Neither past cannabis use (age of initiation and use in the month prior to baseline) nor concurrent use was associated with level of opioid use. CONCLUSIONS Overall, cannabis use had no association with opioid use over 12 weeks in this sample of opioid-dependent youth. While cannabis use remains potentially harmful, it was not a predictor of poor opioid treatment outcome.