Steven Sparenborg

The First Decade of the National Drug Abuse Treatment Clinical Trials Network: Bridging the Gap Between Research and Practice to Improve Drug Abuse Treatment

The National Institute on Drug Abuse established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999 to improve the quality of addiction treatment using science as the vehicle. The network brings providers from community-based drug abuse treatment programs and scientists from university-based research centers together in an alliance that fosters bidirectional communication and collaboration. Collaboration enhanced the relevance of research to practice and facilitated the development and implementation of evidence-based treatments in community practice settings. The CTNs 20 completed trials tested pharmacological, behavioral, and integrated treatment interventions for adolescents and adults; more than 11,000 individuals participated in the trials. This article reviews the rationale for the CTN, describes the translation of its guiding principles into research endeavors, and anticipates the future evolution of clinical research within the Network.

From research to the real world: buprenorphine in the decade of the Clinical Trials Network.

The National Institute on Drug Abuse (NIDA) established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999 to bring researchers and treatment providers together to develop a clinically relevant research agenda. Initial CTN efforts addressed the use of buprenorphine, a mu-opioid partial agonist, as treatment for opioid dependence. Strong evidence of buprenorphines therapeutic efficacy was demonstrated in clinical trials involving several thousand opioid-dependent participants, and in 2002, the Food and Drug Administration approved buprenorphine for the treatment of opioid dependence. With the advent of a sublingual tablet containing both buprenorphine and naloxone to mitigate abuse and diversion (Suboxone), buprenorphine appeared poised to be the first-line treatment for opioid addiction. Notwithstanding its many attributes, certain implementation barriers remained to be addressed in CTN studies, and these efforts have brought a body of knowledge on buprenorphine to frontline clinicians. The purpose of this article is to review CTN-based buprenorphine research and related efforts to overcome challenges to the implementation of buprenorphine therapy in mainstream practice. Furthermore, this article explores current issues and future challenges that may require additional CTN efforts.

Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis

Cannabidiol (CBD), a constituent of cannabis with few psychoactive effects, has been reported in some studies to attenuate certain aspects of Δ9-tetrahydrocannabinol (THC) intoxication. However, most studies have tested only one dose of CBD in combination with one dose of oral THC, making it difficult to assess the nature of this interaction. Further, the effect of oral CBD on smoked cannabis administration is unknown. The objective of this multi-site, randomized, double-blind, within-subject laboratory study was to assess the influence of CBD (0, 200, 400, 800 mg, p.o.) pretreatment on the reinforcing, subjective, cognitive, and physiological effects of smoked cannabis (0.01 (inactive), 5.30–5.80% THC). Non-treatment-seeking, healthy cannabis smokers (n=31; 17M, 14 F) completed eight outpatient sessions. CBD was administered 90 min prior to cannabis administration. The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session. A subset of participants (n=8) completed an additional session to measure plasma CBD concentrations after administration of the highest CBD dose (800 mg). Under placebo CBD conditions, active cannabis (1) was self-administered by significantly more participants than placebo cannabis and (2) produced significant, time-dependent increases in ratings of ‘High’, ‘Good Effect’, ratings of the cannabis cigarette (eg, strength, liking), and heart rate relative to inactive cannabis. CBD, which alone produced no significant psychoactive or cardiovascular effects, did not significantly alter any of these outcomes. Cannabis self-administration, subjective effects, and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules. These findings suggest that oral CBD does not reduce the reinforcing, physiological, or positive subjective effects of smoked cannabis.

Peripheral cocaine-blocking agents : new medications for cocaine dependence : An introduction to immunological and enzymatic approaches to treating cocaine dependence reported by Fox, Gorelick and Cohen in the immediately succeeding articles

Enzymes, antibodies and ethics were the topics of discussion in a panel presentation at the American Society of Addiction Medicine (ASAM) Annual Meeting in Atlanta, Georgia on April 20, 1996. The presentations were part of a day-long symposium sponsored by the National Institute on Drug Abuse (NIDA). Immunological and enzymatic approaches to medical treatment for cocaine dependence and abuse were discussed in this venue to introduce physicians to new concepts being developed with the support of NIDA’s Medications Development Division. Cocaine’s euphoric and rewarding effects result from activity within the brain. This central site of action has traditionally led researchers to look for antidotes that also act centrally, especially on dopamine neurotransmission in the forebrain. Because cocaine increases the extracellular concentration of dopamine in the brain, it is reasonable to expect that dopamine antagonists acting at forebrain neuroreceptors would block its effects. In contrast, the methods discussed in this session were designed to stop cocaine in the plasma before it enters the brain, thus acting as peripheral cocaine-blocking agents (PCBAs). The three new medical approaches highlighted in this immunological/enzymatic session involve the recruitment of natural biological processes to resist cocaine. Each of these approaches should alter the pharmacokinetics of cocaine which presumably will correspondingly modulate cocaine’s actions in the central nervous system (CNS).

Improving drug abuse treatment delivery through adoption of harmonized electronic health record systems

A great divide currently exists between mainstream health care and specialty substance use disorders (SUD) treatment, concerning the coordination of care and sharing of medical information. Improving the coordination of SUD treatment with other disciplines of medicine will benefit SUD patients. The development and use of harmonized electronic health record systems (EHR) containing standardized person-level information will enable improved coordination of healthcare services. We attempt here to illuminate the urgent public health need to develop and implement at the national level harmonized EHR including data fields containing standardized vocabulary/terminologies relevant to SUD treatment. The many advantages and barriers to harmonized EHR implementation in SUD treatment service groups, and pathways to their successful implementation, are also discussed. As the US Federal Government incentivizes Medicare and Medicaid Service providers nationwide for “meaningful use” of health information technology (HIT) systems, relevant stakeholders may face relatively large and time-consuming processes to conform their local practices to meet the federal government’s “meaningful use” criteria unless they proactively implement data standards and elements consistent with those criteria. Incorporating consensus-based common data elements and standards relevant to SUD screening, diagnosis, and treatment into the federal government’s “meaningful use” criteria is an essential first step to develop necessary infrastructure for effective coordination of HIT systems among SUD treatment and other healthcare service providers to promote collaborative-care implementation of cost-effective, evidence-based treatments and to support program evaluations.

A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults

BACKGROUND Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults. METHODS In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18-50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200mg (n=153) or placebo (n=149) twice daily. All participants received contingency management (CM) and medical management. The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment, compared between NAC and placebo participants. RESULTS There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence (odds ratio=1.00, 95% confidence interval 0.63-1.59, p=0.984). Overall, 22.3% of urine cannabinoid tests in the NAC group were negative, compared with 22.4% in the placebo group. Many participants were medication non-adherent; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group. CONCLUSIONS In contrast with prior findings in adolescents, there is no evidence that NAC 1200mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM. This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development, cannabis use profiles, responses to embedded behavioral treatment, medication adherence, and other factors.

Evaluation of buspirone for relapse-prevention in adults with cocaine dependence: an efficacy trial conducted in the real world.

Cocaine dependence is a significant public health problem for which there are currently no FDA-approved medications. Hence, identifying candidate compounds and employing an efficient evaluation process is crucial. This paper describes key design decisions made for a National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) study that uses a novel two-stage process to evaluate buspirone (60 mg/day) for cocaine-relapse prevention. The study includes pilot (N=60) and full-scale (estimated N=264) trials. Both trials will be randomized, double-blind, and placebo-controlled and both will enroll treatment-seeking cocaine-dependent participants engaged in inpatient/residential treatment and scheduled for outpatient treatment post-discharge. All participants will receive contingency management in which incentives are given for medication adherence as evaluated by the Medication Events Monitoring System (MEMS). The primary outcome measure is maximum days of continuous cocaine abstinence, as assessed by twice-weekly urine drug screens (UDS) and self-report, during the 15-week outpatient treatment phase. Drug-abuse outcomes include cocaine use as assessed by UDS and self-report of cocaine use, other substance use as assessed by UDS and self-report of substance use (i.e., alcohol and/or illicit drugs), cocaine bingeing, HIV risk behavior, quality of life, functioning, and substance abuse treatment attendance. Unique aspects of the study include conducting an efficacy trial in community treatment programs, a two-stage process to efficiently evaluate buspirone, and an evaluation of mediators by which buspirone might exert a beneficial effect on relapse prevention.

Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers

BACKGROUND Cannabidiol (CBD) is a naturally occurring constituent of the marijuana plant. In the past few years, there has been great interest in the therapeutic effects of isolated CBD and it is currently being explored for numerous disease conditions (e.g., pain, epilepsy, cancer, various drug dependencies). However, CBD remains a Schedule I drug on the U.S. Controlled Substances Act (CSA). Despite its status, there are no well-controlled data available regarding its abuse liability. METHODS Healthy, frequent marijuana users (n=31) were enrolled in this within subject, randomized, placebo-controlled, double-blind, multisite study that administered oral cannabidiol (0, 200, 400, 800mg) alone and in combination with smoked marijuana (0.01%, 5.3-5.8% THC). Participants received one dose combination across 8 once-weekly outpatient sessions (7.5h). The primary findings on the drug interaction effects were previously reported (Haney et al., 2016). The present study is a secondary analysis of the data to examine the abuse liability profile of oral cannabidiol (200, 400, 800mg) in comparison to oral placebo and active smoked marijuana (5.3-5.8% THC). RESULTS Active marijuana reliably produced abuse-related subjective effects (e.g., high) (p<0.05). However, CBD was placebo-like on all measures collected (p>0.05). CONCLUSIONS Overall, CBD did not display any signals of abuse liability at the doses tested and these data may help inform U.S. regulatory decisions regarding CBD schedule on the CSA.

The National Drug Abuse Treatment Clinical Trials Network: forging a partnership between research knowledge and community practice.

The National Drug Abuse Treatment Clinical Trials Network (CTN) has faced many challenges over its first eleven years. This review explores some of these challenges and the paths the CTN took to meet these challenges, including: designing clinical trials that reflect the CTN’s mission and changing public health needs, finding the synergies in the varied expertise of clinical treatment providers and academic researchers, promoting evidence-based practices and expanding the Network into mainstream medical practices to reach a broader patient population. Included in this exploration are specific examples from CTN clinical trials.

Baseline characteristics and treatment outcomes in prescription opioid dependent patients with and without co-occurring psychiatric disorder

Abstract Background: Given the growing prevalence of prescription opioid dependence and the considerable rates of additional psychopathology in drug dependence, we examined the association between the presence of a co-occurring Axis I psychiatric disorder and sociodemographic and clinical characteristics in this secondary analysis of patients entering a treatment study for dependence on prescription opioids. Treatment outcomes were also compared. Methods: Patients dependent on prescription opioids participated in a multi-site, two-phase, randomized, controlled trial to assess different lengths of buprenorphine-naloxone pharmacotherapy and different intensities of counseling (Clinicaltrials.gov identifier: NCT00316277). Among the 653 participants entering the first phase of the trial, 360 entered the second phase, receiving 12 weeks of buprenorphine-naloxone treatment; they are reported here. Half of those participants (180/360) had a current co-occurring psychiatric disorder in addition to substance dependence. Results: Sociodemographic characteristics were similar overall between those with and without a co-occurring psychiatric disorder, but women were 1.6 times more likely than men to have a co-occurring disorder. On several clinical indicators at baseline, participants with a co-occurring disorder had greater impairment. However, they had better opioid use outcomes at the conclusion of 12 weeks of buprenorphine-naloxone stabilization than did participants without a co-occurring disorder. Conclusions: Prescription opioid–dependent patients with a co-occurring psychiatric disorder had a better response to buprenorphine-naloxone treatment despite demonstrating greater impairment at baseline. Additional research is needed to determine the mechanism of this finding and to adapt treatments to address this population.