Opioid vaccine clinical testing: lessons learned.

PURPOSE OF REVIEW: Opioid use disorder (OUD) presents a serious public health concern, with dramatic increases in opioid-overdose mortality in recent years and a small percentage of those with OUD accessing or remaining engaged with available treatments. Efforts are currently underway to identify and vaccines targeting opioids, which could provide a novel and complimentary approach. The current review provides an overview of existing literature, practical considerations for designing and conducting clinical trials with vaccines for opioids, and future directions. RECENT FINDINGS: This review covers the following themes: clinical trial design and selection of endpoints, timepoint selection, practical considerations and lessons learned from the first (ongoing) trial of a vaccine targeting opioids, and future directions. SUMMARY: Efforts to develop and test vaccines targeting OUD are based on a foundation of preclinical work and close collaboration between preclinical and clinical researchers. Efforts to learn from shortcomings of prior clinical trials of vaccines for other substances are essential in designing and testing effective vaccines for OUD. Design and implementation of clinical trials for a vaccine for OUD requires careful balance of participant safety and strategies for retention and efforts to gather viable data to inform future work.

The influence of drug class on reward in substance use disorders.

In the United States, the societal costs associated with drug use surpass $500 billion annually. The rewarding and reinforcing properties that drive the use of these addictive substances are typically examined concerning the neurobiological effects responsible for their abuse potential. In this review, terms such as "abuse potential," "drug," and "addictive properties" are used due to their relevance to the methodological, theoretical, and conceptual framework for understanding the phenomenon of drug-taking behavior and the associated body of preclinical and clinical literature. The use of these terms is not intended to cast aspersions on individuals with substance use disorders (SUD). Understanding what motivates substance use has been a focus of SUD research for decades. Much of this corpus of work has focused on the shared effects of each drug class to increase dopaminergic transmission within the central reward pathways of the brain, or the "reward center." However, the precise influence of each drug class on dopamine signaling, and the extent thereof, differs considerably. Furthermore, the aforementioned substances have effects on several neurobiological targets that mediate and modulate their addictive properties. The current manuscript sought to review the influence of drug class on the rewarding effects of each of the major pharmacological classes of addictive drugs (i.e., psychostimulants, opioids, nicotine, alcohol, and cannabinoids). Our review suggests that even subtle differences in drug effects can result in significant variability in the subjective experience of the drug, altering rewarding and other reinforcing effects. Additionally, this review will argue that reward (i.e., the attractive and motivational property of a stimulus) alone is not sufficient to explain the abuse liability of these substances. Instead, abuse potential is best examined as a function of both positive and negative reinforcing drug effects (i.e., stimuli that the subject will work to attain and stimuli that the subject will work to end or avoid, respectively). Though reward is central to drug use, the factors that motivate and maintain drug taking are varied and complex, with much to be elucidated.

Development and Validation of a Protective Behavioral Strategies Scale for Individuals who use Opioids: Preliminary Findings and Future Directions.

Background: Protective Behavioral Strategies (PBS) are individually implemented harm reduction (HR) strategies to reduce the frequency or severity of risks associated with drug use. Existing scales measuring PBS for alcohol and cannabis suggest PBS are associated with reductions in associated problems. Despite many HR strategies related to opioid use, no PBS scale has been developed in the context of opioid use. To address this gap, this study aimed to test and validate a PBS scale for individuals using opioids (PBSO). Methods: An online survey utilized a 32-item PBS scale for individuals endorsing recent opioid use, and measured opioid use frequency, HR service use, and experience of opioid overdose. PBSO items were rated on a Likert scale ranging from "never" (0) to "always" (6), and an exploratory factor analysis (EFA) examined factor structure. Results: In the current sample (n=499; 32% female), EFA suggested a 3-factor structure among the 28 items retained, accounting for 51% of total variance. Factor 1 reflected health-service seeking, Factor 2 reflected individually-implemented and dose-reduction strategies, Factor 3 reflected social strategies, and Factor 4 reflected strategies related to injection drug use. Endorsement of PBSO items were slightly above "occasional" (3). PBSO use appeared positively related to past-month HR service utilization and negatively related to opioid use frequency. Conclusions: Findings provide preliminary support for the PBSO scale as a valid and reliable measure. Further work is needed to test this scale in larger samples, and future work should explore the association between PBSO and relevant health outcomes, and whether factor scores differentially impact these outcomes.

A pilot study investigating cognitive impairment associated with opioid overdose.

BACKGROUND: In 2021, while overdose (OD) deaths were at the highest in recorded history, it is estimated that >80% of ODs do not result in a fatality. While several case studies have indicated that opioid-related ODs can result in cognitive impairment, the possible association has not yet been systematically investigated. METHODS: 78 participants with a history of OUD who reported experiencing an OD in the past year (n=35) or denied a lifetime history of OD (n=43) completed this study. Participants completed cognitive assessments including the Test of Premorbid Functioning (TOPF) and the NIH Toolbox Cognition Battery (NIHTB-CB). Comparisons were made between those who experienced an opioid-related OD in the past year versus those who denied a lifetime OD history while controlling for factors including age, premorbid functioning, and number of prior ODs. RESULTS: When comparing those who experienced an opioid-related OD within the past year to those without a history of OD, uncorrected standard scores were generally comparable; however, differences emerged in the multivariable model. Specifically, compared to those without a history of OD, those who experienced a past year OD evidenced significantly lower total cognition composite scores (coef. = -7.112; P=0.004), lower crystalized cognition composite scores (coef. = -4.194; P=0.009), and lower fluid cognition composite scores (coef. = -7.879; P=0.031). CONCLUSIONS: Findings revealed that opioid-related ODs may be associated with, or contribute to, reduced cognition. Extent of the impairment appears contingent upon individuals' premorbid intellectual functioning and the cumulative number of past ODs. While statistically significant, clinical significance may be limited given that performance differences (∼4 - 8 points) were not particularly robust. More rigorous investigation is warranted, and future studies must also account for the many other variables possibly contributing to cognitive impairment.

Immunotherapeutic strategies for treating opioid use disorder and overdose.

INTRODUCTION: Development and implementation of effective treatments for opioid use disorder (OUD) and prevention of overdose are urgent public health needs. Though existing medications for OUD (MOUD) are effective, barriers to initiation and retention in treatment persist. Therefore, development of novel treatments, especially those may complement existing treatments, is needed. AREAS COVERED: This review provides an overview of vaccines for substance use disorders (SUD) and mechanisms underlying their function and efficacy. Next, we focus on existing preclinical and clinical trials of SUD vaccines. We focus briefly on related strategies before providing an expert opinion on prior, current, and future work on vaccines for OUD. We included published findings from preclinical and clinical trials found on PubMed and ScienceDirect as well as ongoing or initiated trials listed on ClinicalTrials.gov. EXPERT OPINION: The present opioid overdose and OUD crises necessitate urgent development and implementation of effective treatments, especially those that offer protection from overdose and can serve as adjuvants to existing medications. Promising preclinical trial results paired with careful efforts to develop vaccines that account for prior SUD vaccine shortcomings offer hope for current and future clinical trials of opioid vaccines. Clinical advantages of opioid vaccines appear to outnumber disadvantages, which may result in improved treatment options.

Fentanyl withdrawal: Understanding symptom severity and exploring the role of body mass index on withdrawal symptoms and clearance.

BACKGROUND AND AIMS: Fentanyl is a highly lipophilic mu opioid receptor agonist, increasingly found in heroin and other drug supplies, that is contributing to marked increases in opioid-related overdose and may be complicating treatment of opioid use disorder (OUD). This study aimed to measure the influence of body mass index (BMI) on fentanyl withdrawal and clearance. DESIGN, SETTING, PARTICIPANTS: This secondary analysis, from a 10-day inpatient study on the safety and efficacy of sublingual dexmedetomidine for opioid withdrawal, includes participants with OUD (n = 150) recruited from three sites in New York, New Jersey and Florida, who were maintained on oral morphine (30 mg four times per day) for 5 days before starting study medication. Most participants (n = 118) tested positive for fentanyl on admission to the inpatient unit. MEASUREMENTS: Urine toxicology and opioid withdrawal symptoms [Clinical Opioid Withdrawal Scale (COWS) and Short Opiate Withdrawal Scale (SOWS)] were assessed daily. The present analysis includes data on opioid withdrawal from days 1-5 of stabilization and urine toxicology data from days 1-10. FINDINGS: Fentanyl status at admission was not significantly associated with COWS or SOWS scores after adjusting for sex, site and polysubstance use. Participants classified as overweight or obese (n = 66) had significantly higher odds of testing positive for fentanyl across days 1-10 [odds ratio (OR) = 1.65; P < 0.01] and higher SOWS maximum scores across morphine stabilization (P < 0.05) compared to those with a healthy BMI (n = 68). CONCLUSIONS: Among inpatients with opioid use disorder, fentanyl status does not appear to be statistically significantly associated with Clinical Opioid Withdrawal Scale and Short Opiate Withdrawal Scale mean and maximum scores. High body mass index status (overweight or obese) appears to be an important predictor of slower fentanyl clearance and higher Short Opiate Withdrawal Scale maximum scores across the inpatient period than lower body mass index status.

A Default Option to Improve Nutrition for Adults With Low Income Using a Prefilled Online Grocery Shopping Cart.

OBJECTIVE: To determine whether a prefilled online grocery shopping (default) cart improves the nutritional quality of groceries purchased compared with receiving nutrition education (NE). DESIGN: Longitudinal study. SETTING: Three food pantries in the US. PARTICIPANTS: Thirty-eight adults with low income. INTERVENTION: Groceries were purchased online for 5 consecutive weeks. After a baseline shopping trip, participants were randomized to receive NE or a nutritionally balanced prefilled online grocery shopping cart (ie, default cart) before shopping (from week 1 [T1] to week 4 [T4]). MAIN OUTCOME MEASURES: Diet quality (Healthy Eating Index [HEI-2015] scores), energy, and energy density of each online cart (ie, grocery purchases). ANALYSIS: Piecewise linear mixed-effects models. RESULTS: From baseline to T1, HEI-2015 scores in the default condition significantly increased (95% confidence interval [CI], 9.79-23.39), whereas total calories (95% CI, -10,942 to -1,663) and energy density (95% CI, -0.70 to -0.45) significantly decreased compared with NE. Improved HEI-2015 scores were maintained through T4. Calories and energy density increased from T1 to T4 in the default condition, but values remained lower (ie, more healthful) than the NE condition. In the NE condition, outcomes did not significantly change during the intervention. CONCLUSIONS AND IMPLICATIONS: Providing an online default cart may improve the nutritional quality of grocery purchases. However, future research is warranted to assess whether adding a second nudge later in the intervention or combining the NE and default cart further promotes healthy purchasing behavior.

Impulsivity in cocaine users compared to matched controls: Effects of sex and preferred route of cocaine use.

BACKGROUND: Impulsivity has been identified as playing a role in cocaine use. The purpose of this study was to explore self-report measures of impulsivity in large groups of male and female cocaine users and matched controls and to determine if differences in impulsivity measures within a group of cocaine users related to self-reported money spent on cocaine and route of cocaine use. METHODS: Eight self-report impulsivity measures yielding 34 subscales were obtained in 230 cocaine users (180 M, 50 F) and a matched group of 119 healthy controls (89 M, 30 F). Correlational analysis of the questionnaires revealed 2 factors: Impulsive Action (Factor 1) consisting of many traditional impulsivity measures and Thrill-seeking (Factor 2) consisting of delay discounting, sensation and thrill seeking. RESULTS: Sex influenced within group comparisons. Impulsive Action scores did not vary as a function of sex within either group. But, male controls and male cocaine users had greater Thrill-seeking scores than females within the same group. Sex also influenced between group comparisons. Male cocaine users had greater Impulsive Action scores while female cocaine users had greater Thrill-seeking scores than their sex-matched controls. Among cocaine users, individuals who preferred insufflating ("snorting") cocaine had greater Thrill-seeking scores and lower Impulsive Action scores than individuals who preferred smoking cocaine. Individuals who insufflate cocaine also spent less money on cocaine. CONCLUSIONS: Greater Impulsive Action scores in males and Thrill-seeking scores in females were associated with cocaine use relative to controls.

Factor analysis of a short form of the Protective Behavioral Strategies for Marijuana scale.

OBJECTIVE: The Protective Behavioral Strategies for Marijuana Scale (PBSM), a 17-item scale targeting strategies for mitigating the negative consequences of cannabis use, highlights a range of behaviors that can reduce harm beyond straightforward decreases in quantity or frequency. The 17-item scale's factor structure remains under-examined but could reveal meaningful distinctions among strategies. This study aimed to confirm the factor structure of the short form of the PBSM. METHODS: This study recruited cannabis-using undergraduates (N = 454,Mage = 19.6, 68.8% female, 39% White), who reported using cannabis approximately 2.3 days per week with mild cannabis-related consequences (CAPQ; M = 9.74). RESULTS: A confirmatory factor analysis demonstrated poor fit for the one-factor model of the PBSM, prompting an exploratory factor analysis. Analyses revealed two internally reliable factors: a "Quantity" factor, strategies specific to mitigating overuse and limiting amounts consumed and an "Context" factor loosely related to troubles with others. This two-factor model accounted for over half of the total variance; invariance testing indicated reduced fit as models became more restrictive. Though each of the factors covaried negatively with both days of use and problems, Context had a stronger relation to both variables compared to Quantity. Only Context predicted fewer cannabis problems and use. CONCLUSIONS: The two-factor solution suggests further work on the psychometric properties of the scale could provide heuristic information to allow for more nuanced approaches in clinical and research settings. Theoretically, each factor might have novel links to some constructs but not others in ways that could assist harm-reduction strategies and treatment.

Gender-based differential item functioning in the Cannabis-Associated Problems Questionnaire: A replication and extension.

BACKGROUND: Gender bias in measures of cannabis problems may differentially affect how men and women endorse items. This gender invariance might mask, exaggerate, or otherwise obscure true distinctions in experiences of cannabis consequences. METHODS: The Cannabis-Associated Problems Questionnaire (CAPQ), a measure of interpersonal deficits, occupational impairment, psychological issues, and physical side effects related to cannabis use, contained items with gender-based differential item functioning (DIF) in previous work-a finding we aim to replicate and extend (Lavender, Looby, & Earleywine, 2008). RESULTS: In a sample of 4053 cannabis users, gender differences were apparent in global scores on the CAPQ. A DIF analysis revealed two gender-biased items, including one identified previously. Removal of these items did not significantly alter the scale's relation to cannabis use. Gender differences on the CAPQ persisted after removal of the two problematic items, indicating true gender differences still exist in men and women's experiences of cannabis-related consequences. Gender appeared to significantly contribute to scores on the full CAPQ and the short-form of the CAPQ with biased item removed, even after controlling for indices of cannabis use. CONCLUSIONS: These findings suggest that the CAPQ evidences less gender bias than previously thought, perhaps due to diminishing gender-based stereotypes. Future work might opt to use the short form of the CAPQ to minimize gender-based DIF. In addition, potential biases in measures of substance use problems deserve more attention.

Savoring Moderates the Link between Marijuana Use and Marijuana Problems.

Background: The changing legal landscape for marijuana requires concerted efforts toward minimizing the potential harms related to use of the plant. Purpose/Objectives: Identifying buffers against negative consequences in regular users could help researchers fashion prevention efforts that could appeal to those who are uninterested in messages related to abstinence. Savoring, a positively-focused, mindful approach to making the most of positive experiences, appears to overlap with facets of treatment that have proven successful with problem users. The present study examined the role of savoring in the development of marijuana-related problems. Methods: We examined the potential role of savoring as a buffer against marijuana problems in 195 participants (27.3% female). Results: Participants in this sample used cannabis 3.06 days per week on average. Correlations revealed that problems decreased as savoring increased. In addition, a significant interaction revealed that savoring moderated the impact of frequent use on problems. As savoring increased, the positive association between frequency of use and negative consequences decreased, suggesting that those who are high on savoring experience fewer negative consequences than those who are low on savoring even when they use marijuana as frequently. Conclusions: These data support the idea of incorporating savoring into the prevention of marijuana problems.

Aversiveness and Meaningfulness of Uncomfortable Experiences with Edible Cannabis.

Cannabis remains the most frequently used illicit drug in the United States. As its legal status has changed, more people have turned to oral administration ("edibles"). 172 individuals who reported an uncomfortable experience with edible cannabis completed an online survey. Despite the aversive nature of the experience, 62.9% of the sample reported that the edible experience was at least somewhat meaningful and the majority of participants (95.2%) did not report any medical problems. The most common non-medical problem reported was going to bed early or lying down (75.8%). Most participants (69.2%) reported that dose was the key contributor to their negative experience. Participants who rated the experience as more aversive were less likely to use edibles again, r (167) = - .180, p < . 05. In addition, the duration of the aversive experience correlated positively with aversiveness rating, r (167) = . 244, p < . 05. With increased legalization of cannabis, edible use may rise. Dose seems to be associated with uncomfortable experiences with edible cannabis. Notwithstanding these uncomfortable experiences, the vast majority of the sample used cannabis edibles again, reported that the experience was at least somewhat meaningful, and did not report significant problems associated with the experience.

The Role of Impulsivity and Expectancies in Predicting Marijuana Use: An Application of the Acquired Preparedness Model.

Impulsivity and substance use covary. Smith and Anderson's acquired preparedness model proposes that impulsivity predicts substance use through a mediational model such that substance use expectancies mediate the relation between impulsivity and drug use. The present study seeks to examine the relation between positive urgency, an important component of impulsivity with specific relations to substance use behavior, marijuana expectancies, and marijuana use patterns. The study focused on a sample of frequent marijuana users (n = 3,616) and assessed positive urgency using the UPPS-P, expectancies using the Biphasic Marijuana Effects Scale, an adapted form of the Biphasic Alcohol Effects Scale to measure the sedative and stimulant properties of marijuana, and also assessed use patterns. Findings suggest that stimulant expectancies predict heavier, more frequent marijuana use than sedative expectancies and that marijuana expectancies vary based on the limb of marijuana intoxication. Examination of the acquired preparedness model revealed that positive urgency's link to marijuana use was fully mediated by expectancies.

Cannabis in End-of-Life Care: Examining Attitudes and Practices of Palliative Care Providers.

Medical cannabis research has become quite extensive, with indications ranging from glaucoma to chemotherapy-induced nausea. Despite increased interest in cannabis' potential medical uses, research barriers, cannabis legislation, stigma, and lack of dissemination of data contribute to low adoption for some medical populations. Of interest, cannabis use appears low in palliative care settings, with few guidelines available to palliative care providers. The present study sought to examine the attitudes, beliefs, and practices of palliative care providers regarding the use of cannabis for terminally ill patients. Palliative care providers (N = 426) completed a one-time online survey assessing these attitudes, beliefs, and practices. Results demonstrated that palliative care providers endorse cannabis for a wide range of palliative care symptoms, end-of-life care generally, and as an adjuvant medication. Nevertheless, the gap between these beliefs and actual recommendation or prescription appears vast. Many who support the use of cannabis in palliative care do not recommend it as a treatment. These data suggest recommendations for healthcare providers and palliative care organizations.

Chronic pain and opioid abuse: Factors associated with health-related quality of life.

BACKGROUND AND OBJECTIVES: While research on the separate relationships between health-related quality of life (HRQOL) and chronic pain, and HRQOL and opioid abuse has been sparse, even less work has investigated the factors associated with HRQOL in individuals who have both chronic pain and meet criteria for opioid use disorder. The data presented in this analysis should allow a better understanding the factors important to quality of life among this dual-diagnosed population. METHODS: Individuals with dual diagnoses of chronic pain and opioid use disorder were recruited for clinical research studies at Columbia University Medical Center. Participants (n = 47) completed inventories to assess pain (Brief Pain Inventory), opioid (ab)use, and depression (Beck Depression Inventory). Variable from these and other inventories, along with demographic factors (age, race, sex, pain severity, depressive symptoms, duration of opioid use, route of opioid use, amount of opioid use) were entered into a regression analysis in order to identify the strongest predictors of SF-36 Health Survey score. RESULTS: In the bivariate analysis we found that demographic and drug use variables were rarely associated with HRQOL. Typically, ratings of pain severity and pain interference were the best predictors. In the multivariate analysis, we found that across the several HRQOL dimensions greater Brief Pain Inventory (BPI) ratings of pain "interference" and Beck Depression Inventory (BDI) scores were consistently associated with lower HRQOL. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These data suggest that insufficient pain management and depression are significant variables contributing to lower quality of life among individuals with chronic pain and opioid use disorder. (Am J Addict 2017;26:815-821).

Placebo Effects of Edible Cannabis: Reported Intoxication Effects at a 30-Minute Delay.

Previous research has demonstrated the ability of non-active smoked cannabis cigarettes to induce subjective effects of intoxication (i.e., placebo effect). No studies have been conduced to test whether edible forms of cannabis, which are associated with a significant delay in onset of effect, are able to induce a placebo effect. In the present study, 20 participants were told that they would receive an edible cannabis lollipop containing a high dose of tetrahydrocannabinol (THC), but were instead given a placebo control. Measures of intoxication and mood were taken at baseline, 30 minutes, and 60 minutes post-ingestion of the placebo lollipop. Results of four repeated-measures ANOVAs found significant and quadratic changes across time in cannabis (ARCI m-scale) intoxication (F(2,18) = 4.90, p = .01, η2 = .22) and negative mood (F(2,18) = 3.99, p = .05, η2 = .19). Changes in positive mood and the overall measure of general intoxication (ARCI) failed to reach significance. The present study provides preliminary evidence that a placebo effect can be induced with inert edible agents when participants are told that they are receiving active THC. This is the first known study to demonstrate an edible cannabis intoxication placebo effect.

Racial Differences in HIV and HCV Risk Behaviors, Transmission, and Prevention Knowledge among Non-Treatment-Seeking Individuals with Opioid Use Disorder.

In light of New York's recently reinforced strategy to end the AIDS epidemic by expanding testing, treatment, and access to pre-exposure prophylaxis (PrEP), we assessed drug use and sexual risk behaviors, along with HIV/Hepatitis C virus (HCV) transmission and prevention knowledge among non-treatment-seeking adults with opioid use disorder (OUD) in New York City. Over the course of 18 months, volunteers screening for research studies in the Opioid Laboratory at the New York State Psychiatric Institute completed a locally developed self-assessment questionnaire. A total of 138 adults with OUD (24 female, 114 male) with a mean age of 46.5 years (SD = 9.5 yrs) were assessed. Significant differences among the four racial/ethnic subgroups (n = 65 African-Americans, n = 34 Hispanics, n = 31 Caucasians or Whites, n = 8 Multiracial) were found. Whites were the youngest (p = 0.001), most frequently injecting drugs (p < 0.001), and engaged more often in risky drug use and sexual behaviors, although their virus transmission knowledge was comparable to that of the other subgroups. Few participants had heard about PrEP. White opioid users showed the most risk behaviors among races/ethnicities, despite comparable prevention knowledge. Better HIV/HCV prevention interventions targeting individuals with opioid use disorders who are not currently in treatment would be desirable, given their large health burden.

The effects of heroin administration and drug cues on impulsivity.

Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and continued use despite negative consequences. Behavioral impulsivity is a strong predictor of the initiation and maintenance of drug addiction. Preclinical data suggest that heroin may exacerbate impulsive characteristics in an individual but this has yet to be assessed in clinical samples. The current secondary data analysis sought to investigate the effects of heroin on impulsivity along with the effects of exposure to drug cues. Using the current data set, we also tentatively assessed the etiological relationship between impulsivity and heroin abuse. Sixteen heroin-dependent participants were recruited to complete Immediate Memory Task/Delayed Memory Task (IMT/DMT) and GoStop tasks following repeated heroin administration, following acute heroin administration, and following a drug cue exposure session. Four preceding days of active heroin availability, compared to four preceding days of placebo drug availability, increased impulsivity assessed using the IMT and DMT. Presentation of drug cues similarly acted to increase impulsivity assessments on all three tasks. It also appears that heavier users were more susceptible to the influence of drug cues on impulsivity. The present study represents a step toward a more comprehensive understanding of the interaction between opioid abuse and impulsivity. A better understanding of these factors could provide critical insight into the maintenance of heroin use and relapse.