Faculty Bibliography

BACKGROUND AND AIMS: Relapse to addiction following incarceration is common. We estimated the feasibility and effectiveness of extended-release naltrexone (XR-NTX) as relapse prevention among opioid-dependent male adults leaving a large urban jail. DESIGN: Eight-week, proof-of-concept, open-label, non-blinded randomized effectiveness trial. SETTING: New York City jails and Bellevue Hospital Center Adult Primary Care clinics, USA. PARTICIPANTS: From January 2010 to July 2013, 34 opioid-dependent adult males with no stated interest in agonist treatments (methadone, buprenorphine) received a counseling and referral intervention and were randomized to XR-NTX (n = 17) versus no medication (n = 17) within one week prior to jail release. INTERVENTION: XR-NTX (Vivitrol((R)) ; Alkermes Inc.), a long-acting injectable mu opioid receptor antagonist. MEASURES: The primary intent-to-treat outcome was post-release opioid relapse at week 4, defined as >/=10 days of opioid misuse by self-report and urine toxicologies. Secondary outcomes were proportion of urine samples negative for opioids and rates of opioid abstinence, intravenous drug use (IVDU), cocaine use, community treatment participation, re-incarceration and overdose. FINDINGS: Acceptance of XR-NTX was high; 15 of 17 initiated treatment. Rates of the primary outcome of week 4 opioid relapse were lower among XR-NTX participants: 38 versus 88% [P<0.004; odds ratio (OR) = 0.08, 95% confidence interval (CI) = 0.01-0.48]; more XR-NTX urine samples were negative for opioids, 59 versus 29% (P<0.009; OR = 3.5, 95% CI = 1.4-8.5). There were no significant differences in the remaining secondary outcomes, including rates of IVDU, cocaine use, re-incarceration and overdose. CONCLUSION: Extended-release naltrexone is associated with significantly lower rates of opioid relapse among men in the United States following release from jail when compared with a no medication treatment-as-usual condition.

BACKGROUND: Substance use screening is widely encouraged in healthcare settings, but the lack of a screening approach that fits easily into clinical workflows has restricted its broad implementation. The Substance Use Brief Screen (SUBS) was developed as a brief, self-administered instrument to identify unhealthy use of tobacco, alcohol, illicit drugs, and prescription drugs. We evaluated the validity and test-retest reliability of the SUBS in adult primary care patients. METHODS: Adults age 18-65 were enrolled from urban safety net primary care clinics to self-administer the SUBS using touch-screen tablet computers for a test-retest reliability study (n=54) and a two-site validation study (n=586). In the test-retest reliability study, the SUBS was administered twice within a 2-week period. In the validation study, the SUBS was compared to reference standard measures, including self-reported measures and saliva drug tests. We measured test-retest reliability and diagnostic accuracy of the SUBS for detection of unhealthy use and substance use disorder for tobacco, alcohol, and drugs (illicit and prescription drug misuse). RESULTS: Test-retest reliability was good or excellent for each substance class. For detection of unhealthy use, the SUBS had sensitivity and specificity of 97.8% (95% CI 93.7 to 99.5) and 95.7% (95% CI 92.4 to 97.8), respectively, for tobacco; and 85.2% (95% CI 79.3 to 89.9) and 77.0% (95% CI 72.6 to 81.1) for alcohol. For unhealthy use of illicit or prescription drugs, sensitivity was 82.5% (95% CI 75.7 to 88.0) and specificity 91.1% (95% CI 87.9 to 93.6). With respect to identifying a substance use disorder, the SUBS had sensitivity and specificity of 100.0% (95% CI 92.7 to 100.0) and 72.1% (95% CI 67.1 to 76.8) for tobacco; 93.5% (95% CI 85.5 to 97.9) and 64.6% (95% CI 60.2 to 68.7) for alcohol; and 85.7% (95% CI 77.2 to 92.0) and 82.0% (95% CI 78.2 to 85.3) for drugs. Analyses of area under the receiver operating curve (AUC) indicated good discrimination (AUC 0.74-0.97) for all substance classes. Assistance in completing the SUBS was requested by 11% of participants. CONCLUSIONS: The SUBS was feasible for self-administration and generated valid results in a diverse primary care patient population. The 4-item SUBS can be recommended for primary care settings that are seeking to implement substance use screening.

Aims: Implementation of substance use screening in general medical settings is hindered by the lack of a brief yet precise and comprehensive screening tool that is compatible with clinical workflows. To address this need, we developed the Substance Use Brief Screen (SUBS); a 4-item screener for tobacco, alcohol, and drug use (illicit and prescription) that is self-administered and may be easily integrated with electronic health records. Methods: Adult patients were recruited consecutively in the waiting area of an urban safety net primary care clinic. The SUBS was self-administered in English on touchscreen tablet computers. Reference standard measures of unhealthy substance use and substance use disorders were then administered, including self reported measures and saliva drug tests. The SUBS was compared against the reference standards to determine its sensitivity, specificity, and area under the curve (AUC) for each substance class. Results: Among the 390 participants, rates of past year use reported on the SUBS were 37% tobacco, 43% alcohol (4+ drinks/day), 20% illicit drugs, and 12% prescription drugs. Sensitivity and specificity of the SUBS for detecting past year unhealthy use were: tobacco 99% and 91% (AUC = .95); alcohol 94% and 68% (AUC = .81); drugs (illicit or prescription) 84% and 89% (AUC = .86). Sensitivity was lower for prescription drugs (57%) than for illicit drugs (78%). For detecting a substance use disorder, sensitivity and specificity were: tobacco 100% and 73% (AUC = .87); alcohol 93% and 64% (AUC = .79); drugs 85% and 82% (AUC = .84). Conclusions: The SUBS accurately identified unhealthy tobacco, alcohol, and drug use in this primary care sample, and had high sensitivity but lower specificity for identifying substance use disorders. Individuals screening positive on the SUBS should receive further assessment. Our findings support use of the SUBS for substance use screening in primary care, but additional tools may be needed for prescription drugs

Aims: To determine if specific single-nucleotide polymorphisms (SNPs) in stress-related genes are associated with heroin addiction. Methods: Case-control hypothesis-driven association study of 112 SNPs from 26 stress-related genes. The sample consists of 852 case subjects and 238 controls. The case subjects are former heroin addicts with a history of at least 1 year of daily multiple uses of heroin, treated at a MMTP. European ancestry was verified by ancestry informative markers (AIMs). Association analysis was performed by logistic regression. Results: Nineteen SNPs in 9 genes (AVP, CRHR1, CRHR2, FKBP5, NR3C2, AVPR1A, GAL, GLRA1 and NPY1R) showed nominally significant association (p < 0.05) with heroin addiction. Two tightly linked FKBP5 SNPs, rs1360780 and rs3800373, from intron 2 and the 3' UTR, respectively, remained significant after correction for multiple testing (experiment-wise p = 3.0E-04;OR= 2.35; 95% CI, 1.5-3.7 and p = 1.6E-05; OR= 2.85; 95% CI, 1.8-4.6, respectively). Conclusions: The study provides evidence for the association of FKBP5 SNPs with heroin addiction. These SNPs were previously associated with diverse affective disorders and showed functional differences in gene expression and stress response. The FKBP5 gene encodes a co-chaperone that regulates glucocorticoid sensitivity. The modulation of the stress response by FKBP5 may contribute to the development of opiate dependence and in turn FKBP5 may also mediate the abuse potential of opioids. The study also corroborates our and others previous reports of association of GAL SNP rs694066 and AVPR1A SNPs rs11174811, rs1587097 and rs10784339 with specific general drug addictions and suggests several new associations

Aims: ED-based SBIRT for alcohol and drug use has the potential to impact public health greatly. Time and resource constraints limit implementation. Targeted intervention may be more efficient and practical. We hypothesized that we could use chief complaints to identify patients at highest risk of positive drug or alcohol use assessments. Methods: Using baseline data from NIDA CTN0047: SMARTED, free text chief complaints of 14,972 subjects from six sites were coded using a tested algorithm (Thompson, 2006). Multiple team members manually reviewed and further collapsed the chief complaint categorization to ensure agreement. We excluded subjects having missing data or complaints related to substance use and chief complaints stated by <15 subjects. Positive screens were defined as AUDIT-C > 4 for men and >3 for women (alcohol) and DAST > 2 (drugs). We ranked-ordered the chief complaints by their sensitivity and positive predictive value to (1) minimize the number of chief complaints and (2) assess the fewest number of ED patients. Our goal was to identify 75% of ED patients having positive assessments using these strategies. Results: The screening assessments were positive in 5805/14,561 (39.9%) for alcohol and 2454/14,494 (16.9%) for drugs. We collapsed the free-text chief complaints into 50 usable categories. To identify 75% of all ED patients having positive assessments using the first strategy would require including 19 chief complaints for alcohol screening and 20 chief complaints for drug screening. Adapting the second strategy, we would need to screen at least 71% and 68% of all ED patients for alcohol and drugs respectively to identify 75% of those having positive assessments. Conclusions: Based on this large, multicenter study, chief complaints provide little assistance in targeting SBIRT for alcohol or drug use in the ED

AIMS: We evaluated the immunogenicity, efficacy, and safety of succinylnorcocaine conjugated to cholera toxin B protein as a vaccine for cocaine dependence. METHODS: This 6-site, 24 week Phase III randomized double-blind placebo-controlled trial assessed efficacy during weeks 8 to 16. We measured urine cocaine metabolites thrice weekly as the main outcome. RESULTS: The 300 subjects (76% male, 72% African-American, mean age 46 years) had smoked cocaine on average for 13 days monthly at baseline. We hypothesized that retention might be better and positive urines lower for subjects with anti-cocaine IgG levels of >/=42 mug/mL (high IgG), which was attained by 67% of the 130 vaccine subjects receiving five vaccinations. Almost 3-times fewer high than low IgG subjects dropped out (7% vs 20%). Although for the full 16 weeks cocaine positive urine rates showed no significant difference between the three groups (placebo, high, low IgG), after week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs 18%), and the high IgG group had the most cocaine-free urines for the last 2 weeks of treatment (OR=3.02), but neither were significant. Injection site reactions of induration and tenderness differed between placebo and active vaccine, and the 29 serious adverse events did not lead to treatment related withdrawals, or deaths. CONCLUSIONS: The vaccine was safe, but it only partially replicated the efficacy found in the previous study based on retention and attaining abstinence.

BACKGROUND & AIM: The dopaminergic pathways have been implicated in the etiology of drug addictions. The aim of this study was to determine if variants in dopaminergic genes are associated with heroin addiction. MATERIALS & METHODS: The study includes 828 former heroin addicts and 232 healthy controls, of predominantly European ancestry. Ninety seven SNPs (13 genes) were analyzed. RESULTS: Nine nominally significant associations were observed at CSNK1E, ANKK1, DRD2 and DRD3. CONCLUSION: The results support our previous report of association of CSNK1E SNP rs1534891 with protection from heroin addiction. CSNK1E interacts with circadian rhythms and DARPP-32 and has been implicated in negative regulation of sensitivity to opioids in rodents. It may be a target for drug addiction treatment. Original submitted 8 August 2014; Revision submitted 8 October 2014.

Hurricane Sandy led to the closing of many major New York City public hospitals including their substance abuse clinics and methadone programs, and the displacement or relocation of thousands of opioid-dependent patients from treatment. The disaster provided a natural experiment that revealed the relative strengths and weaknesses of methadone treatment in comparison to physician office-based buprenorphine treatment for opioid dependence, two modalities of opioid maintenance with markedly different regulatory requirements and institutional procedures. To assess these two modalities of treatment under emergency conditions, semi-structured interviews about barriers to and facilitators of continuity of care for methadone and buprenorphine patients were conducted with 50 providers of opioid maintenance treatment. Major findings included that methadone programs presented more regulatory barriers for providers, difficulty with dose verification due to impaired communication, and an over reliance on emergency room dosing leading to unsafe or suboptimal dosing. Buprenorphine treatment presented fewer regulatory barriers, but buprenorphine providers had little to no cross-coverage options compared to methadone providers, who could refer to alternate methadone programs. The findings point to the need for well-defined emergency procedures with flexibility around regulations, the need for a central registry with patient dose information, as well as stronger professional networks and cross-coverage procedures. These interventions would improve day-to-day services for opioid-maintained patients as well as services under emergency conditions.

Stress is a significant risk factor in the development of drug addictions and in addiction relapse susceptibility. This hypothesis-driven study was designed to determine if specific SNPs in genes related to stress response are associated with heroin and/or cocaine addiction in African Americans. The analysis included 27 genes (124 SNPs) and was performed independently for each addiction. The sample consisted of former heroin addicts in methadone maintenance treatment (n = 314), cocaine addicts (n = 281), and controls (n = 208). Fourteen SNPs showed nominally significant association with heroin addiction (p < 0.05), including the African-specific, missense SNP rs5376 (Asn334Ser) in the galanin receptor type 1 gene (GALR1) and the functional FKBP5 intronic SNP rs1360780. Thirteen SNPs showed association with cocaine addiction, including the synonymous SNPs rs237902, in the oxytocin receptor gene (OXTR), and rs5374 in GALR1. No signal remained significant after correction for multiple testing. Four additional SNPs (GALR1 rs2717162, AVP rs2282018, CRHBP rs1875999, and NR3C2 rs1040288) were associated with both addictions and may indicate common liability. The study provides preliminary evidence for novel association of variants in several stress-related genes with heroin and/or cocaine addictions and may enhance the understanding of the interaction between stress and addictions.