Prescription psychostimulants for cocaine use disorder: A review from molecular basis to clinical approach.

Cocaine use is a public health concern in many countries worldwide, particularly in the Americas and Oceania. Overdose deaths involving stimulants, such as cocaine, have been increasing markedly in North America, especially with concurrent opioid involvement. To date, no pharmacological treatment is available to treat stimulant (including cocaine) use disorders. Prescription psychostimulants (PPs) could be useful to treat cocaine use disorder (CUD) as they share the pharmacological effects with cocaine, as evidenced by a recent meta-analysis that assessed 38 randomized clinical trials (RCTs). PPs were found to promote sustained abstinence and reduce drug use in patients with CUD. The aim of this paper is to provide a narrative review of the clinical pharmacology of PPs and comment on the current stage of evidence supporting PPs to treat CUD. We also propose a model of care that integrates PPs with evidence-based psychosocial interventions (such as cognitive-behavioural therapy [CBT] and contingency management [CM]), a harm reduction approach and case management with social support.

Telehealth for opioid use disorder: retention as a function of demographics and rurality.

Background: Despite lifesaving medications such as buprenorphine and methadone, the majority of individuals with opioid use disorder (OUD) face access barriers to evidence-based treatment. COVID-19 era regulatory reforms have shown that telehealth can improve access to care, although disparities in clinical outcomes are likely to persist.Objective: We aimed to analyze 180-day and 365-day retention in treatment with buprenorphine for OUD overall and by demographics, hypothesizing that retention would be lower among racial/ethnic minorities and rural patients.Methods: We analyzed data from a cohort of individuals with OUD enrolled in treatment from April 1, 2020 to September 30, 2021, in Pennsylvania and New York using a virtual-first telehealth OUD treatment platform to assess rates of 180-day and 365-day retention. Associations between demographic characteristics and retention were assessed using unadjusted and adjusted logistic regression models.Results: Among 1,378 patients (58.8% male), 180-day retention was 56.4%, and 365-day retention was 48.3%. Adjusted analyses found that only an association between older age and greater odds of 180-day retention was significant (aOR for patients aged 30-50 vs. <30: 1.83 [1.37-2.45]). There were no significant associations between sex, race/ethnicity, state, or rurality with retention.Conclusion: While we were unable to control for socioeconomic variables, we found retention within telehealth services for buprenorphine was high irrespective of geography or race/ethnicity, but disparities with age indicate a subset of patients who may benefit from more intensive services early in care.

Shapes of subcortical structures in adolescents with and without familial history of substance use disorder.

It has been suggested that intergenerational transmission of risk for substance use disorder (SUD) manifests in the brain anatomy of substance naïve adolescents. While volume and shapes of subcortical structures (SSS) have been shown to be heritable, these structures, especially the pallidum, putamen, nucleus accumbens, and hippocampus, have also been associated with substance use disorders. However, it is not clear if those anatomical differences precede substance use or are the result of that use. Therefore, we examined if volume and SSS of adolescents with a family history (FH+) of SUD differed from adolescents without such a history (FH-). Because risk for SUD is associated with anxiety and impulsivity, we also examined correlations between these psychological characteristics and volume/SSS. Using structural MRI and FSL software, we segmented subcortical structures and obtained indices of SSS and volumes of 64 FH+ and 58 FH- adolescents. We examined group differences in volume and SSS, and the correlations between volume/SSS and trait anxiety and impulsivity. FH+ adolescents had a significant inward deformation in the shape of the right anterior hippocampus compared to FH- adolescents, while the volume of this structure did not differ between groups. Neither shape nor volume of the other subcortical structures differed between groups. In the FH+ adolescents, the left hippocampus shape was positively correlated with both trait anxiety and impulsivity, while in FH- adolescents a negative correlation pattern of SSS was seen in the hippocampus. SSS appears to capture local anatomical features that traditional volumetric analysis does not. The inward shape deformation in the right anterior hippocampus in FH+ adolescents may be related to the known increased risk for behavioral dysregulation leading to SUD in FH+ offspring. Hippocampus shape also exhibits opposite patterns of correlation with anxiety and impulsivity scores across the FH+ and FH- adolescents. These novel findings may reveal neural correlates, not captured by traditional volumetric analysis, of familial transmission of increased vulnerability to SUD.

Google Trends Data: A Potential New Tool for Monitoring the Opioid Crisis.

INTRODUCTION: There is a need to strengthen the standard surveillance of the opioid overdose crisis in the USA. The role of Google Trends (GT) was explored in this context. METHODS: In this study, a systemic GT search was done for a period from January 2004 to December 2018. "Naloxone" and "drug overdose" were chosen as search inputs. By using locally weighted scatterplot smoothing, we locally regressed and smoothed the relative search data generated by the GT search. We conducted a changepoint analysis (CPA) to detect significant statistical changes in the "naloxone" trend from 2004 to 2018. Cross-correlation function analyses were done to examine the correlation between 2 time series: year-wise relative search volume (RSV) for "naloxone" and "drug overdose" with the age-adjusted drug overdose mortality rate. Pearson's correlation was performed for the state-wise age-adjusted mortality rate due to drug overdose and RSV for "naloxone" and "drug overdose." RESULTS: Smoothed and regressed GT of "naloxone" were similar to the "opioid overdose" trend published by the National Center for Health Statistics. The CPA showed 2 statistically significant points in 2011 and 2015. CPA of year-wise RSV for "naloxone" and "drug overdose" showed significantly positive correlation with the age-adjusted drug overdose mortality at lag zero. State-wise RSV for "naloxone" and "drug overdose" too showed a strong and significant positive correlation with the state-wise mortality data. DISCUSSION/CONCLUSION: Inexpensive, publicly accessible, real-time GT data could supplement and strengthen the monitoring of opioid overdose epidemic if used in conjunction with the existing official data sources.

Pilot randomized placebo-controlled clinical trial of high-dose gabapentin for alcohol use disorder.

BACKGROUND: Despite advances in the development of pharmacotherapy for alcohol use disorder (AUD), there remains a need for medications that can be administered to actively drinking outpatients to promote a reduction in harmful alcohol consumption. The primary aim of this pilot study was to determine whether high-dose gabapentin (3600 mg/daily) is more effective than placebo in reducing harmful alcohol consumption in outpatients with AUD. METHODS: Forty patients (27 men) who met DSM-IV-TR criteria for alcohol dependence and reporting at least 4 heavy drinking days (HDD) per week were recruited at a single site. Participants were actively drinking at study entry and received double-blind gabapentin (3600 mg/day; n = 19) or placebo (n = 20) for 8 weeks. Study medication was titrated over 5 days and administered in three divided doses (1200 mg three times per day). The proportion of HDD (primary outcome) and percent days abstinent (PDA; secondary outcome) were analyzed using generalized longitudinal mixed models with the predictors being study arm, week, study arm by week interaction, and corresponding baseline drinking measure. RESULTS: There was a significant interaction between study arm and week for the proportion of HDD per week, F (7, 215) = 3.33, p = 0.002 . There was also a significant interaction between study arm and week for PDA per week, F (7, 215) = 3.11, p = 0.004. The overall retention rate was 67.5% with no significant difference in time-to-dropout between treatment groups. There were no serious adverse events. No participants were removed from the trial due to the development of moderate-to-severe alcohol withdrawal (CIWA-Ar ≥ 13). CONCLUSIONS: Gabapentin treatment rapidly titrated to a dosage of 3600 mg/day is associated with a reduction in the proportion of HDD per week and an increase in PDA per week in actively drinking outpatients with AUD. High-dose gabapentin is potentially a feasible approach to treating AUD and deserving of further study.

The utility of a formative one-station objective structured clinical examination for Substance use disorders in a dental curriculum.

Substance use disorders (SUD) are chronic relapsing medical conditions characterised by compulsive substance seeking and use. They constitute a substantial disease burden globally. Labelling of persons with SUD has created barriers to treatment but there are effective management strategies. The dental profession has embraced reforms designed to address the SUD epidemic by promoting continuing education for practitioners and initiating curriculum changes in dental schools. Screening, Brief Intervention and Referral to Treatment (SBIRT) is an evidence-based model for managing patients with SUD. The use of a formative 1-station Objective Structured Clinical Examination (OSCE) for learning and assessment in SBIRT, operationalised with the MD3 rating scale is presented in this study. In 3 years of implementation, the SBIRT OSCE successfully integrated into the curriculum of the College of Dental Medicine, Columbia University. Mean score of total adherent behaviours was 11.80 (SD =4.23) (range: 2 - 24) and Cronbach's coefficient alpha for across-items reliability in adherent behaviours was 0.66. Adherent behaviours correlated with the global ratings (r = 0.66). Mean of global rating scores were 2.90 (SD =1.01) for collaboration and 2.97 (SD =1.00) for empathy and the global rating scores correlated with each other (r = 0.85). Histograms of global rating scores resembled normal distribution. The 1-station OSCE is a good model for learning about SBIRT. Psychometric analysis was useful in understanding the underlying construct of the MD3 rating scale and supported its reliability, validity and utility in dental education.

A week-long outpatient induction onto XR-naltrexone in patients with opioid use disorder.

BACKGROUND: Extended-release (XR) naltrexone can prevent relapse to opioid use disorder following detoxification. However, one of the barriers to initiating XR-naltrexone is the recommendation for a 7-10-day period of abstinence from opioids prior to the first dose. OBJECTIVES: The current study evaluated the feasibility of an XR-naltrexone induction protocol that can be implemented over 1 week in the outpatient clinic. METHODS: Participants (N = 44) were seen in the clinic daily. On Day 1, after abstaining from opioids for at least 12 h, they received buprenorphine 6-8 mg. Adjunctive medications (clonidine, clonazepam, zolpidem, trazodone, and prochlorperazine) were dispensed on Days 2-5, while ascending oral doses of naltrexone were given on Days 3-5 starting with 1 mg dose. An injection of XR-naltrexone was given on Day 5, 1 h after receiving and tolerating naltrexone 24 mg. RESULTS: Of the 44 participants (38 males), 35 (80%) were heroin users and 9 (20%) used prescription opioids. A total of 26 participants (59%) completed the induction and received their first injection of XR-naltrexone. XR-naltrexone was initiated in 54% (19/35) of heroin users and 78% (7/9) of prescription opioid users. CONCLUSION: The results support the feasibility of a week-long outpatient induction onto XR-naltrexone with ascending doses of naltrexone and standing doses of adjunctive medications. By circumventing the need for a protracted period of abstinence and mitigating the severity of withdrawal symptoms experienced during naltrexone titration, this strategy has the potential to increase patient acceptability and access to relapse prevention treatment with XR-naltrexone.

Development of a Cascade of Care for responding to the opioid epidemic.

Amid worsening opioid overdose death rates, the nation continues to face a persistent addiction treatment gap limiting access to quality care for opioid use disorder (OUD). Three FDA-approved medications (methadone, buprenorphine, and extended-release naltrexone) have high quality evidence demonstrating reductions in drug use and overdose events, but most individuals with OUD do not receive them. The development of a unified public health framework, such as a Cascade of Care, could improve system level practice and treatment outcomes. In response to feedback from many stakeholders over the past year, we have expanded upon the OUD treatment cascade, first published in 2017, with additional attention to prevention stages and both individual-level and population-based services to better inform efforts at the state and federal level. The proposed cascade framework has attracted considerable interest from federal agencies including the Centers for Disease Control and Prevention (CDC) and National Institute on Drug Abuse (NIDA) along with policy-makers nationwide. We have reviewed recent literature and evidence-based interventions related to prevention, identification, and treatment of individuals with OUD and modeled updated figures from the 2016 National Survey on Drug Use and Health. Many currently employed interventions (prescriber guidelines, prescription monitoring programs, naloxone rescue) address prevention of OUD or downstream complications but not treatment of the underlying disorder itself. An OUD Cascade of Care framework could help structure local and national efforts to combat the opioid epidemic by identifying key targets, interventions, and quality indicators across populations and settings to achieve these ends. Improved data collection and reporting methodology will be imperative.

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).

Long-term follow-up study of community-based patients receiving XR-NTX for opioid use disorders.

BACKGROUND AND OBJECTIVES: Extended-release naltrexone (XR-NTX) is FDA-approved to prevent relapse in patients with Opioid Use Disorder. However little is known about long-term use among community-based outpatients. METHODS: Retrospective chart review and long-term follow-up survey among individuals (N = 168) who entered an outpatient XR-NTX trial between 2011 and 2015, during which participants were offered three monthly injections of XR-NTX at no cost. The survey consisted of 35 questions covering a total of four domains: (1) substance use; (2) treatment continuation; (3) barriers; and (4) attitudes. RESULTS: Fifty-seven respondents were successfully surveyed, including 50% of those initially receiving all three XR-NTX injections ("study completers") in the parent study. Study completion was associated with superior outcomes and less likely relapse (defined as daily use), with a much greater time to relapse despite higher rates of concurrent non-opioid substance use. However the majority of participants discontinued treatment with XR-NTX at study completion, largely due to attitudes of "feeling cured" and "wanting to do it on my own" rather than external barriers such as cost or side effects. CONCLUSION: Patients who initiate treatment with XR-NTX might benefit from anticipatory guidance and motivational techniques to encourage long-term adherence as many will experience internal barriers to continuation. Our findings are reassuring that few patients experience side effects or adverse events complicating the effectiveness or safety of long-term use of XR-NTX. SCIENTIFIC SIGNIFICANCE: Among outpatients who successfully receive 3 monthly XR-NTX injections, many will prematurely discontinue treatment due to internal attitudes, such as "feeling cured." (Am J Addict 2017;26:319-325).

A review of a national training initiative to increase provider use of MAT to address the opioid epidemic.

BACKGROUND AND OBJECTIVES: The Providers' Clinical Support System for Medication Assisted Treatment (PCSS-MAT) initiative focuses on training and mentoring health professionals in the treatment of opioid use disorders (OUD) using pharmacological strategies. Led by the American Academy of Addiction Psychiatry (AAAP), PCSS-MAT is a consortium representing four of the five national professional organizations authorized by DATA 2,000-AAAP, American Osteopathic Academy of Addiction Medicine, American Psychiatric Association, and American Society of Addiction Medicine. DATA organizations are authorized to train physicians to prescribe buprenorphine for OUD treatment. The primary aim of PCSS-MAT is to substantially increase evidence-based practices with medications for OUD. METHODS: This review describes the development of PCSS-MAT, an ongoing national initiative funded by the Substance Abuse and Mental Health Services Administration (SAMHSA), to address the training needs posed by this critical public health problem. Core initiatives include: (1) Training and mentoring activities for primary care physicians; (2) Outreach to multidisciplinary professional organizations, (3) Creating a resource portal for families, patients, and communities for OUD treatment. RESULTS: Educational outreach to providers addresses the needs of patients with OUD and common co-occurring psychiatric and medical disorders. DISCUSSION AND CONCLUSIONS: The overall scope of PCSS-MAT is to increase access to evidence-based treatment of substance use disorders as a public health priority. Recently enacted legislation requires office-based opioid treatment programs to offer all Food and Drug Administration-approved (FDA) forms of MAT. SCIENTIFIC SIGNIFICANCE: Working with health care providers to effectively deliver MAT is key to integrating behavioral and physical medicine. (Am J Addict 2016;25:603-609).

Baseline characteristics of patients predicting suitability for rapid naltrexone induction.

BACKGROUND AND OBJECTIVES: Extended-release (XR) injection naltrexone has proved promising in the treatment of opioid dependence. Induction onto naltrexone is often accomplished with a procedure known as rapid naltrexone induction. The purpose of this study was to evaluate pre-treatment patient characteristics as predictors of successful completion of a rapid naltrexone induction procedure prior to XR naltrexone treatment. METHODS: A chart review of 150 consecutive research participants (N = 84 completers and N = 66 non-completers) undergoing a rapid naltrexone induction with the buprenorphone-clonidine procedure were compared on a number of baseline demographic, clinical and psychosocial factors. Logistic regression was used to identify client characteristics that may predict successful initiation of naltrexone after a rapid induction-detoxification. RESULTS: Patients who failed to successfully initiate naltrexone were younger (AOR: 1.040, CI: 1.006, 1.075), and using 10 or more bags of heroin (or equivalent) per day (AOR: 0.881, CI: 0.820, 0.946). Drug use other than opioids was also predictive of failure to initiate naltrexone in simple bivariate analyses, but was no longer significant when controlling for age and opioid use level. CONCLUSIONS: Younger age, and indicators of greater substance dependence severity (more current opioid use, other substance use) predict difficulty completing a rapid naltrexone induction procedure. Such patients might require a longer period of stabilization and/or more gradual detoxification prior to initiating naltrexone. SCIENTIFIC SIGNIFICANCE: Our study findings identify specific characteristics of patients who responded positively to rapid naltrexone induction.

A randomized, double-blind, placebo-controlled trial of venlafaxine for the treatment of depressed cocaine-dependent patients.

OBJECTIVE: This study tested the hypothesis that the antidepressant venlafaxine would be an effective treatment for cocaine abusers with concurrent depressive disorders. METHODS: This was a randomized, 12-week, double-blind, placebo-controlled trial of outpatients (N = 130) meeting DSM-IIIR criteria for cocaine dependence and major depression or dysthymia (by SCID interview). Participants were treated with venlafaxine, up to 300 mg/day versus placebo. All patients received weekly individual manual-guided relapse prevention therapy. Weekly outcome measures included Clinical Global Impression Scale (CGI), self-reported cocaine use, urine toxicology and the Hamilton Depression Scale (Ham-D). RESULTS: Mood response, defined as a 50% reduction in the Ham-D between randomization and end of study, was 41% (26/64) on venlafaxine, and 33% (22/66) on placebo (p = .39). Measures of depression (Ham-D and CGI) improved more rapidly on venlafaxine than placebo, but these differences disappeared by weeks 6-8. Cocaine outcomes did not differ between treatment groups, and the proportion of patients achieving three or more consecutive weeks of urine-confirmed abstinence was low (venlafaxine: 16%; placebo: 15%). Reduction in cocaine use was associated with mood response. CONCLUSIONS: Overall, venlafaxine was not superior to placebo on either mood or cocaine use outcomes. Mood improvement was associated with improvement in cocaine use. However, placebo mood response was only moderate, and the proportion of patients achieving sustained abstinence was low. This suggests that the subgroup of cocaine-dependent patients with depressive disorders is relatively treatment resistant, and that further research is needed to improve outcomes for these patients.

Open-label pilot study of quetiapine treatment for cannabis dependence.

BACKGROUND: There are no efficacious pharmacotherapies for cannabis dependence. The effects of quetiapine are well matched to the symptoms of cannabis withdrawal and could be useful in the treatment of cannabis dependence. OBJECTIVES: To evaluate quetiapine for the treatment of cannabis dependence and determine the optimal dosing. METHODS: In an eight-week open-label outpatient pilot trial, we evaluated the feasibility of quetiapine treatment for cannabis dependence in 15 outpatients. Quetiapine was gradually titrated to 600 mg or the maximum tolerated dose. RESULTS: The mean study retention was 6.5 weeks (±2.3), with 67% of participants completing all eight weeks of the trial. The mean maximum dose achieved was 197 mg/day (range: 25-600 mg/day). Only two of the 15 participants were able to achieve the target dose of 600 mg daily. There were no serious adverse events and no participants were discontinued from the trial due to adverse effects. The most common reported adverse effects were fatigue (80% of participants) and somnolence (47%). From baseline to week 8, the modeled overall decrease in daily dollar value of marijuana was 76.3% (CI: 63.4%, 84.7%). Over the eight weeks of the study, there was a 46.9% (CI: 11%, 68.3%) decrease in urine tetrahydrocannabinol-9-carboxylic acid (THCOOH) levels. CONCLUSIONS: These preliminary results are promising in that quetiapine treatment was tolerated by cannabis-dependent patients and associated with decreased cannabis use. The recommended maximum target dose for cannabis-dependent patients is 300 mg daily. These preliminary data support further evaluation of quetiapine as a treatment for cannabis dependence.

Changes in Recovery Capital Among Patients Receiving Buprenorphine Treatment for Opioid Use Disorder in a Telehealth Setting.

BACKGROUND: Medications for the treatment of opioid use disorder (MOUD) such as buprenorphine are the most effective treatment available for OUD; yet, beyond drug testing results and retention in care, systematically measured clinical outcomes have proven elusive. There is growing interest in integrating systematic monitoring of patient-reported outcomes and measurement-based care as strategies to improve patients' success in treatment. METHODS: We analyzed changes in recovery capital assessed via the Brief Assessment of Recovery Capital (BARC-10) from baseline to 30-120 days post-intake among patients initiating buprenorphine treatment from May to October 2023 at Ophelia, a telehealth MOUD provider, who were retained for ≥90 days. Differences in baseline characteristics were assessed between patients with and without high "remission-predictive" baseline scores (≥47) using chi-squared and t-tests. Changes in scores from baseline to follow-up were assessed using paired t-tests. RESULTS: In all, 791 patients initiated treatment during the study period, 742 (93.8%) of whom had a baseline BARC-10 score, 542 (73.0%) of whom were retained in treatment for ≥90 days, and 477 of whom (88.0%) had a follow-up BARC-10 score and represent the analysis sample. Older patients, those not requiring buprenorphine induction, and those not using heroin or fentanyl at intake were more likely to have remission-predictive baseline BARC-10 scores (P < .05). Patients with remission-predictive baseline scores (n = 257) had a mean increase of 1.4 (SD = 5.9) from 52.7 (SD = 4.1) (P < .001), and 234 (91%) sustained remission-predictive scores throughout the assessment period. Patients without remission-predictive baseline scores (n = 220) had a mean increase of 9.2 (SD = 8.2) from 38.4 (SD = 6.6) (P < .001), and 129 (59.0%) achieved a remission-predictive score at follow-up. CONCLUSIONS: Most patients had increased or sustained already high levels of recovery capital, an established predictor of sustained remission. Further research is required to better understand variability across patients and how it may relate to long-term outcomes.

Clinical Implications of the Relationship Between Naltrexone Plasma Levels and the Subjective Effects of Heroin in Humans.

BACKGROUND: Extended-release naltrexone (NTX) is an opioid antagonist approved for relapse prevention after medical withdrawal. Its therapeutic effect is dependent on the NTX plasma level, and as it decreases, patients may lack protection against relapse and overdose. Therefore, identifying the minimally effective NTX level needed to block opioid-induced subjective effects has important clinical implications. METHODS: This secondary, individual-level analysis of data collected in a human laboratory study was conducted to evaluate the relationship between NTX levels and subjective effects of an intravenously administered 25-mg challenge dose of heroin in non-treatment-seeking participants with opioid use disorder (N = 12). Subjective ratings of drug liking using a 100-mm visual analog scale (VAS) and NTX levels were measured across 6 weeks after participants received a single injection of either extended-release NTX 192 mg (N = 6) or 384 mg (N = 6). Cubic spline mixed-effects models were used to provide 95% prediction intervals for individual changes in liking scores as a function of NTX levels. RESULTS: Naltrexone levels above 2 ng/mL blocked nearly all VAS ratings of drug liking after intravenous heroin administration. Participants with NTX levels ≥ 2 ng/mL had minimal (≤20 mm) changes from placebo in VAS ratings of drug liking based on 95% prediction intervals. In contrast, NTX levels < 2 ng/mL were associated with greater variability in individual-level subjective responses. CONCLUSIONS: In clinical practice, a plasma level range of 1 to 2 ng/mL is considered to be therapeutic in providing heroin blockade. The current findings suggest that a higher level (>2 ng/mL) may be needed to produce a consistent blockade.