Concerns With Statistical Analysis of CDC Opioid Guideline and Sickle Cell Outcomes—Reply

In Reply We appreciate the comments regarding our study, “Opioid Prescribing and Outcomes in Patients With Sickle Cell Disease Post-2016 CDC Guideline,” which accessed the periods before and after the changed approach for chronic pain in patients with sickle cell disease (SCD). First, we would like to restate our interpretation of the study findings. Although the interrupted time series method is a robust quasi-experimental design and has been widely used to evaluate the impact of health policies on health care outcomes, we clearly stated that our study finding was an association of the 2016 CDC guideline’s release with the outcomes (ie, a decrease in opioid prescription outcomes and an increase in pain-related hospitalizations in patients with SCD). Equally important, it is well documented that patients with SCD experience stigmatization despite having substantially lower opioid-related death rates compared to individuals with other chronic pain conditions. As we discussed, the CDC acknowledged that the 2016 guideline was not applicable to patients with SCD; additionally, SCD was listed as an excluded condition in the updated 2022 guideline and the use of a disease-specific guideline was recommended. It is our hope that the revised guideline and our research will change restrictive opioid prescription regulations at the state, payer, and/or institutional levels, thus providing prescribers with the latitude to treat patients with opioid analgesics in a clinically appropriate manner.

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Settembre 2024

AI and Big Data approaches to addressing the opioid crisis: a scoping review protocol

Introduction
This paper outlines the steps necessary to assess the latest developments in artificial intelligence (AI) as well as Big Data technologies and their relevance to the opioid crisis. Fatal opioid overdoses have risen to over 82 998 annually in the USA. This highlights the need for urgent and effective data-driven solutions. AI approaches, such as machine learning, deep learning and natural language processing, have been employed to analyse patterns and trends in overdose data and facilitate timely interventions. However, a comprehensive scoping review on the effectiveness of AI-driven technologies to detect, treat, prevent or respond to the opioid crisis remains absent. Thus, it is important to identify recent advancements in AI and Big Data technologies in addressing the opioid crisis.

Methods and analysis
We will electronically search four scientific databases (PubMed, Web of Science, Engineering Village and PsycInfo), including finding reference lists and grey literature from 2013 to 2023. Covidence will be used for screening and selecting papers. We will extract information such as citation details, study context, data used, AI/Big Data technologies, features, algorithms and evaluation metrics. This data will be synthesised, analysed and summarised to draw meaningful conclusions and identify future directions to tackle the opioid crisis.

Ethics and dissemination
Ethics approval is not required. Results will be disseminated via conference presentations and peer-reviewed publication.

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Agosto 2024

Protocol for a randomised trial of a self-directed digital pain management intervention (Empowered Relief) tailored to adults with chronic pain and prescription opioid misuse/disorder: the MOBILE Relief study

Introduction
Chronic pain increases the risk of prescription opioid misuse or opioid use disorder (OUD). Non-pharmacological treatments are needed to dually address pain and opioid risks. The purpose of the Mobile and Online-Based Interventions to Lessen Pain (MOBILE Relief) study is to compare a one-session, video-based, on-demand digital pain relief skills intervention for chronic pain (‘Empowered Relief’ (ER); tailored to people at risk for opioid misuse or with opioid misuse/OUD) to a one-session digital health education intervention (‘Living Better’; no pain management skills).

Methods and analysis
MOBILE Relief is an international online randomised controlled clinical trial. Study participants are adults with chronic, non-cancer pain (≥6 months) with daily pain intensity ≥3/10, taking ≥10 morphine equivalent daily dose and score ≥6 on the Current Opioid Misuse Measure. Participants are recruited through clinician referrals and clinic advertisements. Study procedures include electronic eligibility screening, informed consent, automated 1:1 randomisation to the treatment group, baseline measures, receipt of assigned digital treatment and six post-treatment surveys spanning 3 months. Study staff will call participants at baseline and 1-month and 3 months post-treatment to verify the opioid prescription. The main statistical analyses will include analysis of covariance and mixed effects model for repeated measurements regression.

Main outcomes
Primary outcomes are self-reported pain catastrophising, pain intensity, pain interference, opioid craving and opioid misuse at 1-month and 3 months post-treatment. We will determine the feasibility of ER (≥50% participant engagement, ≥70% treatment appraisal ratings). We hypothesise the ER group will be superior to the Living Better group in the reduction of multiprimary pain outcomes at 1-month post-treatment and opioid outcomes at 1-month and 3 months post-treatment.

Ethics and dissemination
The study protocol was approved by the Stanford University School of Medicine Institutional Review Board (IRB 61643). We will publish results in peer-reviewed journals; National Institute of Drug Abuse (funder) and MOBILE Relief participants will receive result summaries.

Trial registration number
NCT05152134.

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Agosto 2024

'Unusual HCV genotype subtypes: origin, distribution, sensitivity to direct-acting antiviral drugs and behaviour on antiviral treatment and retreatment

The high genetic diversity of hepatitis C virus (HCV) has led to the emergence of eight genotypes and a large number of subtypes in limited geographical areas. Currently approved pangenotypic DAA regimens have been designed and developed to be effective against the most common subtypes (1a, 1b, 2a, 2b, 2c, 3a, 4a, 5a and 6a). However, large populations living in Africa and Asia, or who have migrated from these regions to industrialised countries, are infected with ‘unusual’, non-epidemic HCV subtypes, including some that are inherently resistant to currently available direct-acting antiviral (DAA) drugs due to the presence of natural polymorphisms at resistance-associated substitution positions. In this review article, we describe the origin and subsequent global spread of HCV genotypes and subtypes, the current global distribution of common and unusual HCV subtypes, the polymorphisms naturally present in the genome sequences of unusual HCV subtypes that may confer inherently reduced susceptibility to DAA drugs and the available data on the response of unusual HCV subtypes to first-line HCV therapy and retreatment. We conclude that the problem of unusual HCV subtypes that are inherently resistant to DAAs and its threat to the global efforts to eliminate viral hepatitis are largely underestimated and warrant vigorous action.

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Agosto 2024

Implementation of time-limited parenteral hydromorphone in people with treatment-resistant injecting opioid use disorder: a protocol for a single-site, uncontrolled, open-label study to assess feasibility, safety and cost

Introduction
Supervised injectable opioid treatment (SIOT) is an evidence-based intervention targeting opioid-dependent people for whom existing treatments have been ineffective. This project will primarily assess the feasibility and the acceptability of time-limited SIOT using injectable hydromorphone delivered in an existing Australian public opioid treatment programme, with secondary outcomes of safety, cost, changes in drug use and other health outcomes. If feasible, the goal is to scale up the intervention to be more widely available in Australia.

Methods and analysis
Between 20 and 30 participants will be offered two times per day hydromorphone to inject under direct observation, in addition to their current opioid agonist treatment (OAT), for up to 2 years. At the end of 2 years of supervised hydromorphone treatment, participants will be continued on standard OAT only. Informed consent will be obtained from all participants included in the study. This is a single-site, uncontrolled, open-label study where quantitative and qualitative interview data will be collected at baseline, 12 months and lastly at 3 months following their final hydromorphone dose. The main outcome measures are feasibility, as assessed by recruitment, retention and participation in treatment, and acceptability to participants, clinic staff and other stakeholders assessed by qualitative interviews. Secondary outcome measures of safety, as assessed by adverse events, and cost will also be assessed, as well as a range of other drug and health outcomes.

Ethics and dissemination
This study received ethical approval from the St Vincent’s Hospital Human Research Ethics Committee (2019/ETH00418). This will be the first study of time-limited SIOT in the Australian setting. All results will be submitted to peer-reviewed journals, scientific conferences and local practice meetings. A preliminary report on outcomes will also be presented to local health policy makers. A consumer and community forum will also be held to feedback results to a broader audience.

Trial registration number
ACTRN12621001729819.

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Agosto 2024

Opioid prescribing in the Netherlands during the COVID-19 pandemic: a national register-based study

Objectives
The COVID-19 pandemic and related lockdown measures disrupted global healthcare provision, including opioid prescribing. In North America, opioid sales declined while opioid-related deaths increased. In Europe, the effect of the pandemic on prescribing is not yet known. Given the ongoing increase in opioid-related harm and mortality, it is crucial to analyse the impact of the COVID-19 crisis and lockdown measures on opioid prescribing. Therefore, the objective of this study was to characterise opioid prescribing in the Netherlands during the COVID-19 pandemic.

Design
A nationwide register-based study characterising opioid prescribing using aggregated insurance reimbursement data.

Setting
Dutch healthcare during the first 2 years of the COVID lockdown.

Participants
The whole Dutch population.

Primary and secondary outcome measures
Comparing the number of opioid prescriptions during the pandemic with a prepandemic period using a risk ratio (RR), with separate analysis on the prescription type (first-time or repeat prescription), patients’ sex, age and socioeconomic status. We also explored lockdown effects.

Results
During the first lockdown, the total number of new opioid prescriptions and prescriptions to young patients (briefly) decreased (RR 0.88, 95% CI 0.88 to 0.89 and RR 0.73, 95% CI 0.70 to 0.75, respectively), but the overall number of opioid prescriptions remained stable throughout the pandemic compared with prepandemic. Women, older patients and patients living in lower socioeconomic areas received more opioids per capita, but the pandemic did not amplify these differences.

Conclusions
The pandemic appears to have had a limited impact on opioid prescribing in the Netherlands. Yet, chronic use of opioids remains an important public health issue.

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Agosto 2024

PT-IN-MIND: study protocol for a multisite randomised feasibility trial investigating physical therapy with integrated mindfulness (PT-IN-MIND) for patients with chronic musculoskeletal pain and long-term opioid treatment who attend outpatient physical therapy

Introduction
Many individuals receiving outpatient physical therapy have musculoskeletal pain and up to one-third use prescription opioids. The impact of physical therapist-led mindfulness-based interventions integrated with evidence-based physical therapy (I-EPT) to manage patients with chronic musculoskeletal pain and long-term opioid treatment has not been elucidated. This project evaluates the feasibility of conducting a cluster randomised trial to test the effectiveness of I-EPT.

Methods and analysis
Study 1 aim: Refine and manualise the I-EPT treatment protocol. Our approach will use semistructured interviews of patients and physical therapists to refine an I-EPT training manual. Study 2 aim: Evaluate different intensities of physical therapist training programmes for the refined I-EPT treatment protocol. Physical therapists will be randomised 1:1:1 to high-intensity training (HighIT), low-IT (LowIT) training and no training arms. Following training, competency in the provision of I-EPT (LowIT and HighIT groups) will be assessed using standardised patient simulations. Study 3 aim: Evaluate the feasibility of the I-EPT intervention across domains of the Reach, Effectiveness, Adoption, Implementation, Maintenance implementation framework. The refined I-EPT treatment protocol will be tested in two different health systems with 90 patients managed by the randomised physical therapists. The coprimary endpoints for study 3 are the proportions of the Pain, Enjoyment of Life and General Activity Scale and the Timeline Followback for opioid use/dose collected at 12 weeks.

Ethics and dissemination
Ethics approval for the study was obtained from the University of Utah, University of Florida and Florida State University Institutional Review Boards. Informed consent is required for participant enrolment in all phases of this project. On completion, study data will be made available in compliance with NIH data sharing policies.

Trial registration number
NCT05875207.

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Luglio 2024

Effect of modified opioid sparing anaesthesia on postoperative quality of recovery in patients undergoing laparoscopic bariatric surgery: protocol for a monocentre, double-blind randomised controlled trial – the MOSA study

Introduction
Obesity patients undergoing laparoscopic bariatric surgery (LBS) are frequently encountered perioperative adverse events related to opioids-based anaesthesia (OBA) or opioids-free anaesthesia (OFA). While modified opioid-sparing anaesthesia (MOSA) has been shown to lower the occurrence of adverse events related to OBA and OFA. This study is to assess the efficacy of MOSA in enhancing the recovery quality among individuals undergoing LBS.

Methods and analysis
A single-centre, prospective, double-blind, randomised controlled trial is conducted at a tertiary hospital. A total of 74 eligible participants undergoing elective LBS will be recruited and randomly allocated. Patients in the MOSA group will receive a combination of low-dose opioids, minimal dexmedetomidine, esketamine and lidocaine, while in the OBA group will receive standard general anaesthesia with opioids. Patients in both groups will receive standard perioperative care. The primary outcome is the quality of recovery-15 score assessed at 24 hours after surgery. Secondary outcomes include pain levels, anxiety and depression assessments, gastrointestinal function recovery, perioperative complication rates, opioid consumption and length of hospital stay.

Ethics and dissemination
Ethical approval has been provided by the Ethical Committee of Yan’an Hospital of Kunming City (approval No. 2023-240-01). Eligible patients will provide written informed consent to the investigator. The outcomes of this trial will be disseminated in a peer-reviewed scholarly journal.

Trial registration number
The study protocol is registered at https://www.chictr.org.cn/ on 19 December 2023. (identifier: ChiCTR2300078806). The trial was conducted using V.1.0.

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Luglio 2024

Short-term and long-term stroke risk following SARS-CoV-2 infection in relation to disease severity: a Danish national cohort study

Objectives
Studies have reported high incidences of stroke in patients hospitalised with SARS-CoV-2, but the impact of disease severity is unexplored. We aimed to estimate the risk of incident ischaemic stroke in SARS-CoV-2 test-positive individuals compared with test-negative individuals stratified by disease severity during acute infection and post infection.

Design
A register-based cohort study.

Setting
A Danish nationwide study.

Participants
All Danish adults who had PCR tests for SARS-CoV-2 performed between 1 March 2020 and 30 November 2021. Test-positive individuals were included at their first positive test. For individuals tested prior to 30 November 2021, we randomly sampled an index date from the distribution of test dates among SARS-CoV-2 test-positive individuals. Test-positive individuals were followed during the acute phase of infection (days 0–14) and post infection (180 days after the acute phase). Test-negative individuals were followed in equivalent time periods.

Primary and secondary outcome measures
Incident ischaemic stroke risk in SARS-CoV-2 test-positive individuals compared with test-negative individuals during acute infection and post infection. We calculated subdistribution HRs (SHR) with death as a competing risk using propensity score weighting as confounder control. The risk was stratified according to disease severity: community managed, hospitalised, or admission to the intensive care unit.

Results
Among 3 910 219 SARS-CoV-2 PRC-tested individuals, 356 421 test-positive and 3 067 456 test-negative individuals were included. A positive SARS-CoV-2 test was associated with an SHR of 3.32 (95% CI 2.60 to 4.25) overall for stroke compared with test negative in the acute phase. In the postinfection period, the risk of stroke remained increased in individuals hospitalised during the acute phase (SHR 1.85, 95% CI 1.45 to 2.37). Individuals with community-managed SARS-CoV-2 had no increased long-term risk of stroke (SHR 1.01, 95% CI 0.88 to 1.16).

Conclusion
SARS-CoV-2 infection is associated with increased stroke risk. Disease severity seems to be an important factor. Individuals with community-managed SARS-CoV-2 had no increased stroke risk.

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Luglio 2024