Resilience Phenotypes and Psychological Functioning among Individuals with Opioid Use Disorder.

BACKGROUND: Opioid use disorder (OUD) is a heterogeneous disorder. However, there is a lack of deep phenotyping investigations focusing on important psychological constructs such as resilience that may impact OUD. The present study aimed to investigate the relationship between trait resilience and the five-factor model of personality (FFM) among individuals with opioid use disorder (OUD). We also explored whether the FFM and trait resilience form specific phenotypes associated with psychological functioning. METHODS: This secondary analysis of an epigenetic study included participants of African ancestry (n = 72), an understudied population, who met DSM-5 criteria for OUD. Participants completed measures to assess personality traits, trait resilience, current and previous drug use, and psychological functioning (depression, anxiety, and stress). RESULTS: Linear regression revealed a significant relationship between resilience (CD-RISC-25 score) and the FFM, R2 = 0.56, F(5,62) = 15.7, p<.001. Further, a two-cluster classification emerged as the optimal solution from the cluster analysis. Cluster 1 (n = 33, 45.8% of the sample) showed lower resilience (CD-RISC-25 score: M = 58.6, SD = 11.2) compared to Cluster 2 (n = 35, 48.6%; CD-RISC-25 score: M = 76.1, SD = 11.9). The "High-Resilience Cluster" (Cluster 2) was characterized by higher FFM traits of: Extraversion, Openness, Agreeableness, and Conscientiousness, and lower Neuroticism versus Cluster 1. Multivariate analysis of variance revealed statistically significant differences between the two resilience clusters concerning other psychological symptoms, Λ = 0.732, F(4, 50) = 7.05, p < 0.003. CONCLUSIONS: These findings suggest associations between the FFM and trait resilience among individuals with OUD. Two distinct "resilience phenotypes" emerged, with high-resilience individuals displaying less stress, anxiety, and depressive symptoms. Results highlight the clinical importance of resilience as a potential target for intervention in people with OUD.

A pilot study examining the relationship between chronic heroin use and telomere length among individuals of African ancestry.

BACKGROUND: Prior research has suggested a possible link between heroin use and shortened telomere length (TL), a marker of cellular aging and genomic stability. We sought to replicate these findings by examining the relationship between TL and heroin use among individuals of African ancestry. METHODS: This cross-sectional study examined TL among 57 participants [17.5 % female; mean age 48.0 (±6.80) years] of African ancestry with Opioid Use Disorder (OUD) and a mean heroin use duration of 18.2 (±10.7) years. Quantitative polymerase chain reaction (qPCR) was used to calculate TL as the ratio between telomere repeat copy number (T) and a single-copy gene, copy number (S). The primary dependent variable was TL (T/S Ratio) measured in kilobase pairs. Covariates included heroin use years and personality traits. Using a hybrid approach, multiple linear regression and Bayesian linear regression examined the association of chronological age, heroin use years and personality traits with TL. RESULTS: The multiple linear regression model fit the data well, R2 = 0.265, F(7,49) = 2.53, p < .026. Chronological age (ß = -0.36, p = .017), neuroticism (ß = 0.46, p = .044), and conscientiousness (ß = 0.52, p = .040) were significant predictors of TL. Bayesian linear regression provided moderate support for the alternate hypothesis that chronological age and TL are associated, BF10 = 5.77, R2 = 0.120. The posterior summary of the coefficient was M = 0.719 (SD = 0.278, 95 % credible interval [-1.28, -0.163]). CONCLUSIONS: Contrary to prior studies, these findings suggest that heroin use duration may not be significantly associated with TL among individuals of African ancestry, highlighting the need for more rigorous research to elucidate the complexity of this relationship.

No evidence of accelerated epigenetic aging among black heroin users: A case vs control analysis.

This study sought to assess the association between illicit opioid use and accelerated epigenetic aging (A.K.A. DNAm Age) among people of African ancestry who use heroin. DNA was obtained from participants with opioid use disorder (OUD) who confirmed heroin as their primary drug of choice. Clinical inventories of drug use included: the Addiction Severity Index (ASI) Drug-Composite Score (range: 0-1), and Drug Abuse Screening Test (DAST-10; range: 0-10). A control group of participants of African ancestry who did not use heroin was recruited and matched to heroin users on sex, age, socioeconomic level, and smoking status. Methylation data were assessed in an epigenetic clock to determined and compare Epigenetic Age to Chronological Age (i.e., age acceleration or deceleration). Data were obtained from 32 controls [mean age 36.3 (±7.5) years] and 64 heroin users [mean age 48.1 (±6.6) years]. The experimental group used heroin for an average of 18.1 (±10.6) years, reported use of 6.4 (±6.1) bags of heroin/day, with a mean DAST-10 score of 7.0 (±2.6) and ASI Score of 0.33 (±0.19). Mean age acceleration for heroin users [+0.56 (± 9.5) years] was significantly (p< 0.05) lower than controls [+5.19 (± 9.1) years]. This study did not find evidence that heroin use causes epigenetic age acceleration.

Sublingual dexmedetomidine (BXCL501) reduces opioid withdrawal symptoms: findings from a multi-site, phase 1b/2, randomized, double-blind, placebo-controlled trial.

Background: Like other alpha-2-adrenergic receptor agonists, dexmedetomidine may reduce the severity of opioid withdrawal but with fewer adverse cardiovascular effects.Objective: This study assessed the safety of sublingual dexmedetomidine (BXCL501) and its preliminary efficacy in treating opioid withdrawal (ClinicalTrials.gov: NCT04470050).Methods: Withdrawal was induced among individuals with physiological dependence on opioids via discontinuation of oral morphine (Days 1-5). Participants were randomized to receive placebo or active BXCL501: 30, 60, 90, 120, 180, and 240 µg twice daily (Days 6-12). Treatment-emergent adverse events (TEAEs) were the primary outcome measure. Secondary outcomes included the Clinical and Subjective Opiate Withdrawal Scales (COWS and SOWS-Gossop, respectively), and the Agitation and Calmness Evaluation Scale (ACES).Results: Of 225 participants enrolled, 90 discontinued during morphine stabilization. Post-BXCL501 randomization (Day 6) data were available from 135 participants (73% male), with 33% completing thru Day 12. In total, 36 subjects reported 1 or more TEAE. Higher doses of BXCL501 (i.e. 180 and 240 µg, twice daily) increased the frequency of: hypotension, orthostatic hypotension, and somnolence. TEAEs related to BXCL501 were mild or moderate in severity, except for one participant in the 120 µg condition whose orthostatic hypotension and bradycardia were classified as severe. Higher BXCL501 dose conditions (120, 180, and 240 µg) resulted in statistically significant reductions in COWS & SOWS scores. Mean ratings on the ACES were between 3 (mild), 4 (normal), and 5 (mild calmness), with few significant differences as a function of dose.Conclusions: These findings support the continued development of BXCL501 for the management of opioid withdrawal.

The subjective experience of heroin effects among individuals with chronic opioid use: Revisiting reinforcement in an exploratory study.

Aims: Consistent with the opponent process theory individuals with chronic opioid use should predominantly endorse the avoidance of aversive negative emotional and/or physiological states as the motivation for continued opioid use (source of reinforcement: reductions in negative states). The primary aim of this study was to explore whether this view is supported by the subjective effects of heroin reported by individuals with opioid use disorder (OUD). Methods: Responses during in-person interviews of participants to the question "What do you like about heroin? " were categorized as positive, negative, or mixed (positive and negative) reinforcement. In addition, we examined differences between these "reinforcement groups" in sociodemographic and clinical variables. Results: Participants (N = 307) with OUD were predominantly male (78.1%), with chronic heroin use (M = 15.8 years, SD = 11.5), and 46.1% currently used heroin and were not enrolled in treatment. Agreement between two raters concerning the categorization of participant-reported effects of heroin into reinforcement categories was high, κ= 0.924, p < .0005. Approximately half (49.8%) of participant-reported effects of heroin were categorized as attributable to positive reinforcement. About one-fourth (22.8%) were categorized as negative reinforcement and 9.0% as "mixed ". There were no statistically significant differences between the three reinforcement groups in any of the socio-demographic variables, duration of heroin use, or treatment status/interest. Conclusions: The results of this study indicate marked heterogeneity of heroin effects experienced by individuals with OUD and their source of reinforcement, respectively. Better integration of how individuals construe their drug use is important to understand the psychological-and neurobiological-processes in the development and maintenance of OUD.

UNDERSTANDING PREFERENCES FOR TYPE OF TAKE-HOME NALOXONE DEVICE: INTERNATIONAL QUALITATIVE ANALYSIS OF THE VIEWS OF PEOPLE WHO USE OPIOIDS.

Background: Take-home naloxone (THN) is provided to non-medically trained people to reverse potential opioid overdoses. There is an increasing range of effective intramuscular (IM) and intranasal (IN) naloxone devices and this paper explores the types preferred by people who use opioids, using consumer behaviour literature to interpret the findings. Methods: Data derive from two unconnected qualitative studies involving audio-recorded semi-structured interviews. Study 1 was conducted in the United States (n=21 users of non-medical/illicit opioids). Study 2 was conducted in Australia (n=42 users of non-medical/illicit or prescribed opioids). Findings: Most participants preferred IN naloxone. Preferences were based on the ease, speed, safety and comfort of each device and underpinned by accounts of overdose revivals as being very rushed and frightening situations. Preferences related to complex interactions between the naloxone device ('product'); the knowledge, skills, experience and attitudes of the lay responder ('consumer'), and when, where and how naloxone was to be used ('usage situation'). Conclusions: THN programs should offer choice of device when possible and nasal naloxone if resources permit. Asking people which devices they prefer and why and treating them as valued consumers of naloxone products can generate insights that improve future naloxone technology and increase THN uptake and usage.

A randomized clinical trial of the effects of brief versus extended opioid overdose education on naloxone utilization outcomes by individuals with opioid use disorder.

BACKGROUND: Overdose education and naloxone distribution (OEND) trains people who use opioids (PWUO) in how to intervene in cases of opioid overdose but best practices have not been assessed empirically. METHODS: PWUO along with a significant other (SO) were randomized to one of three training conditions. In the Treatment-as-Usual (TAU) condition, participants were randomized to receive minimal overdose-related education. In the extended training (ET) condition, PWUO received an extended training, while their SO received no overdose training. In the final condition, both the participant and SO received the extended overdose training (ETwSO). Outcome measures were naloxone use and overdose knowledge and competency assessed immediately before and after training, and at 1-, 3-, 6-, and 12-month timepoints following training. RESULTS: Three hundred and twenty-one PWUO (w/ a SO) were randomized. All intensities of OD training were associated with sustained increases in OD knowledge/ competency (versus pre-training baseline p's < 0.01). PWUO intervened in 166 ODs. The 12-month incidence of naloxone use did not significantly differ between groups. Extended training (ET + ETwSO) compared to TAU resulted in significantly greater naloxone utilization by: 30 days (10.1% vs 4.1%, p = 0.041), 60 days (16.4% vs 5.2%, p<0.001) and 90 days (17.9% vs 9.5%, p = 0.039). CONCLUSIONS: All intensities of OD training were associated with sustained increases in OD knowledge and competency, and equivalent rates of successful naloxone use. More extensive training increased naloxone utilization during the first 3 months. However, the benefits of more comprehensive training should be balanced against feasibility.

The effects of acute oral naltrexone pretreatment on the abuse potential of intranasal methamphetamine, and the relationship between reward/punishment sensitivity and methamphetamine's effects.

One potential medication for treating methamphetamine use disorder is the opioid antagonist naltrexone (NLTX). Despite encouraging preclinical findings, the results of clinical studies have been mixed. The primary aim of the current trial was to examine the effects of acute NLTX pretreatment on the subjective and reinforcing effects of intranasal methamphetamine. Nonmedical psychostimulant users completed outpatient testing sessions in which they received oral placebo (0 mg) or NLTX (50 mg) before intranasal methamphetamine (30 mg/70 kg). Primary outcome measures were peak positive subjective effects (e.g. drug 'Liking') assessed on a visual analog scale (0-100), and methamphetamine self-administration using an operant self-administration task. Participants also completed a probabilistic categorization task to assess reward and punishment learning sensitivity. Complete data were available from 13 male and 1 transgender (male-to-female) participant (age: 33.4 ± 7.6 years). Intranasal methamphetamine significantly increased subjective ratings of drug 'Liking', 'Good Effect' and 'High' from baseline (P's < 0.01), but did not significantly vary as a function of placebo or NLTX pretreatment. Similarly, methamphetamine self-administration did not vary between the placebo and NLTX pretreatment conditions. This sample did not demonstrate a significant 'bias' in learning from positive and negative outcomes (i.e. reward and punishment sensitivity), and reward/punishment sensitivity was not correlated with the effects of methamphetamine or the effects of NLTX on methamphetamine. The current study argues against the use of NLTX as a stand-alone medication for treating methamphetamine use disorder.

Emotional reactions of trained overdose responders who use opioids following intervention in an overdose event.

Background: Our aim was to explore emotional reactions to intervening in an overdose event from the perspective of individuals who use opioids (peer responders). In addition, we were interested in the impact this experience may have on peer responders' feelings about helping in an overdose situation in the future. Methods: For this qualitative sub-study of a randomized controlled trial (RCT), data from 61 interviews were analyzed thematically using an inductive approach. Results: Peer responders had diverse emotional reactions to the overdose event. These ranged from a sense of pride and other positive feelings associated with their ability to help to ambivalence about being involved in situations perceived as challenging and burdensome. There were few reports of the overdose event as an exclusively negative experience. Many peer responders perceived it as their duty to use naloxone again if required. However, some had ambivalent feelings toward this responsibility, which may be related to negative experiences with previous intervention efforts. Conclusions: The capacity of people who use opioids to help reduce the harms associated with opioid overdose is experienced as empowering by some. Nonetheless, engaging peer responders in strategies to reduce opioid-related mortality should be coupled with appropriate resources to process their experiences and emotional responses.

Multi-informant Implementation and Intervention Outcomes of Opioid Overdose Education and Naloxone Distribution in New York City.

Overdose Education and Naloxone Distribution (OEND) is an effective public health intervention to reduce opioid overdose fatalities (McDonald and Strang, Addiction 111:1177-1187, 2016). However, we know little about OEND implementation outcomes (i.e., indicators of implementation success), specifically the fidelity of training delivery, and how these may relate to intervention outcomes (i.e., indicators of the success or effectiveness of an intervention), such as overdose knowledge and attitudes. This study evaluated 16 OEND trainings conducted at different Opioid Overdose Prevention Programs in New York City. Trainees (N = 75) completed the Opioid Overdose Knowledge and Attitude Scales before and after training (intervention outcomes). Implementation outcomes were fidelity (competence and adherence of the trainer, N = 10; modified Fidelity Checklist) and acceptability of OEND (Acceptability of Intervention Measure), assessed from multiple perspectives (trainees, trainers, and an independent observer). Trainees' overdose knowledge, t(71) = - 8.12, p < 0.001, 95% CI [- 6.54, - 3.96], and attitudes, t(65) = - 6.85, p < 0.001, 95% CI [- 0.59, - 0.33], improved significantly from pre- to post-training. Stepwise multiple regression models indicated that adherence of the trainer rated from the observer perspective added significantly to the prediction of changes in overdose knowledge, F(1, 67) = 9.81, p = 0.003, and explained 13% of the variance in outcome. However, fidelity measures from the perspective of trainees or trainers and acceptability of OEND were not associated with changes in trainees' overdose knowledge or attitudes. OEND implementation outcomes and their relationship with intervention outcomes differed depending on the role of the fidelity rater in relation to the intervention. Specifically, our findings indicate that fidelity should be measured from an independent perspective (i.e., an individual who is experienced with fidelity rating but not directly involved in the intervention). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43477-021-00021-4.

Relative potency of intravenous oxymorphone compared to other µ opioid agonists in humans - pilot study outcomes.

AIMS: Intravenous (IV) misuse of the µ opioid analgesic oxymorphone has caused significant public health harms; however, no controlled data on its IV abuse potential are available. The primary aims of this pilot study were to directly compare IV oxymorphone to IV oxycodone, morphine, and hydromorphone on a subjective measure of drug liking and to assess relative potency. METHODS: Participants (n = 6) with opioid use disorder, physical dependence, and current IV use completed this two-site, within-subject, double-blind, placebo-controlled, inpatient pilot study. During each session, one IV dose (mg/70 kg) was administered: oxymorphone (1.8, 3.2, 5.6, 10, 18, 32), hydromorphone (1.8, 3.2, 5.6, 10, 18), oxycodone (18, 32, 56), morphine (18, 32), and placebo. Data were collected before and for 6 h after dosing. Primary outcomes included safety/physiological effects, subjective reports of drug liking, and relative potency estimates. RESULTS: All active test drugs produced prototypical, dose-related µ opioid agonist effects (e.g., miosis). Oxymorphone was more potent than the comparator opioids on several measures, including drug liking and respiratory depression (p < 0.05). Across abuse-related subjective outcomes, oxymorphone was 2.3-2.8-fold more potent than hydromorphone and 12.5-14-fold more potent than oxycodone (p < 0.05). CONCLUSIONS: Despite the relatively small sample size, this pilot study detected robust oxymorphone effects. Oxymorphone was far more potent than the comparator opioids, particularly on abuse potential outcomes. Overall, these findings may help explain surveillance reports that demonstrate, after adjusting for prescription availability, oxymorphone is injected at the highest frequency, relative to other prescription opioids.

Factor structure and psychometric properties of the Connor-Davidson resilience scale (CD-RISC) in individuals with opioid use disorder.

AIMS: Resilience is defined as the capacity for an individual to maintain normal functioning and resist the development of psychiatric disorders in response to stress and trauma. Although previous investigators have acknowledged the important role of resilience in those with substance use disorders, this is the first study to investigate the reliability, validity, and factor structure of the Connor-Davidson Resilience Scale (CD-RISC-25) in a sample of individuals with opioid use disorder (OUD). Additionally, we explored the relationship between trait resilience and the severity of drug-related problems. METHODS: Four hundred and three participants (22 % female) with OUD completed the CD-RISC-25, Beck Depression Inventory (BDI-II), and the self-report Addiction Severity Index (ASI). Confirmatory factor analysis (CFA) tested the originally proposed 5-factor solution of the CD-RISC-25. RESULTS: CFA results indicated that a 5-factor model of the CD-RISC-25 performed somewhat better than the 1-factor solution. Pearson correlation revealed a negative association between CD-RISC-25 (M = 75.82, SD = 15.78) and ASI drug-use composite score (M = .25, SD=-0.16), r=-0.148, p<.01, and between CD-RISC-25 and BDI-II (M = 11.33, SD = 10.58), r=-.237, p<.001. CONCLUSIONS: Albeit providing only limited support for the original 5-factor structure, our results indicate that the scale may be useful for screening individuals with OUD who have a vulnerability to stress. Consistent with prior studies, higher resilience was associated with lower depression symptoms and addiction severity, further demonstrating the CD-RISC-25 ability to predict psychiatric stability. To inform the development of more targeted interventions, future studies should examine resilience longitudinally, in addition to exploring more comprehensive approaches to measuring resilience.

Improving Translational Research Outcomes for Opioid Use Disorder Treatments.

Purpose of Review: Pharmacotherapies are the most effective means of reducing the harms associated with opioid use disorder (OUD). Translational research seeking to develop novel medications to treat OUD has been challenging due to the complex etiology of addiction. Preclinical outcome measures are often behavioral, and it is difficult, if not impossible, to fully mirror the various emotional and cognitive processes that motivate opioid use in humans. The goal of the current narrative review was to summarize the translational progression of three potential medications for OUD, which had varying levels of success. Recent Findings: Memantine, lorcaserin, and lofexidine all showed promise in preclinical studies; however, only lofexidine was able to consistently replicate these findings in human subjects, and receive FDA approval. It was the authors' objective to use this review to identify areas of needed improvement in translational research for OUD. Summary: Preclinical studies vary significantly in their ability to forecast effectiveness in clinical trials. Among the various preclinical models, suppression of opioid self-administration appears to have the best predictive validity. As they model a mostly physiological phenomenon, preclinical assessments of opioid withdrawal also appear to have high predictive validity. In our review of the literature, the authors noted numerous examples of clinical trials that were underpowered, lack precision, and proper outcomes. Better-validated preclinical targets and improved design of proof-of-concept human studies should allow investigators to more efficiently develop and test medications for OUD.

Intervention in an opioid overdose event increases interest in treatment among individuals with opioid use disorder.

Background: This study sought to explore whether intervening in suspected cases of opioid overdose alters interest in treatment for opioid use disorder (OUD). Data were collected as a part of a trial comparing the effects of different overdose education and naloxone distribution (OEND) training curricula on overdose outcomes. Methods: Following OEND training, participants completed four in-person follow-up visits at 1-, 3-, 6- and 12-months. Participants were also regularly contacted to inquire about overdose events they responded to, witnessed, or experienced themselves. Other assessments included the Addiction Severity Index that queries participants' perceived importance of drug treatment on a scale of: 0 (Not at All) to 4 (Extremely). For the current secondary data analysis, treatment importance was assessed at the time points most immediately preceding and following participant intervention in an overdose event using naloxone. Results: The sample reported a mean duration of opioid use of 14.9 (± 11.5) years, with 67% having witnessed an overdose event prior to the study. Of the 321 enrolled, 92 participants used naloxone in response to 166 suspected cases of an opioid overdose. For the entire sample, mean treatment importance did not significantly change throughout the study. Among participants who utilized naloxone, treatment importance increased following the event (Before: 3.03, After: 3.39, p = 0.02). Due to the amount of time between the overdose event and assessment of post-event treatment importance (40.5 days, ±40.2), the current study most likely underestimates this effect. Conclusions: The current study suggests that responding to an overdose event increases interest in OUD treatment. Currently only considered an acute intervention to reduce overdose morbidity and mortality, OEND may have the potential to increase enrollment in medications to treat OUD. However, a prospective investigation needs to determine if the impact of an overdose event could be utilized to increase treatment engagement.

The Increasing Prevalence of Fentanyl: A Urinalysis-Based Study Among Individuals With Opioid Use Disorder in New York City.

BACKGROUND AND OBJECTIVES: Opioid-related overdose deaths in North America have increased drastically, partially due to the increased prevalence of illicitly manufactured fentanyl. The current study sought to assess the prevalence and intentionality of fentanyl use among individuals with opioid use disorder (OUD). METHODS: For this secondary analysis (study 1) we screened a total of 1118 urine samples from 316 participants with OUD from 2016 to 2019. Fentanyl knowledge and intentionality of use were assessed in a separate OUD sample (study 2; N = 33). RESULTS: In study 1, 34.6% of all urine samples tested positive for fentanyl. Overall, 149 (47.2%) participants provided more than or equal to one urine sample that tested fentanyl-positive, and 93 (29.4%) provided more than or equal to two fentanyl-positive samples. The number of fentanyl-positive samples, relative to the number of samples tested each year, increased by 330% from year 1 to 3. Study 2 found all participants had pre-existing knowledge that drugs may be adulterated with fentanyl, yet 67% were surprised by their own fentanyl-positive test result. DISCUSSION AND CONCLUSIONS: Like previous studies, our data indicate the high prevalence of fentanyl exposure and low perception of fentanyl-related risk among individuals with OUD, respectively, suggesting that opioid overdose harm reduction efforts may need to focus more on drug users' understanding of risks related to fentanyl use and adulteration of drugs. SCIENTIFIC SIGNIFICANCE: The current studies provide longitudinal data on fentanyl exposure prevalence and risk perception that is uniquely granular by assessing OUD treatment status, and by identifying potential associations between fentanyl exposure with the presence of other drug use and nonfatal overdose. (Am J Addict 2021;30:65-71).

A qualitative study of repeat naloxone administrations during opioid overdose intervention by people who use opioids in New York City.

BACKGROUND: Take-home naloxone (THN) kits have been designed to provide community members (including people who use drugs, their families and/or significant others) with the necessary resources to address out-of-hospital opioid overdose events. Kits typically include two doses of naloxone. This 'twin-pack' format means that lay responders need information on how to use each dose. Advice given tends to be based on dosage algorithms used by medical personnel. However, little is currently known about how and why people who use drugs, acting as lay responders, decide to administer the second dose contained within single THN kits. The aim of this article is to explore this issue. METHODS: Data were generated from a qualitative semi-structured interview study that was embedded within a randomised controlled trial examining the risks and benefits of Overdose Education and Naloxone Distribution (OEND) training in New York City (NYC). Analysis for this article focuses upon the experiences of 22 people who use(d) opioids and who provided repeat naloxone administrations (RNA) during 24 separate overdose events. The framework method of analysis was used to compare the time participants believed had passed between each naloxone dose administered ('subjective response interval') with the 'recommended response interval' (2-4 minutes) given during OEND training. Framework analysis also charted the various reasons and rationale for providing RNA during overdose interventions. RESULTS: When participants' subjective response intervals were compared with the recommended response interval for naloxone dosing, three different time periods were reported for the 24 overdose events: i. 'two doses administered in under 2 minutes' (n = 10); ii. 'two doses administered within 2-4 minutes' (n = 7), and iii. 'two doses administered more than 4 minutes apart' (n = 7). A variety of reasons were identified for providing RNA within each of the three categories of response interval. Collectively, reasons for RNA included panic, recognition of urgency, delays in retrieving naloxone kit, perceptions of recipients' responsiveness/non-responsiveness to naloxone, and avoidance of Emergency Response Teams (ERT). CONCLUSION: Findings suggest that decision-making processes by people who use opioids regarding how and when to provide RNA are influenced by factors that relate to the emergency event. In addition, the majority of RNA (17/24) occurred outside of the recommended response interval taught during OEND training. These findings are discussed in terms of evidence-based intervention and 'evidence-making intervention' with suggestions for how RNA guidance may be developed and included within future/existing models of OEND training.

The acute and repeated effects of cigarette smoking and smoking-related cues on impulsivity.

INTRODUCTION AND AIMS: Impulsivity may be a risk factor that increases vulnerability to nicotine dependence. However, nicotine exposure itself may directly increase impulsivity. This is a secondary analysis of the first study in a controlled laboratory setting, which assessed the effects of nicotine administration (acute and repeated) and exposure to smoking cues on behavioural impulsivity in humans (ClinicalTrials.gov Identifier: NCT01395797). DESIGN AND METHODS: Twenty-seven smokers completed three tasks to assess behavioural impulsivity (the Immediate Memory Task and the Delayed Memory Task assessing response initiation, and the GoStop Task assessing response inhibition) following: (i) 4 days of cigarette smoking (nicotinised or denicotinised cigarette); (ii) acute cigarette smoking (nicotinised); and (iii) exposure to smoking-related cues. RESULTS: Four days of nicotinised cigarette smoking (vs. denicotinised) did not significantly increase Immediate Memory Task, Delayed Memory Task and GoStop scores. However, acute cigarette smoking increased GoStop impulsivity, but only following 4 days of smoking nicotinised cigarettes (P < 0.05). Exposure to smoking-related cues had no statistically significant effect on impulsivity. DISCUSSION AND CONCLUSIONS: Our results suggest that repeated nicotine exposure may sensitise subsequent acute nicotine effects on behavioural impulsivity in heavy smokers.

Factors associated with withdrawal symptoms and anger among people resuscitated from an opioid overdose by take-home naloxone: Exploratory mixed methods analysis.

INTRODUCTION: Take-home naloxone (THN) is a clinically effective and cost-effective means of reducing opioid overdose fatality. Nonetheless, naloxone administration that successfully saves a person's life can still produce undesirable and harmful effects. AIM: To better understand factors associated with two widely reported adverse outcomes following naloxone administration; namely the person resuscitated displays: i. withdrawal symptoms and ii. anger. METHODS: A mixed methods study combining a randomized controlled trial of overdose education and naloxone prescribing to people with opioid use disorder and semi-structured qualitative interviews with trial participants who had responded to an overdose whilst in the trial. All data were collected in New York City (2014-2019). A dataset (comprising demographic, pharmacological, situational, interpersonal, and overdose training related variables) was generated by transforming qualitative interview data from 47 overdose events into dichotomous variables and then combining these with quantitative demographic and overdose training related data from the main trial. Associations between variables within the dataset and reports of: i. withdrawal symptoms and ii. anger were explored using chi-squared tests, t-tests, and logistic regressions. RESULTS: A multivariate logistic regression found that people who had overdosed were significantly more likely to display anger if the person resuscitating them criticized, berated or chastised them during resuscitation (adjusted OR = 27 [95% CI = 4.0-295]). In contrast, they were significantly less likely to display anger if the person resuscitating them communicated positively with them (OR = 0.10 [95% CI = 0.01-0.78]). Both positive and negative communication styles were independently associated with anger, and communication was associated with 59% of the variance in anger. There was no evidence that people who displayed withdrawal symptoms were more likely to display anger than those not displaying withdrawal symptoms, and neither displaying withdrawal symptoms nor displaying anger were associated with using more drugs after resuscitation. CONCLUSIONS: Contrary to common assumptions, withdrawal symptoms and anger following naloxone administration may be unrelated phenomena. Findings are consistent with previous research that has suggested that a lay responder's positive or reassuring communication style may lessen anger post overdose. Implications for improving THN programmes and naloxone administration are discussed.