Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use: A Post Hoc Analysis of a Randomized Clinical Trial.

Importance: Fentanyl has exacerbated the opioid use disorder (OUD) and opioid overdose epidemic. Data on the effectiveness of medications for OUD among patients using fentanyl are limited. Objective: To assess the effectiveness of sublingual or extended-release injection formulations of buprenorphine for the treatment of OUD among patients with and without fentanyl use. Design, Setting, and Participants: Post hoc analysis of a 24-week, randomized, double-blind clinical trial conducted at 35 outpatient sites in the US from December 2015 to November 2016 of sublingual buprenorphine-naloxone vs extended-release subcutaneous injection buprenorphine (CAM2038) for patients with OUD subgrouped by presence vs absence of fentanyl or norfentanyl in urine at baseline. Study visits with urine testing occurred weekly for 12 weeks, then 6 times between weeks 13 and 24. Data were analyzed on an intention-to-treat basis from March 2022 to August 2023. Intervention: Weekly and monthly subcutaneous buprenorphine vs daily sublingual buprenorphine-naloxone. Main Outcomes and Measures: Retention in treatment, percentage of urine samples negative for any opioids (missing values imputed as positive), percentage of urine samples negative for fentanyl or norfentanyl (missing values not imputed), and scores on opiate withdrawal scales and visual analog craving scales. Results: Of 428 participants, 123 (subcutaneous buprenorphine, n = 64; sublingual buprenorphine-naloxone, n = 59; mean [SD] age, 39.1 [10.8] years; 75 men [61.0%]) had evidence of baseline fentanyl use and 305 (subcutaneous buprenorphine, n = 149; buprenorphine-naloxone, n = 156; mean [SD] age, 38.1 [11.1] years; 188 men [61.6%]) did not have evidence of baseline fentanyl use. Study completion was similar between the fentanyl-positive (60.2% [74 of 123]) and fentanyl-negative (56.7% [173 of 305]) subgroups. The mean percentage of urine samples negative for any opioid were 28.5% among those receiving subcutaneous buprenorphine and 18.8% among those receiving buprenorphine-naloxone in the fentanyl-positive subgroup (difference, 9.6%; 95% CI, -3.0% to 22.3%) and 36.7% among those receiving subcutaneous buprenorphine and 30.6% among those receiving buprenorphine-naloxone in the fentanyl-negative subgroup (difference, 6.1%; 95% CI, -1.9% to 14.1%), with significant main associations of baseline fentanyl status and treatment group. In the fentanyl-positive subgroup, the mean percentage of urine samples negative for fentanyl during the study was 74.6% among those receiving subcutaneous buprenorphine vs 61.9% among those receiving sublingual buprenorphine-naloxone (difference, 12.7%; 95% CI, 9.6%-15.9%). Opioid withdrawal and craving scores decreased rapidly after treatment initiation across all groups. Conclusions and Relevance: In this post hoc analysis of a randomized clinical trial of sublingual vs extended-release injection buprenorphine for OUD, buprenorphine appeared to be effective among patients with baseline fentanyl use. Patients with fentanyl use had fewer opioid-negative urine samples during the trial compared with the fentanyl-negative subgroup. These findings suggest that the subcutaneous buprenorphine formulation may be more effective at reducing fentanyl use. Trial Registration: ClinicalTrials.gov Identifier: NCT02651584.

Evaluating the Abuse Potential of Lenabasum, a Selective CB2 Cannabinoid Receptor Agonist.

Background: Endocannabinoids, which are present throughout the central nervous system (CNS), can activate CB1 and CB2 receptors. CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. Methods: This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n=56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120mg) were compared to placebo, and nabilone (3 and 6mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Results: Lenabasum was safe and well tolerated. Compared to placebo, a 20mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3mg and 6mg, which is a currently FDA-approved medication. Conclusions: At a target therapeutic dose (20mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120mg) did elicit subjective ratings of Drug Liking compared to placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared to 3mg and 6mg of nabilone, suggesting that lenabasum does have abuse potential and should be used cautiously in clinical settings. Significance Statement This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well-tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.

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 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.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Are you thinking what I'm thinking? Defining what we mean by "polysubstance use."

The rise in drug overdoses and harms associated with the use of more than one substance has led to increased use of the term "polysubstance use" among researchers, clinicians, and public health officials. However, the term retains no consistent definition across contexts. The current authors convened from disciplines including sociology, epidemiology, neuroscience, and addiction psychiatry to propose a recommended definition of polysubstance use. An iterative process considered authors' formal and informal conversations, insights from relevant symposia, talks, and conferences, as well as their own research and clinical experiences to propose the current definition. Three key concepts were identified as necessary to define polysubstance use: (1) substances involved, (2) timing, and (3) intent. Substances involved include clarifying either (1) the number and type of substances used, (2) presence of more than one substance use disorder, or (3) primary and secondary substance use. The concept of timing is recommended to use clear terms such as simultaneous, sequential, and same-day polysubstance use to describe short-term behaviors (e.g., 30-day windows). Finally, the concept of intent refers to clarifying unintentional use or exposure when possible, and greater attention to motivations of polysubstance use. These three components should be clearly defined in research on polysubstance use to improve consistency across disciplines. Consistent definitions of polysubstance use can aid in the synthesis of evidence to better address an overdose crisis that increasingly involves multiple substances.

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

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

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.

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.

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.

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.

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.

Preliminary attitudes on medications for opioid use disorders (MOUDs) in Southeastern Switzerland and New York City.

The United States (US) and Switzerland are affluent countries with different responses to surges in opioid use disorder (OUD) cases over the last thirty years. The Swiss "PROVE" trail implemented heroin-assisted treatment (HAT) for OUD alongside other medications for opioid use disorder (MOUD). In contrast, heroin remains highly controlled, HAT is inaccessible, and MOUD programs are generally more restrictive in the US than in Switzerland. We conducted a survey to compare practitioners' attitudes toward HAT across sites in both countries. Surveys were distributed electronically for voluntary, uncompensated completion (N = 120) at two mental health delivery sites, Psychiatrische Dienste Graubünden (PDGR) in Graubünden, Switzerland and Montefiore Medical Center (MMC) in the Bronx, NY. The survey instrument included 10 demographic and 19 "beliefs" questions measuring agreement level with a statement on a 5-point scale. Analysis included 79 PDGR respondents (mean age = 43.2, 59.5% women) and 41 MMC respondents (mean age = 44.7, 63.4% women), and did not show differences in confidence to treat OUD, addictions, and psychiatric disorders. For belief in HAT, Swiss respondents had a significantly more favorable view (b = 0.62) than those in New York (p = 0.00027). This study shows a difference in attitudes toward HAT among demographically similar staff treating OUD patients across sites. The cohorts demonstrate an overall positive attitude toward HAT but a more robust positive attitude was evident in Switzerland. Previously unreported attitude comparisons across sites with dissimilar OUD treatment availability may explain differences in practices and success in reducing harm from this disorder.

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review.

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous µ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

Accuracy of diagnostic codes for prenatal opioid exposure and neonatal opioid withdrawal syndrome.

OBJECTIVE: Determine the accuracy of diagnostic codes in identifying Prenatal Opioid Exposure (POE) and Neonatal Opioid Withdrawal Syndrome (NOWS). STUDY DESIGN: A cross-sectional study of 374,222 mother-infant dyads with delivery from 01/01/2010 to 12/31/2019. We ascertained maternal diagnostic codes for opioid use during pregnancy and infant diagnostic codes for drug exposure and withdrawal. We assessed sensitivity and positive predictive value (PPV) for POE and NOWS, defined using laboratory, pharmacy, and clinical data. RESULTS: Maternal codes had low sensitivity (36.4%) and PPV (34.7%) for POE. Infant codes for drug exposure were neither sensitive for POE (14%) nor NOWS (31.6%) and had low PPV. Codes for newborn withdrawal had low sensitivity (31.6%) for detecting NOWS, but high PPV (85%). Sensitivity improved (95.1%) for NOWS requiring pharmacologic treatment. CONCLUSIONS: Diagnostic codes identify POE and NOWS poorly. Improved case identification would include pharmacy and laboratory results, and clearly defined criteria for evidence of 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.

A novel long-acting formulation of oral buprenorphine/naloxone produces prolonged decreases in fentanyl self-administration by rhesus monkeys.

BACKGROUND: Due to the poor oral bioavailability of buprenorphine, an oral formulation has not been thought possible. Lyndra Therapeutics is developing a once-weekly long-acting oral product containing buprenorphine. We evaluated the efficacy of this formulation in reducing intravenous (i.v.) fentanyl self-administration by three male and three female rhesus monkeys. METHODS: Buprenorphine HCl and naloxone HCl were co-formulated using an 11:1 ratio of buprenorphine:naloxone in a controlled-release gastric residence formulation administered in an oral capsule (LYN-013). Naloxone was included to determine the feasibility of combining naloxone with buprenorphine in the formulation as an abuse deterrent. Complete fentanyl dose-response functions were determined during each session. The efficacy of single doses of 56/5, 112/10 and 168/15 mg buprenorphine/naloxone in reducing fentanyl self-administration was examined over 13 days. RESULTS: LYN-013 significantly decreased the rate of responding for fentanyl for 3 days and significantly reduced total intake of fentanyl for 8 days. Time to maximal buprenorphine levels (Tmax) ranged between 56 and 68 h for all 3 doses. The maximal buprenorphine level (Cmax) following 168 mg was 2.3 ng/ml which was significantly greater that those observed for 56 mg (1.22 ng/ml) and 112 mg (1.35 ng/ml). Finally, the area-under-curves (AUCtau) were buprenorphine dose-dependently increased from 88 to 127-265 h*ng/ml. There were no signs of non-specific changes in behavior. CONCLUSIONS: A once-weekly oral buprenorphine/naloxone formulation produced sustained suppression of fentanyl self-administration in monkeys suggesting that oral delivery of buprenorphine with this formulation could provide a new opportunity to treat opioid use disorders (OUD).

Psychedelic drug abuse potential assessment research for new drug applications and Controlled Substances Act scheduling.

New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled globally. The implications of the CSA for research and medicines development, the path to approval of medicines, and their subsequent removal from Schedule I in the US are discussed. This entire process occurs within the framework of the CSA in the US and its counterparts internationally in accordance with international drug control treaties. Abuse potential related research in the US informs the eight factors of the CSA which provide the basis for rescheduling actions that must occur upon approval of a drug that contains a Schedule I substance. Abuse-related research also informs drug product labeling and the risk evaluation and mitigation strategies (REMS) will likely be required for approved medicines. Human abuse potential studies typically employed in CNS drug development may be problematic for substances with strong hallucinogenic effects such as psilocybin, and alternative strategies are discussed. Implications for research, medicinal development, and controlled substance scheduling are presented in the context of the US CSA and FDA requirements with implications for global regulation. We also discuss how abuse-related research can contribute to understanding mechanisms of action and therapeutic effects as well as the totality of the effects of the drugs on the brain, behavior, mood, and the constructs of spirituality and consciousness.

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.