Pharmacotherapies For Substance Use Disorders Research Articles

Neuroimmune modulators as novel pharmacotherapies for substance use disorders

One promising avenue of research is the use of neuroimmune modulators to treat substance use disorders (SUDs). Neuroimmune modulators target the interactions between the nervous system and immune system, which have been found to play a crucial role in the development and maintenance of SUDs. Multiple classes of substances produce alterations to neuroimmune signaling and peripheral immune function, including alcohol, opioids, and psychostimulants Preclinical studies have shown that neuroimmune modulators can reduce drug-seeking behavior and prevent relapse in animal models of SUDs. Additionally, early-phase clinical trials have demonstrated the safety and feasibility of using neuroimmune modulators as a treatment for SUDs in humans. These therapeutics can be used as stand-alone treatments or as adjunctive. This review summarizes the current state of the field and provides future directions with a specific focus on personalized medicine.

1.70 AACAP Medication Tables Summarizing and Grading Research on Pharmacotherapy for Substance Use Disorders in Children and Adolescents

1.70 AACAP Medication Tables Summarizing and Grading Research on Pharmacotherapy for Substance Use Disorders in Children and Adolescents

Project Harmony: A Meta-Analysis With Individual Patient Data on Behavioral and Pharmacologic Trials for Comorbid Posttraumatic Stress and Alcohol or Other Drug Use Disorders.

Treatment efficacy for co-occurring posttraumatic stress disorder (PTSD) and substance use disorders is well established, yet direct evidence for comparative effectiveness across treatments is lacking. The present study compared the effectiveness of several behavioral and pharmacological therapies for adults with co-occurring PTSD and alcohol or other drug use disorders. A systematic search of PsycINFO, MEDLINE, and ClinicalTrials.gov was conducted through December 2020 for trials targeting PTSD, alcohol or other drug use disorders, or both disorders (36 studies, N=4,046). Primary outcomes were severity scores for PTSD, alcohol use, and drug use, estimated via moderated nonlinear factor analysis. Propensity score weight-adjusted multilevel models were used. Model-predicted effect sizes were estimated for each treatment, and comparative effect sizes for each active arm against treatment as usual, at end of treatment and at 12-month follow-up. Compared with treatment as usual, combining trauma-focused therapy and pharmacotherapy for substance use disorders showed the largest comparative effect sizes for PTSD severity (d=-0.92, 95% CI=-1.57, -0.30) and alcohol use severity (d=-1.10, 95% CI=-1.54, -0.68) at end of treatment. Other treatments with large comparative effect sizes included pharmacotherapies for alcohol or other drug use disorders, trauma-focused integrated therapies, and trauma-focused nonintegrated therapies. Reductions in outcomes for PTSD symptoms and alcohol use were observed for nearly all treatments. The findings provide support for treating comorbid PTSD and substance use disorders using a variety of approaches, with alcohol-targeted pharmacotherapies and trauma-focused behavioral therapies as a combination of treatments that lead to early and sustained improvements in PTSD and alcohol use severity. Further treatment development is indicated for combining behavioral and pharmacological treatments for synergized impact and understanding the mechanisms of action and conditions under which each treatment type is optimized.

Neutral CB1 Receptor Antagonists as Pharmacotherapies for Substance Use Disorders: Rationale, Evidence, and Challenge.

Cannabinoid receptor 1 (CB1R) has been one of the major targets in medication development for treating substance use disorders (SUDs). Early studies indicated that rimonabant, a selective CB1R antagonist with an inverse agonist profile, was highly promising as a therapeutic for SUDs. However, its adverse side effects, such as depression and suicidality, led to its withdrawal from clinical trials worldwide in 2008. Consequently, much research interest shifted to developing neutral CB1R antagonists based on the recognition that rimonabant’s side effects may be related to its inverse agonist profile. In this article, we first review rimonabant’s research background as a potential pharmacotherapy for SUDs. Then, we discuss the possible mechanisms underlying its therapeutic anti-addictive effects versus its adverse effects. Lastly, we discuss the rationale for developing neutral CB1R antagonists as potential treatments for SUDs, the supporting evidence in recent research, and the challenges of this strategy. We conclude that developing neutral CB1R antagonists without inverse agonist profile may represent attractive strategies for the treatment of SUDs.

Research Participation in Substance Use Disorder Trials: Design and Methods of a Multi-Site Nested Qualitative Study

Background Given the health and social harms of problematic substance use, randomized controlled trials (RCTs) are critical in developing and testing pharmacotherapies for substance use disorders. However, substance use RCTs can be challenging to conduct, considering the social and structural barriers to participating in research among people with substance use disorders (PSUD), including stigma, poverty, and criminalization—factors that can shape trial recruitment, enrollment, protocol adherence and study retention. Despite these barriers, adequate representation and participation of PSUD in RCT research is essential to assessing and developing treatments, and thus a deeper understanding of RCT participation dynamics among PSUD is needed to support clinical trial research. Methods We conducted a nested qualitative study within a Canadian, multisite, phase IV, open-label, pragmatic RCT that tested two approved opioid agonist treatments, methadone and buprenorphine/naloxone, among patients with prescription opioid use disorder. A subset of individuals ( n = 60) participating in this RCT were interviewed across four different regions in Canada at the beginning and end of their trial involvement, as well as study clinicians ( n = 16) and staff ( n = 16) operating the trial. Conclusion As a nested study within a real-world addiction medicine trial, this research offers an innovative approach to investigating the experiences, strategies, and challenges associated with RCTs among PSUD. While we acknowledge challenges related to the operations of multisite research and engaging marginalized populations in experimental research, this study has the potential to generate critical insights around the RCT experiences of PSUDs and trial staff to inform the conduct of future RCTs.

Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders.

Over three decades of evidence indicate that dopamine (DA) D3 receptors (D3R) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective D3R antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, D3R are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the D3R system. Third, the synthesis and characterization of highly potent and selective D3R antagonists/partial agonists have further strengthened the role of the D3R in SUD. Based on extensive preclinical and preliminary clinical evidence, the D3R shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective D3R antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective D3R antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.

Trust in research physicians as a key dimension of randomized controlled trial participation in clinical addictions research

Background: In the development of pharmacotherapies for substance use disorders, willingness to participate in randomized controlled trials (RCTs) among people who use drugs (PWUD) is influenced by numerous social and structural factors. Considering the criminalization and stigma experienced by PWUD and range of experiences in healthcare and research, PWUD may vary in their trust of health providers, health research physicians, or medical research processes. We therefore examine associations between trust in these three domains and willingness to participate in a hypothetical RCT for a novel pharmacotherapy for stimulant use among PWUD. Methods: Data were derived from a cross-sectional questionnaire administered to participants using crack and/or cocaine from three cohort studies of PWUD in Vancouver (N = 229). Results: A majority of participants were “definitely” or “probably” willing to participate in an RCT. In multivariable ordinal regression, trust in research physicians was positively associated with willingness to participate, while trust in primary care providers or medical research processes were not significantly associated. Conclusions: This data suggests trust in research physicians plays a role in RCT decision-making among PWUD, while trust in healthcare providers and research processes appears less relevant. These findings highlight opportunities for supporting RCT recruitment by building trust in research physicians.

Professional education to reduce provider stigma toward harm reduction and pharmacotherapy

Aims A novel professional training was developed to reduce stigma toward harm reduction and pharmacotherapy for substance use disorders. Methods The training was delivered over three sessions to n = 147 health professionals in Utah between 2019 and 2020, including n = 40 substance use disorder treatment professionals. Pre and post-training survey measures provided evaluation information on knowledge, attitudes, and planned action regarding harm reduction and pharmacotherapy. Items were grouped into a stigma score, and multilevel modeling, regression analyses, and McNemar tests were used to quantify changes in overall stigma toward harm reduction interventions both before and after the training. Results The training significantly decreased the total stigma score toward harm reduction (b = −0.09, p < .001, β = −0.34). At the individual item level, 6 of the 22 items showed significant change in reduced stigma (all p < .047), and all items moved in the direction of decreased stigma. These items include both attitudes and planned action aspects of the total stigma score. Conclusions This study suggests that education targeting prejudice and discriminatory actions against harm reduction and pharmacotherapy interventions among healthcare professionals may contribute to stigma reduction. These results provide a basis for intervention effectiveness, addressing preconceived ideas, and show community need for such substance use interventions, as a component of future stigma reduction efforts.

Pharmacotherapy of substance use disorders in the neuroscience-based nomenclature (NbN)

In the field of substance use disorders (SUDs), medications are frequently labeled according to their main symptomatic effect (e.g., "anticraving drugs") or according to imprecise and sometimes old concepts related to treatment strategies (e.g., "replacement therapies", "antabuse drugs", or "substitution treatments"). By contrast, the neuroscience-based nomenclature (NbN) offers a clearer and more consistent rationale, according to which the main element of classification is based on the pharmacological mode of action of the medication. This review aims to display the different approved treatments used in SUDs, and to discuss the pros and cons of using this new conceptual framework in the field of addiction. According to the NbN classification, medications approved in the different SUDs can be classified in the different following categories: 1) nicotinic drugs; 2) GABAergic drugs; 3) opioid drugs; and 4) others. More specifically, medications can be distinguished between whether they mimic the same pharmacological action of the "substance" whose use should be stopped or reduced, or whether they target other more general pharmacological systems, that are supposed to be common to all SUDs, as they reflect the "universal" addiction process. The NbN offers obvious advantages, compared with previous classifications. In particular, it allows to no longer mix drugs with very different pharmacological targets under the same label. The main limitation of the NbN, when applied to psychopharmacology in general, and to SUDs medications in particular, is that drugs frequently have a "dirty" action, with multiple pharmacological targets. In this respect, it may be hard to classify drugs according to the NbN classification, without making the individual profile of each medicine more complex.

671: Healthcare care providers’ roles and attitudes towards substance use disorder during pregnancy

Patients with substance use disorders (SUD) may be stigmatized by healthcare providers, leading to delayed care and worse outcomes. We assessed attitudes toward SUD as a potential barrier to care during and after pregnancy by provider role. The Collaborative Values Inventory from the National Center on Substance Abuse and Child Welfare was distributed to inpatient and outpatient staff at a tertiary care center for women and infants from July-Sept 2018. Self-reported interaction with pregnant, postpartum, or newborn patients was a criterion for participation. The 57-item survey addressed drug testing, parenting, child removal/reunification, treatment/relapse, SUD as a disease, and confidence in the response to SUD. Respondents were classified based on their self-reported role: 1) MD/NP 2) RN 3) PCT/Other [patient care technicians, surgical technicians, ultrasound technicians, respiratory therapists] or 4) Clerical staff. Groups were compared using chi square or analysis of variance (ANOVA) tests as appropriate. Of 942 employees, 237 (25%) responded. Exposure groups differed in terms of age, race, years of experience, and gender. The majority of respondents supported universal drug screening of pregnant women and infants, though MD/NP were less likely to endorse universal screening or to view drug screens as the best indicator of recovery (Fig 1). While >90% reported SUD is a disease, MD/NP were more likely to support pharmacotherapy for SUD during pregnancy and recognize that treatment beyond pharmacotherapy and withdrawal management is needed (Fig 2). Although the majority of respondents recognized SUD as a disease, responses regarding treatment highlight discrepancies in perception of the need for pharmacotherapy and indications for drug testing. Educational efforts should be targeted based on providers’ roles in an aim to improve uniformity around an evidence-based approach to SUD treatment during pregnancy among different provider types.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Neuroimmune mechanisms of psychostimulant and opioid use disorders.

Substance use disorders are global health problems with few effective treatment options. Unfortunately, most potential pharmacological treatments are hindered by abuse potential of their own, limited efficacy, or adverse side effects. As a consequence, there is a pressing need for the development of addiction treatments with limited abuse potential and fewer off target effects. Given the difficulties in developing new pharmacotherapies for substance use disorders, there has been growing interest in medications that act on non-traditional targets. Recent evidence suggests a role for dysregulated immune signaling in the pathophysiology of multiple psychiatric diseases. While there is evidence that immune responses in the periphery and the central nervous system are altered by exposure to drugs of abuse, the contributions of neuroimmune interactions to addictive behaviors are just beginning to be appreciated. In this review, we discuss the data on immunological changes seen in clinical populations with substance use disorders, as well as in translational animal models of addiction. Importantly, we highlight those mechanistic findings showing causal roles for central or peripheral immune mediators in substance use disorder and appropriate animal models. Based on the literature reviewed here, it is clear that brain-immune system interactions in substance use disorders are much more complex and important than previously understood. While much work remains to be done, there are tremendous potential therapeutic implications for immunomodulatory treatments in substance use disorders.

McCance-Katz Leads Effort to Focus SAMHSA on Serious Mental Illness

McCance-Katz Leads Effort to Focus SAMHSA on Serious Mental Illness

Minding the brain: the role of pharmacotherapy in substance-use disorder treatment

With its medicalization as a brain-based disease, addiction has come to be regarded as amenable to biomedical treatment approaches, most commonly pharmacotherapy. Various vulnerabilities are recognized to contribute to maladaptive substance use, and have been linked to diverse neurobiological alterations that may be targeted with pharmacotherapy: withdrawal, craving and cue reactivity, and aberrant reward processing are the most significant. Here, we summarize current thinking regarding pharmacotherapy for substance-use disorders, grouping medications by the type of vulnerability they propose to address and providing insight into their neurobiological mechanisms. We also examine the limitations of the brain-based disease model in addiction treatment, especially as these shortcomings pertain to the place of pharmacotherapy in recovery. We conclude by sketching a framework whereby medications might be integrated fruitfully with other interventions, such as behavioral, existential, or peer-based treatments, targeting aspects of addiction beyond neurobiological deficits.

Current and Promising Pharmacotherapies for Substance Use Disorders among Justice-Involved Populations

Growing recognition of the biological underpinnings of substance use disorders (SUDs) has led to increased acceptance of pharmacotherapy-based treatments for general populations and, more recently, for individuals under criminal justice supervision, including those in correctional settings. This paper focuses on pharmacotherapies that have been approved by the United States Food and Drug Administration (FDA) for treatment of alcohol use disorder and opioid use disorder. For alcohol use disorder, these medications are disulfiram, naltrexone, and acamprosate; for opioid use disorder, these are methadone, buprenorphine, and naltrexone. Promising pharmacotherapies for stimulant use disorder are also briefly summarized. The paper concludes with three “lessons learned,” specifically: (1) treatment and policy should reflect the fact that substance misuse and addiction is a medical disorder, (2) interventions for SUDs should be integrated into primary care, and (3) reductions in substance use among pharmacotherapy-treated patients do not necessarily lead to concomitant reductions in crime (nor should this be the primary rationale for providing such treatment).

Utility of Nonhuman Primates in Substance Use Disorders Research.

Substance use disorders (i.e., drug addiction) constitute a global and insidious public health issue. Preclinical biomedical research has been invaluable in elucidating the environmental, biological, and pharmacological determinants of drug abuse and in the process of developing innovative pharmacological and behavioral treatment strategies. For more than 70 years, nonhuman primates have been utilized as research subjects in biomedical research related to drug addiction. There are already several excellent published reviews highlighting species differences in both pharmacodynamics and pharmacokinetics between rodents and nonhuman primates in preclinical substance abuse research. Therefore, the aim of this review is to highlight three advantages of nonhuman primates as preclinical substance abuse research subjects. First, nonhuman primates offer technical advantages in experimental design compared to other laboratory animals that afford unique opportunities to promote preclinical-to-clinical translational research. Second, these technical advantages, coupled with the relatively long lifespan of nonhuman primates, allows for pairing longitudinal drug self-administration studies and noninvasive imaging technologies to elucidate the biological consequences of chronic drug exposure. Lastly, nonhuman primates offer advantages in the patterns of intravenous drug self-administration that have potential theoretical implications for both the neurobiological mechanisms of substance use disorder etiology and in the drug development process of pharmacotherapies for substance use disorders. We conclude with potential future research directions in which nonhuman primates would provide unique and valuable insights into the abuse of and addiction to novel psychoactive substances.

Linear-rank testing of a non-binary, responder-analysis, efficacy score to evaluate pharmacotherapies for substance use disorders.

The design of pharmacological trials for management of substance use disorders is shifting toward outcomes of successful individual-level behavior (abstinence or no heavy use). While binary success/failure analyses are common, McCann and Li (CNS Neurosci Ther 2012; 18: 414-418) introduced "number of beyond-threshold weeks of success" (NOBWOS) scores to avoid dichotomized outcomes. NOBWOS scoring employs an efficacy "hurdle" with values reflecting duration of success. Here, we evaluate NOBWOS scores rigorously. Formal analysis of mathematical structure of NOBWOS scores is followed by simulation studies spanning diverse conditions to assess operating characteristics of five linear-rank tests on NOBWOS scores. Simulations include assessment of Fisher's exact test applied to hurdle component. On average, statistical power was approximately equal for five linear-rank tests. Under none of conditions examined did Fisher's exact test exhibit greater statistical power than any of the linear-rank tests. These linear-rank tests provide good Type I and Type II error control for comparing distributions of NOBWOS scores between groups (e.g. active vs. placebo). All methods were applied to re-analyses of data from four clinical trials of differing lengths and substances of abuse. These linear-rank tests agreed across all trials in rejecting (or not) their null (equality of distributions) at ≤ 0.05.

Pharmacotherapy for Substance Use Disorders in Youths

ABSTRACTDespite recent advances in psychosocial treatments targeting adolescent substance use disorders (SUD), effect sizes generally remain small to modest, and few treatment-enrolled youths achieve sustained abstinence. Among adults, SUD-targeted pharmacotherapies have emerged as viable options to complement psychosocial treatments and enhance outcomes. Developmental differences exist in pharmacodynamics and treatment response, and comparatively little research has focused on SUD-targeted pharmacotherapies for youths. This article provides a review and synthesis of relevant published clinical trials focusing on youth SUDs and co-occurring/comorbid psychiatric and substance use disorders. It offers recommendations for clinical practice and further research based on the limited findings to date.

Animal Models and the Development of Vaccines to Treat Substance Use Disorders.

The development of pharmacotherapies for substance use disorders (SUDs) is a high priority in addiction research. At present, there are no approved pharmacotherapies for cocaine and methamphetamine use disorders, while treatments for nicotine and opioid use are moderately effective. Indeed, many of these treatments can cause adverse drug side effects and have poor medication compliance, which often results in increased drug relapse rates. An alternative to these traditional pharmacological interventions is immunotherapy or vaccines that can target substances associated with SUDs. In this chapter, we discuss the current knowledge on the efficacy of preclinical vaccines, particularly immunogens that target methamphetamine, cocaine, nicotine, or opioids to attenuate drug-induced behaviors in animal models of SUDs. We also review vaccines (and antibodies) against cocaine, nicotine, and methamphetamine that have been assessed in human clinical trials. While preclinical studies indicate that several vaccines show promise, these findings have not necessarily translated to the clinical population. Thus, continued effort to design more effective vaccine immunogens using SUD animal models is necessary in order to support the use of immunotherapy as a viable option for individuals with SUDs.

A collaborative opioid prescribing (CoOP) model linking opioid treatment programs with office-based buprenorphine providers

Background Despite abundant research demonstrating good efficacy, pharmacotherapies for substance use disorders are underutilized. Buprenorphine holds promise to significantly increase the availability of medication-assisted therapy for opioid use disorder; yet despite dramatic increases in overdose deaths driven largely by prescription opioid use, only about half of DATA-waivered physicians prescribe buprenorphine.

Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders

There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs.