Characteristics and Prescribing Patterns of Clinicians Waivered to Prescribe Buprenorphine for Opioid Use Disorder Before and After Release of New Practice Guidelines.

Importance: In April 2021, the US Department of Health and Human Services (HHS) released practice guidelines exempting educational requirements to obtain a Drug Addiction Treatment Act (DATA) waiver to treat up to 30 patients with opioid use disorder with buprenorphine. Objective: To compare demographic and practice characteristics of clinicians who received traditional DATA waivers before and after release of the education-exempted HHS practice guidelines and those who were approved under the guidelines. Design, Setting, and Participants: This survey study was conducted electronically from February 1 to March 1, 2022. Eligible survey recipients were US clinicians who obtained an initial DATA waiver between April 2020 and November 2021. Exposure: DATA waiver approval pathway. Main Outcome and Measures: The outcomes were clinician demographic and practice characteristics, buprenorphine prescribing barriers, and strategies to treat patients with opioid use disorder, measured using χ2 tests and z tests to assess for differences among the waivered groups. Results: Of 23 218 eligible clinicians, 4519 (19.5%) responded to the survey. This analysis was limited to 2736 respondents with a 30-patient limit at the time of survey administration who identified their DATA waiver approval pathway. Among these respondents, 1365 (49.9%; female, 831 [61.9%]; male, 512 [38.1%]) received their DATA waiver prior to the education-exempted practice guidelines (prior DATA waiver), 550 (20.1%; female, 343 [63.4%]; male, 198 [36.6%]) received their waiver after guidelines were released but met education requirements (concurrent DATA waiver), and 821 (30.0%; female, 396 [49.2%]; male, 409 [50.8%]) received the waiver under the education-exempted guidelines (practice guidelines). Among practice guidelines clinicians, 500 (60.9%) reported that traditional DATA waiver educational requirements were a reason for not previously obtaining a waiver. Demographic and practice characteristics differed by waiver approval type. Across all groups, a large minority had not prescribed buprenorphine since obtaining a waiver (prior DATA waiver, 483 [35.7%]; concurrent DATA waiver, 226 [41.2%]; practice guidelines, 359 [44.3%]; P < .001). Clinicians who prescribed buprenorphine in the past 6 months reported treating few patients in an average month: 27 practice guidelines clinicians (6.0%) prescribed to 0 patients and 338 (75.1%) to 1 to 4 patients compared with 16 (2.2%) and 435 (59.9%) for prior and 11 (3.6%) and 166 (55.0%) for concurrent DATA waiver clinicians, respectively (P < .001). Across waiver types, clinicians reported multiple challenges to buprenorphine prescribing. Conclusions and Relevance: In this survey of DATA-waivered clinicians, clinician- and systems-level challenges that limit buprenorphine prescribing were observed, even among clinicians approved under the education-exempted guidelines pathway. The findings suggest that as implementation of legislation removing the DATA waiver begins, addressing these barriers could be essential to increasing buprenorphine access.

Comparison of the Usability of Apple M2 and M1 Processors for Various Machine Learning Tasks.

Thispaper compares the usability of various Apple MacBook Pro laptops were tested for basic machine learning research applications, including text-based, vision-based, and tabular data. Four tests/benchmarks were conducted using four different MacBook Pro models-M1, M1 Pro, M2, and M2 Pro. A script written in Swift was used to train and evaluate four machine learning models using the Create ML framework, and the process was repeated three times. The script also measured performance metrics, including time results. The results were presented in tables, allowing for a comparison of the performance of each device and the impact of their hardware architectures.

Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study.

BACKGROUND: Cebranopadol is a nociceptin/orphanin FQ peptide/opioid receptor agonist with central antinociceptive activity. We hypothesize that this novel mechanism of action may lead to a lower risk of abuse compared with pure µ-opioid peptide receptor agonists. METHODS: We conducted a single-dose, nested-randomized, double-blind crossover study in nondependent recreational opioid users to evaluate the abuse potential of single doses of cebranopadol relative to hydromorphone immediate release and placebo. The study consisted of a qualification phase and a 7-period treatment phase (cebranopadol 200, 400, and 800 µg; hydromorphone 8 and 16 mg; and 2 placebos). The primary end point was the peak effect of drug liking at this moment, measured by visual analog scale (VAS). Various secondary end points (eg, VAS rating for good drug effects, high, bad drug effects, take drug again, drug similarity, and pupillometry) were also investigated. RESULTS: Forty-two subjects completed the study. Cebranopadol 200 and 400 µg did not differentiate from placebo on the abuse potential assessments and generated smaller responses than hydromorphone. Responses observed with cebranopadol 800 µg were similar to hydromorphone 8 mg and smaller than hydromorphone 16 mg. The maximum effect for VAS drug liking at this moment was delayed compared with hydromorphone (3 and 1.5 hours, respectively). Cebranopadol administration was safe; no serious adverse events or study discontinuation due to treatment-emergent adverse events occurred. CONCLUSIONS: These results confirm our hypothesis that cebranopadol, a nociceptin/orphanin FQ peptide/opioid receptor agonist, has lower abuse potential than hydromorphone immediate release, a pure µ-opioid peptide agonist.

Evaluation of the safety, pharmacodynamic, and pharmacokinetic effects following oral coadministration of immediate-release morphine with ethanol in healthy male participants.

OBJECTIVE: This paper aimed to evaluate the effects of coadministered immediate-release morphine and ethanol on safety, pharmacokinetic, and pharmacodynamic measures. METHODS: In the first stage of a randomized, double-blind, placebo-controlled, crossover study, 16 healthy men with a history of moderate drinking received morphine 50 mg+ethanol 0.7 g/kg, morphine 50 mg+ethanol placebo, and morphine placebo+ethanol 0.7 g/kg. In the second stage, participants received either a lower (30 mg) or higher (80 mg) morphine dose (alone and in combination with ethanol) depending on their tolerability to treatments in stage 1. Safety, pharmacodynamic (including visual analog scales, pupillometry, capnography, and psychomotor and cognitive measures), and pharmacokinetic assessments were conducted. RESULTS: With the exception of one severe adverse event (AE), all others were mild or moderate in intensity. Morphine resulted in dose-related increases in AEs. When morphine was administered with ethanol, similar AEs were observed (dizziness, headache, somnolence, nausea, and vomiting), but these were sometimes more frequent compared with those observed with either drug alone. No consistent additive or interaction effects were observed on pharmacodynamic measures. Ethanol had no apparent effects on the pharmacokinetics of morphine or its metabolites. CONCLUSIONS: Coadministration of single doses of morphine and ethanol tested in this study did not affect the safety, pharmacodynamics, or pharmacokinetics of morphine or ethanol administered alone. Copyright © 2014 John Wiley & Sons, Ltd.

Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations.

Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.

The implications of tamper-resistant formulations for opioid rotation.

Because rates of both opioid prescribing and opioid abuse have increased, drug companies have responded by considering strategies to make opioid formulations less attractive for abuse without compromising safety or efficacy for patients with legitimate pain management needs. The emergence of tamper-resistant opioid formulations is intended to deter abuse by creating obstacles to crushing or dissolving opioid tablets and capsules. At present, 2 long-acting and 1 immediate-release (IR) opioids are available in tamper-resistant formulations. Oxycodone controlled-release and oxymorphone extended-release tablets have each been reformulated with a hardened matrix that resists crushing or dissolution in liquids, making them difficult to prepare for nasal insufflation or intravenous use. Oxycodone IR has been reformulated with aversive ingredients that create nasal discomfort if the tablet is crushed and insufflated. Tamper-resistant opioid formulations are likely to be selected for patients who are identified as being at risk for abuse. However, patients vary in their response to individual opioids and may require rotation to a series of alternative opioids before finding one that is effective and sufficiently well tolerated. With only a few tamper-resistant opioid formulations currently available, switching and rotation may become difficult. As a result, patients who do not respond to a tamper-resistant opioid formulation or experience intolerable adverse events may require rotation to a formulation without tampering safeguards. Prescribers will need to be on guard for patients who may make false claims of poor response or adverse events to avoid tamper-resistant opioid formulations. Moreover, prescribers need to be aware of any tamper-resistance mechanisms that may affect efficacy or tolerability in patients with legitimate pain management needs compared with formulations without tampering safeguards.

Core outcome measures for opioid abuse liability laboratory assessment studies in humans: IMMPACT recommendations.

A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.

Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND AND OBJECTIVE: Given the dual public health challenges of undertreated pain and opioid abuse, there is a need to reduce attractiveness of opioid analgesics to drug abusers. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules, indicated for treatment of chronic, moderate to severe pain, contain polymer-coated pellets of morphine, each with a core of sequestered naltrexone intended for release only upon tampering (crushing). The purpose of this study was to assess the pharmacodynamic effects (including drug-liking and euphoria) of whole and crushed ALO-01 versus morphine sulfate solution (MSS) and placebo. METHODS: This was a randomized, double-blind, placebo-controlled, triple-dummy, four-way crossover study carried out at a clinical research centre. Participants were experienced non-dependent opioid users. Subjects were given either two ALO-01 60 mg capsules, crushed pellets from two ALO-01 60 mg capsules, MSS 120 mg or placebo; there was a 14- to 21-day washout between treatments. The primary endpoints were drug-liking visual analogue scale score, scores on items from the Addiction Research Center Inventory (ARCI) and Cole/ARCI scales characterizing abuse potential and euphoria, and pupil diameter as measured by pupillometry. RESULTS: Morphine plasma concentrations were similar after ALO-01 crushed and MSS, with a median time to reach maximum plasma concentration (t(max)) of 1.1 and 1.2 hours, respectively; the plasma naltrexone median t(max) was 1.1 hours after ALO-01 crushed. By comparison, the median t(max) for morphine with ALO-01 whole was 8.1 hours. The maximum effect (E(max)) of MSS was significantly greater than placebo on pupillometry and the subjective measures (all p < 0.001). ALO-01 whole and crushed produced lower E(max) values and flatter effect-time profiles for subjective measures and caused less pupillary constriction than MSS. CONCLUSION: The results of this study demonstrated that ALO-01, whether taken orally whole as intended or tampered with by crushing and taken orally, had reduced desirability compared with MSS.

Intraadministration associations: conditional hyperalgesia elicited by morphine onset cues.

There is evidence that exteroceptive cues associated with drug administration elicit conditional compensatory responding (e.g., hyperalgesia in organisms with a history of morphine administration). Recently it has become apparent that, within each administration, interoceptive early-drug onset cues (DOCs) may become associated with the later, larger drug effect (intraadministration associations). The present experiments evaluated DOC-elicited conditional hyperalgesia in rats intravenously infused with morphine. The results indicated that DOC-elicited hyperalgesia contributes to tolerance to the analgesic effect of morphine, and such DOC-elicited hyperalgesia is an associative phenomenon, rather than a sensitized response to the opiate. The findings suggest that associative analyses of tolerance should acknowledge the conditional responding elicited by DOCs, and extinction-based addiction treatments should incorporate extinction of DOC-elicited conditional responding.