Pilot Study Evaluating the Trends in Utilization of Compounded Products Pre- and Post- COVID-19 Pandemic

Objectives: To assess utilization differences in compounded products before and after the COVID-19 pandemic. Secondary objectives were to understand if there were changes in patient cost sharing and types of products compounded pre- and post- pandemic. Method(s): A cross-sectional study was completed using a large national claims database for patients who received at least one COVID-related vaccine, test, or treatment from October 2015 to July 2022. Claims included in the analysis are those identified as paid, listed as compounded, and were filled in 2019, 2020, or 2021. Chi-Square and T-Tests were used to determine if there are differences between each year. Result(s): The prevalence of paid claims for compounded products was 0.00055% (14,101) in 2019, 0.00042% (11,551) in 2020, and 0.00048% (14,005) in 2021. In each year, most claims for compounded products were through commercial insurance 70% in 2019, 62% in 2020, and 65% in 2021. On average there were approximately 2 claims per patient. The most frequently compounded product was lidocaine hydrochloride 20mg/ML topical solution. In 2020 there was an increase in utilization of naltrexone hydrochloride, a treatment for opioid use disorder (OUD). Between 2019 and 2020 the number of compounded claims decreased 17.6% while the number of total claims increased by 9.01%. From 2020 to 2021 the number of claims for compounded products returned to pre-pandemic levels with a 21.24% increase. In the same period, the total number of claims increased 5.86%. The average patient cost sharing for compounded products was $42.57 (SD: $60.02) in 2019, $40.07 ($80.36) in 2020, and $42.61 ($60.02) in 2021. Conclusion(s): We found that there were fewer patients receiving compounded products following the COVID-19 pandemic. We found no change in the number of compounded claims for hydroxychloroquine and ivermectin, though in 2020, there was a notable increase in the number of claims for naltrexone hydrochloride.Copyright © 2023

Covid-19 Fatigue: Diagnosis and Treatment for the Osteopathic Physician

The novel coronavirus disease 2019 (COVID-19) has given rise to a global pandemic, as well as a multitude of long-term sequelae that continue to perplex physicians around the world, including in the United States. Among the most common and impactful long-haul symptoms experienced by survivors is COVID-19 fatigue. This review will use long COVID-19, post-acute COVID-19 syndrome (PCS), and PostAcute Sequelae of COVID-19 (PASC) as synonymous terms to refer to the chronic symptomatology;chronic fatigue associated with PASC will be referred to as COVID-19 fatigue. While the knowledge and research on the exact pathophysiological mechanisms involved in the disease is still limited, parallels have been drawn between fatigue as a component of long COVID-19 and myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). Current studies suggest applying principles of pathophysiology, diagnosis, and treatment similar to those for ME/CFS in order to aid in managing chronic fatigue in COVID-19 survivors, particularly in the primary care setting. The osteopathic family physician can use the proposed pharmacologic agents, along with osteopathic manipulative treatment (OMT), as therapeutic modalities that can be tailored to each patient's unique case. Nevertheless, research on proven successful treatments is still scarce. For that reason, it is essential that COVID-19 fatigue is recognized early, especially since its longitudinal impacts may be debilitating for many. This review of the available literature on COVID-19 fatigue aims to help provide quality care and lessen the disease burden experienced by patients.Copyright © 2023 by the American College of Osteopathic Family Physicians. All rights reserved.

The Promise and Challenges of Integrating Real-World Evidence in Clinical Research

The role of real-world evidence (RWE) in regulatory, drug development, and healthcare decision-making is rapidly expanding. While RWE cannot substitute the evidence obtained from randomized controlled studies (RCTs), the two can be viewed as complementary sources with the same goal of understanding and improving patient's outcomes. However, the hopes of RWE have been tempered by several critical aspects/ challenges such as quality of data sources, potential for systematic bias, or formulating a research question using causal inference framework. In this session, we will discuss commonly encountered issues and recommend key methodological considerations and potential solutions for (1) assessing representativeness and generalizing results from experimental to non-experimental studies, (2) identifying under-represented groups in clinical trials for pharmacotherapy for opioid use disorder, (3) characterizing and increasing diversity in clinical trials, and (4) assessing biases and constructing valid ''synthetic control'' arms for (oncology) clinical trials. Each speaker will have 15-20 min each, followed by a 10-min discussion. Additional Q&A time will be allocated at the end of the session. The individual s are described in more detail below. (1) Ben Ackerman;Title: Using real-world data to assess representativeness and improve generalizations of study findings Randomized trials are considered the gold standard for estimating causal effects. Trial findings are often used to inform policy and programming efforts, yet their results may not generalize well to a relevant target population if the trial sample is not representative of the population of interest. More specifically, generalizations will be hindered if a trial is not similar to the population with respect to characteristics that moderate the treatment effect. Statistical methods have been developed to assess representativeness and improve generalizability by combining trials with data from non-experimental studies. Real-world datasets derived from electronic health records are promising resources that can supplement trial data when applying such methods. However, identifying the right real-world data source with the appropriate characteristics captured can be challenging in practice. In this talk, we will articulate a framework for combining trial and real-world data to assess representativeness and ultimately addressing concerns of generalizability. Through this framework, we will provide guidance on defining the target population of interest, identifying a suitable real-world data source describing that population, harmonizing across the data sources, and drawing meaningful comparisons between the trial and target population. This work will provide researchers with methods and tools to contextualize trial findings within the target population of interest through the use of real-world data. (2) Kara Rudolph;Title: Characterizing subgroups that are under-represented in clinical trials for pharmacotherapy for opioid use disorder The opioid epidemic in the United States is a public health emergency, exacerbated by the Covid-19 pandemic. Medications for opioid use disorder (MOUD)- injection naltrexone, buprenorphine, and methadone- are the most effective tools for improving outcomes and preventing overdose among persons with opioid use disorder (OUD), but engagement in MOUD, especially long-term engagement typically required for a successful outcome, is unacceptably low. Long-term engagement rates tend to be even lower in real-world settings-what National Institute on Drug Abuse (NIDA) has termed the research-to-practice gap. This discrepancy between trial and real-world MOUD effectiveness could be partially attributable to differences between clinical trial and real-world population characteristics (e.g. in terms of psychiatric and substance use comorbidities, previous treatment experience, and immigration status) if treatment effects are modified (increased/decreased) by some of these characteristics that also relate to trial participation. We identif and characterize clinically meaningful, interpretable subgroups of persons seeking OUD treatment in US usualcare settings who are not represented or underrepresented in MOUD trials based on multiple characteristics simultaneously. This moves us beyond existing approaches for assessing representation that have generally been limited to considering one individual-level characteristic at a time (e.g. race/ethnicity). (3) Madison Stoms;Title: Minority representation in clinical trials: generalizing trial results to diverse populations Since its origin, medical research has persistently lacked minority representation. In 2020 alone, the US Food and Drug Administration (FDA) reported that a mere 6% and 11% of clinical trial participants report Black and Hispanic race, respectively. Along with efforts to directly increase representation, via revised recruitment strategies, methods are being developed to leverage external data containing information on under-represented populations. The field from which these methods arise, real-world evidence (RWE), is rapidly emerging and aims to address clinical questions outside the scope of clinical trials. In this talk, we focus on generalizability and transportability methods, which can be used to extrapolate results from mostly racially homogeneous samples to diverse populations. We will also discuss the current state of diversity in clinical trials, important assumptions of generalizability and transportability methods, and applications relevant to increasing racial/ethnic representation. (4) Elizabeth Garrett-Mayer;Title: Leveraging RWD for new indications for FDA-approved anticancer agents: are we there yet? Vast amounts of health outcome data are available in real-world datasets (RWDs), like electronic health record databases and medical claim databases. In rare disease settings, performing randomized trials may be resource-intensive and inefficient due to accrual challenges. Efforts have been made to derive ''control arms'' from RWDs, representing a standard of care treatment arm, so all (or most) patients prospectively enrolled in a trial can be assigned to an experimental arm. Major challenges exist in ensuring that comparisons between the arms are meaningful, valid, and unbiased. This talk will discuss challenges, including potential for biases, harmonizing outcome measures, and efforts moving forward that will facilitate supplementing clinical trial data with RWD.

The impact of COVID-19 on the treatment of opioid use disorder in carceral facilities: a cross-sectional study.

While the COVID-19 pandemic disrupted healthcare delivery everywhere, persons with carceral system involvement and opioid use disorder (OUD) were disproportionately impacted and vulnerable to severe COVID-associated illness. Carceral settings and community treatment programs (CTPs) rapidly developed protocols to sustain healthcare delivery while reducing risk of COVID-19 transmission. This survey study assessed changes to OUD treatment, telemedicine use, and re-entry support services among carceral and CTPs participating in the National Institute on Drug Abuse (NIDA)-funded study, Long-Acting Buprenorphine vs. Naltrexone Opioid Treatments in Criminal Justice System-Involved Adults (EXIT-CJS) study. In December 2020, carceral sites (n = 6; median pre-COVID 2020 monthly census = 3468 people) and CTPs (n = 7; median pre-COVID 2020 monthly census = 550 patients) participating in EXIT-CJS completed a cross-sectional web-based survey. The survey assessed changes pre- (January-March 2020) and post- (April-September 2020) COVID-19 in OUD treatment, telemedicine use, re-entry supports and referral practices. Compared to January-March 2020, half of carceral sites (n = 3) increased the total number of persons initiating medication for opioid use disorder (MOUD) from April-September 2020, while a third (n = 2) decreased the number of persons initiated. Most CTPs (n = 4) reported a decrease in the number of new admissions from April-September 2020, with two programs stopping or pausing MOUD programs due to COVID-19. All carceral sites with pre-COVID telemedicine use (n = 5) increased or maintained telemedicine use, and all CTPs providing MOUD (n = 6) increased telemedicine use. While expansion of telemedicine services supported MOUD service delivery, the majority of sites experienced challenges providing community support post-release, including referrals to housing, employment, and transportation services. During the COVID-19 pandemic, this small sample of carceral and CTP sites innovated to continue delivery of treatment for OUD. Expansion of telemedicine services was critical to support MOUD service delivery. Despite these innovations, sites experienced challenges providing reintegration supports for persons in the community. Pre-COVID strategies for identifying and engaging individuals while incarcerated may be less effective since the pandemic. In addition to expanding research on the most effective telemedicine practices for carceral settings, research exploring strategies to expand housing and employment support during reintegration are critical.

Low-dose naltrexone reduced anxiety in persons with multiple sclerosis during the COVID-19 pandemic.

Persons with multiple sclerosis (PwMS) have been considered at high risk for vaccination and/or acquisition of COVID-19 related to their reduced immune systems and daily regimen of immune suppressing therapy. Substantiated and unsubstantiated reports on these unknown circumstances increased anxiety and depression. Low-dose naltrexone (LDN) is a potentially effective off-label therapy shown to be effective at controlling fatigue for several autoimmune disorders including MS. This study utilized a small population of PwMS from central Pennsylvania in order to determine whether LDN therapy altered their perceived anxiety or depression during the early months of COVID-19. Utilizing mailed surveys, self-reported anxiety and depression scores were found to be significantly lower for PwMS who were prescribed LDN either alone or as an adjuvant to a standard disease modifying therapy (DMT) in comparison to those on oral disease-modifying therapies (DMTs). The data suggest that the non-toxic, inexpensive biotherapeutic may be beneficial in lessening anxiety.

The impact of COVID-19 and rapid policy exemptions expanding on access to medication for opioid use disorder (MOUD): A nationwide Veterans Health Administration cohort study.

BACKGROUND: In March 2020, Veterans Health Administration (VHA) enacted policies to expand treatment for Veterans with opioid use disorder (OUD) during COVID-19. In this study, we evaluate whether COVID-19 and subsequent OUD treatment policies impacted receipt of therapy/counseling and medication for OUD (MOUD). METHODS: Using VHA's nationwide electronic health record data, we compared outcomes between a comparison cohort derived using data from prior to COVID-19 (October 2017-December 2019) and a pandemic-exposed cohort (January 2019-March 2021). Primary outcomes included receipt of therapy/counseling or any MOUD (any/none); secondary outcomes included the number of therapy/counseling sessions attended, and the average percentage of days covered (PDC) by, and months prescribed, each MOUD in a year. RESULTS: Veterans were less likely to receive therapy/counseling over time, especially post-pandemic onset, and despite substantial increases in teletherapy. The likelihood of receiving buprenorphine, methadone, and naltrexone was reduced post-pandemic onset. PDC on MOUD generally decreased over time, especially methadone PDC post-pandemic onset, whereas buprenorphine PDC was less impacted during COVID-19. The number of months prescribed methadone and buprenorphine represented relative improvements compared to prior years. We observed important disparities across Veteran demographics. CONCLUSION: Receipt of treatment was negatively impacted during the pandemic. However, there was some evidence that coverage on methadone and buprenorphine may have improved among some veterans who received them. These medication effects are consistent with expected COVID-19 treatment disruptions, while improvements regarding access to therapy/counseling via telehealth, as well as coverage on MOUD during the pandemic, are consistent with the aims of MOUD policy exemptions.

Alcohol Use and misuse during the COVID-19 pandemic

GPs can play a pivotal role in the identification and management of alcohol problems at any time, and their role is even more important during the COVID-19 pandemic as more and more patients are resorting to alcohol to manage the stress and anxiety created by the pandemic. © 2021 Medicine Today Pty Ltd. All rights reserved.

PRESCRIBER AND PRACTICE CHARACTERISTICS ASSOCIATED WITH SUPPORT FOR OFFICE-BASED METHADONE: FINDINGS FROM A NATIONAL SURVEY

BACKGROUND: Methadone reduces opioid-related harms and overdose deaths in those with opioid use disorder (OUD) yet in the US is restricted to federal and state-regulated opioid treatment programs (OTPs). Methadone access remains limited, particularly in rural settings. We sought to determine prescriber and practice characteristics associated with support for provision of methadone through office-based settings. METHODS: We performed a secondary analysis of the Opioid Use Disorder Provider COVID-19 Survey, a survey collaboratively developed with multistakeholder input to explore the impact of COVID-19-related practice changes among X-waivered buprenorphine prescribers. Data were collected from July to August 2020 electronically and analyses herein were restricted to prescribers who provided outpatient, longitudinal care for adults with OUD. The outcome variable was selecting “The opportunity for patients to receive office-based methadone” when asked “Which of the pandemic-related federal policy changes or new policy changes would you like to be continued after the pandemic?” Sequential multivariable logistic regression analyses were performed to determine prescriber and practice characteristics associated with support for the opportunity for patients to receive office-based methadone. RESULTS: Among invited participants, 1,900 initiated and completed the survey. Among the 739 respondents included in the analysis, 52% were men, 60% were ≥50 years old, 81% were White, 39% were board certified in Addiction Medicine/Psychiatry, 44% were practicing in family medicine or internal medicine, and 20% in psychiatry. Nineteen percent had prescribed medications to treat OUD (MOUD) for ≥15 years, 20% had ordered methadone previously, and 21% worked in OTPs. Twenty-nine percent indicated support for office-based methadone. In sequential multivariable logistic regression models, factors associated with support for office-based methadone, compared to being White, were being Asian (AOR=2.23;95% [CI] = 1.01, 5.04), Black/African-American (AOR=3.36;95% [CI] = 1.30, 8.71);having prescribed MOUD for ≥15 years (OR=2.06;95% [CI] = 1.15, 3.66) compared to 0-5 years;having ordered methadone previously (AOR=1.71;95% [CI] = 1.03, 2.83) or having prescribed injectable naltrexone previously (AOR=1.70;95% [CI] = 1.14, 2.56) compared to not prescribing MOUD previously;and working in an academic medical center (AOR=1.87;95% [CI] = 1.11, 3.14) compared to working in other clinical practice settings. CONCLUSIONS: Nearly a third of X-waivered buprenorphine prescribers supported provision of office-based methadone, specifically prescribers of Asian, Black, or African-American backgrounds, who had spent a longer time treating OUD, and had experience providing methadone. Future efforts should explore pathways to include office-based methadone to improve access to OUD treatment.

A COMPARISON BETWEEN REAL WORLD WEIGHT LOSS OUTCOMES WITH ANTI-OBESITY MEDICATIONS BEFORE AND DURING COVID-19 PANDEMIC

Background: Obesity is a chronic and relapsing disease, with a rising prevalence and a high economic burden. Obesity is a risk factor for COVID-19 infection severity and mortality. Anti-obesity medications (AOMs) are safe and effective for weight loss. However, weight loss outcomes with AOMs during the COVID-19 pandemic are yet to be described. We hypothesized that weight loss outcomes with AOMs during COVID-19 are inferior to those before this period. Methods: We performed a systematic review of electronic medical record of patients from the Mayo Clinic Health System. We included all patients who started a long-term FDA-approved AOM (phentermine-topiramate extended release [PHEN-TOP], naltrexone-bupropion sustained release [NBSR], and liraglutide 3.0 mg). We excluded patients with a history of bariatric surgery or endoscopic procedure, those taking ≥2 AOMs, ≥3 months of prescribed AOM, and/or pregnancy. Demographic and anthropometric data were ed from in person or virtual encounters. Analysis was divided by 1) those who started an AOM at least a year before COVID-19 restrictions were set in place in the USA (i.e. first quarter of 2019 period or earlier, defined as “PreCOVID-19”), and 2) those who started an AOM during or after the first quarter of 2020, (defined as “COVID-19''). We calculated the total body weight loss percentage (TBWL%) at 3, 6, and 12 months after AOM initiation along with the percentage of patients who achieved a TBWL ³5% and ³10%, after one year of starting an AOM. Our primary endpoint was the TBWL% at 12 months. All tests were two-tailed and p-value <0.05 was considered statistically significant. Values are presented as mean ± standard deviation (SD). Results: A total of 249 patients were included in the analysis (77% female, age 48.8±12.6 years, body-mass index [BMI] 41.9±8.6 kg/m2). There were no differences in baseline characteristics between both groups (Table 1). Fifty-five percent of the patients were prescribed PHEN-TOP, 16% NBSR, and 29% liraglutide. There was a statistical difference in TBWL% between the PreCOVID-19 group compared to the COVID-19 group: 5.3±3.5% vs 4±3.7% (p=0.03) and 9.6±7% vs 6.5±5.3% (p=0.02) at 3 and 12 months, respectively (Fig. 1A). After 1 year follow-up, 53.6% of patients in the COVID-19 group achieved >5% TBWL compared with 75.3% in the PreCOVID-19 group (p=0.04), and 17.9% of patients in the COVID-19 group achieved 105% TBWL compared with 44.7% in the PreCOVID-19 group (p=0.01) (Fig. 1B). Conclusion: This study shows that weight loss outcomes to AOMs were inferior when prescribed during COVID-19 pandemic, compared to the outcomes observed prior to this. Further studies are needed to understand whether this observation is due to changes in care delivery during the pandemic or due to individual factors such as stress, decreased physical activity, remote working, among others.(Table Presented)Table 1. The demographic, antiobesity medications, and weight loss outcome distribution among patients Pre- and COVID-19.(Figure Presented) Figure 1. The weight loss outcomes of patients (Pre and COVID-19) after one year of AOM therapy (A). The distribution of patients (Pre and COVID-19) achieving >5% and >10% TBWL following one year of AOM (B).

Medication prescribing for alcohol use disorders during alcohol-related encounters in a Colorado regional healthcare system.

RATIONALE: Investigations show that medications for alcohol use disorders (MAUD) reduce heavy drinking and relapses. However, only 1.6% of individuals with alcohol use disorders (AUD) receive MAUD across care settings. The epidemiology of MAUD prescribing in the acute care setting is incompletely described. We hypothesized that MAUD would be under prescribed in inpatient acute care hospital settings compared to the outpatient, emergency department (ED), and inpatient substance use treatment settings. METHODS: We evaluated electronic health record (EHR) data from adult patients with an International Classification of Diseases, 10th revision (ICD-10) alcohol-related diagnosis in the University of Colorado Health (UCHealth) system between January 1, 2016 and 31 December, 2019. Data from patients with an ICD-10 diagnosis code for opioid use disorder and those receiving MAUD prior to their first alcohol-related episode were excluded. The primary outcome was prescribing of MAUD, defined by prescription of naltrexone, acamprosate, and/or disulfiram. We performed bivariate and multivariate analyses to identify independent predictors of MAUD prescribing at UCHealth. RESULTS: We identified 48,421 unique patients with 136,205 alcohol-related encounters at UCHealth. Encounters occurred in the ED (42%), inpatient acute care (17%), inpatient substance use treatment (18%), or outpatient primary care (12%) settings. Only 2270 (5%) patients received MAUD across all settings. Female sex and addiction medicine consults positively predicted MAUD prescribing. In contrast, encounters outside inpatient substance use treatment, Hispanic ethnicity, and black or non-white race were negative predictors of MAUD prescribing. Compared to inpatient substance use treatment, inpatient acute care hospitalizations for AUD was associated with a 93% reduced odds of receiving MAUD. CONCLUSIONS: AUD-related ED and inpatient acute care hospital encounters in our healthcare system were common. Nevertheless, prescriptions for MAUD were infrequent in this population, particularly in inpatient settings. Our findings suggest that the initiation of MAUD for patients with alcohol-related diagnoses in acute care settings deserves additional evaluation.

WORSENING OF LETHARGY POST SARS-COV-2 VACCINATION IN A PATIENT WITH ME/CFS

Introduction: Since the SARS-CoV-2 (severe acute respiratory syndrome coronavirus2) vaccination started there have been multiple reports of different off target adverse effects related to the vaccination, such as myocarditis, immune mediated thrombosis, thrombocytopenia and allergic reactions. W Murphy and Dan Longo in the NEJM November 2021 reported these adverse effects associated with Anti-idiotype antibodies (Ab2) in SARS-CoV-2 vaccination. The pathologic cascade of Ab2 is described in several ways as the antibodies can bind to the protective normal antibodies (Ab1) resulting in immune complex formation and clearance thus impairing Ab1 efficacy. Another action of the Ab2 could be inhibiting normal ligands affecting interaction with angiotensin converting enzyme 2 (ACE2) receptors or stimulating the ACE2 receptor and downregulating the ACE2 function. There is also a description of complementmediated and immune cell attack on ACE2 expressing cells (1). The case reported in this manuscript is related to a severe deterioration in a male with previous diagnose of ME/CFS with worsening lethargy and cognitive skills after SARS-CoV-2 vaccination. The outstanding clinical improvement after starting oral Colchicine is the reason for this paper. Case Report: A 46-year-old male with a previous history of Sarcoidosis and Haemochromatosis had ME/CFS since 2016. He was followed up at Noosa Hospital clinic related to his ME/CFS. His general symptoms related to this condition were under control and he was able to work and study at the University. After the second dose of his SARS-CoV-2 (Pfizer -BioNTech COVID-19) vaccination in August 2021 his general condition deteriorated. During September-October 2021 his cognitive skills declined and he had to stop his university studies. The patient also stopped driving his car because of lethargy and could not do any sport recreational activity. Because of ME/CFS he was on treatment with multivitamins and low dose Naltrexone and Spironolactone before vaccination. After the ME/CFS clinical deterioration the decision was to start Colchicine 0.5 mg a day (November 2021). After four weeks of Colchicine plus his previous medication, his level of energy and cognitive skills recovered to pre vaccination status. Discussion: The immunologic cascade after SARS-CoV-2 vaccination triggered by Ab2 ended in activation of pyrin domain containing protein3 (NRLP3 Inflammasome). This is the pattern of activation for interleukin (IL-1beta). This may determine a general increase in the systemic and microglia inflammation as described in ME/CFS. The clinical manifestation in the present case was worsening in the symptoms of the ME/CFS. The patient was already on Spironolactone targeting the increase on number of macrophages ACE2 receptors as immune modulation. An anti-inflammatory synergy between Colchicine and Spironolactone is currently the focus of research in atherosclerosis. Colchicine has a direct effect on phagocytes leading to inflammasome inhibition and impaired production of IL-1 beta. Conclusion: The Colchicine had a beneficial effect in recovering this patient from an exacerbation of his ME/CFS induced by SARS-CoV-2 vaccination.

Real-World Dispensing of Buprenorphine and Methadone from MAR 2019 to MAR 2021 in California

Objectives: The US is amid a national opioid crisis before and during the COVID-19 pandemic. The Food and Drug Administration has approved methadone, buprenorphine, and naltrexone as medications for opioid use disorder (MOUD). This study examined the real-world dispensing of MOUD. Methods: All dispensing pharmacies, clinics, or other dispensers of Schedule II-V controlled substances in California report to the Controlled Substance Utilization Review and Evaluation System (CURES) on the day of prescriptions refills. Leveraging the data of buprenorphine (schedule III) and methadone (Schedule II) prescriptions from Mar 2019-Mar 2021 employing California’s deidentified CURES database, this study examined real-world dispensing of methadone and buprenorphine before (03/19/2019-03/18/2020) and during the pandemic (03/19/2020-03/18/2021). We did not review naltrexone dispensing, which is not a controlled substance. Results: In Mar 2019-Mar 2021, 182,367 patients≥18 in California obtained 875,051 buprenorphine and methadone prescriptions: Before the pandemic, there were 482,965 MOUD prescriptions dispensed to 116,644 patients;since the pandemic, 97,887 patients received 392,086 prescriptions, of which 32,164 patients(as “non-naïve” patients) started their MOUD before Mar 2020. On average, patients refilled their prescriptions 4.1 times/year before the pandemic and 4.0 times/year since the pandemic. The MOUD non-naïve patients (n=32,164) received 8.1 prescriptions/year before Mar 2020 and 7.4 refills/year afterward. The MOUD medications most widely prescribed in Mar 2019-Mar 2021 were buprenorphine (473,206 (98.0%) and 383,297 (97.8%), respectively, before and after the pandemic), which included 802,936 counts of buprenorphine alone and 53,567 combination medications of buprenorphine and naloxone. The number of methadone prescriptions declined from 9,759 before Mar 2020 to 8,789 during the pandemic. Conclusions: Buprenorphine is the leading MOUD prescribed for patients in California. The decline in MOUD dispensing for non-naïve patients may indicate restricted access to medication-assisted treatment under the pandemic. Policymakers should maintain or modify the policy strategies to help support medication access.

Fibromyalgia syndrome: year in review

The aim of this review is to describe the most recent findings concerning the diagnosis, aetiopathogenesis and treatment of fibromyalgia syndrome (FM) that were published between January 2021 and January 2022 and appearing on PubMed database. Year 2021 saw the publication of many papers which tried to estimate the big COVID-19 impact on FM patient's lives, both from a physical and a mental point of view (1-3). Moreover, more and more attention has been put on juvenile fibromyalgia, which is surging as a distinct clinical entity which needs prompt diagnosis (4), and, as the adult counterpart, if it is comorbid with a rheumatic disease, it increases the perception of disease activity with respect to physician's evaluation. The most important publications last year were centered on the aetiopathogenesis of FM. One of the things that has to be kept in mind is the extreme importance of trauma in the life of these individuals. An interesting metaanalysis by Kaleycheva et al. (5) comprising nineteen studies confirms that there is a significant association between stressor exposure and adult FM, with the strongest associations observed for physical abuse (physical abuse (OR 3.23, 95% confidence interval 1.99-5.23) and total abuse (3.06, 1.71-5.46);intermediate for sexual abuse (2.65, 1.85-3.79) and smaller for medical trauma (1.80, 1.19-2.71), other lifetime stressors (1.70, 1.31-2.20), and emotional abuse (1.52, 1.27-1.81)). In addition, an autoantibody-centered theory is now developing. The most important recent study in this perspective comes from a study by Goebel et al. published on Journal of Clinical Investigation (6). Researchers found that mice treated with IgG from FM patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FM IgG displayed an increased responsiveness to cold and mechanical stimulation. From the therapeutic point of view, few studies worth mentioning focused on the pharmacological treatment of FM;in particular, well-conducted clinical trials were about ketamine and low-dose naltrexone (7, 8). Most of 2021 studies focused on neurostimulation in FM patients, in particular on repetitive transcranial magnetic stimulation (rTMS) or direct current stimulation (DCS) (9, 10 etc.).

Repurposing low-dose naltrexone for the prevention and treatment of immunothrombosis in COVID-19.

Coronavirus disease 2019 (COVID-19) is characterized by striking dysregulation of the immune system, with evidence of hyperinflammation, an impaired induction of interferons, and delayed adaptive immune responses. In addition to dysfunctional immune responses, thrombosis is a hallmark of severe COVID-19. Because traditional anticoagulation strategies are associated with increased bleeding, novel strategies that address both the immune and thrombotic dysfunction associated with COVID-19 would be of tremendous benefit. In this commentary, we discuss the unique properties of low dose naltrexone (LDN) which could be leveraged to reduce the immune-mediated thrombotic complications in COVID-19. Mechanistically, LDN can blunt innate immune responses and Toll-like receptor (TLR) signaling, reducing interleukin1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interferon (IFN) levels. Because of the immune-mediated thrombotic mechanisms that underlie COVID-19, we hypothesize that the immune-modulating and known pharmacologic properties of LDN could be leveraged as a novel therapeutic strategy in COVID-19.

Trends in pharmacy-based dispensing of buprenorphine, extended-release naltrexone, and naloxone during the COVID-19 pandemic by age and sex - United States, March 2019 - December 2020.

BACKGROUND: COVID-19 stay-at-home orders may reduce access to substance use treatment and naloxone, an opioid overdose reversal drug. The objective of this analysis was to compare monthly trends in pharmacy-based dispensing rates of medications for opioid use disorder (MOUD) (buprenorphine and extended-release [ER] naltrexone) and naloxone in the United States during March 2019-December 2020 by age and sex. METHODS: We calculated monthly prescription dispensing rates per 100,000 persons using IQVIA New to Brand. We used Joinpoint regression to calculate monthly percent change in dispensing rates and Wilcoxon Rank Sum tests to examine differences in median monthly rates overall, and by age and sex between March 2019-December 2019 and March 2020-December 2020. RESULTS: Buprenorphine dispensing increased among those aged 40-64 years and ≥ 65 years from March 2019 to December 2020. Median rates of total ER naltrexone dispensing were lower in March 2020-December 2020 compared to March 2019-December 2019 for the total population, and for females and males. From March 2019 to December 2020, ER naltrexone dispensing decreased and naloxone dispensing increased for those aged 20-39 years. CONCLUSIONS: Dispensing ER naltrexone declined during the study period. Given the increase in substance use during the COVID-19 pandemic, maintaining equivalent access to MOUD may not be adequate to accommodate rising numbers of new patients with opioid use disorder. Access to all MOUD and naloxone could be further expanded to meet potential needs during and after the public health emergency, given their importance in preventing opioid overdose-related harms.

Prescribers' satisfaction with delivering medications for opioid use disorder.

BACKGROUND: Expanding access to medications for opioid use disorder (MOUD), such as buprenorphine and extended release (XR) naltrexone, is critical to addressing the US opioid epidemic, but little is known about prescriber satisfaction with delivering these two types of MOUD. The current study describes the satisfaction of prescribers delivering buprenorphine and XR-naltrexone while examining whether satisfaction is associated with current patient census and organizational environment. METHODS: As part of a cluster randomized clinical trial (RCT) focused on expanding access to medication for opioid use disorder, 41 MOUD prescribers in Florida, Ohio, and Wisconsin completed a web-based survey. The survey included measures of prescriber satisfaction with delivering buprenorphine treatment and XR-naltrexone. In addition, the survey measured several prescriber characteristics and their perceptions of the organizational environment. RESULTS: Prescribers were generally satisfied with their work in delivering these two types of MOUD. Prescribers reporting a greater number of patients (r = .46, p = .006), those who would recommend the center to others (r = .56, p < .001), and those reporting positive relationships with staff (r = .56, p < .001) reported significantly greater overall satisfaction with delivering buprenorphine treatment. Prescribers who more strongly endorsed feeling overburdened reported lower overall buprenorphine satisfaction (r = -.37, p = .02). None of the prescriber characteristics or perceptions of the organizational environment were significantly associated with overall satisfaction with delivering XR-naltrexone treatment. CONCLUSIONS: The generally high levels of satisfaction with both types of MOUD is notable given that prescriber dissatisfaction can lead to turnover and impact intentions to leave the profession. Future research should continue to explore the prescriber characteristics and organizational factors associated with satisfaction in providing different types of MOUD. REGISTRATION: ClinicalTrials.gov. NCT02926482. Date of registration: September 9, 2016. https://clinicaltrials.gov/ct2/show/NCT02926482 .

Treatment of overdose in the synthetic opioid era.

Overdose deaths are often viewed as the leading edge of the opioid epidemic which has gripped the United States over the past two decades (Skolnick, 2018a). This emphasis is perhaps unsurprising because opioid overdose is both the number-one cause of death for individuals between 25 and 64 years old (Dezfulian et al., 2021) and a significant contributor to the decline in average lifespan (Dowell et al., 2017). Exacerbated by the COVID 19 pandemic, it was estimated there were 93,400 drug overdose deaths in the United States during the 12 months ending December 2020, with more than 69,000 (that is, >74%) of these fatalities attributed to opioid overdose (Ahmad et al., 2021). However, the focus on mortality statistics (Ahmad et al., 2021; Shover et al., 2020) tends to obscure the broader medical impact of nonfatal opioid overdose. Analyses of multiple databases indicate that for each opioid-induced fatality, there are between 6.4 and 8.4 non-fatal overdoses, exacting a significant burden on both the individual and society. Over the past 7-8 years, there has been an alarming increase in the misuse of synthetic opioids ("synthetics"), primarily fentanyl and related piperidine-based analogs. Within the past 2-3 years, a structurally unrelated class of high potency synthetics, benzimidazoles exemplified by etonitazene and isotonitazene ("iso"), have also appeared in illicit drug markets (Thompson, 2020; Ujvary et al. 2021). In 2020, it was estimated that over 80% of fatal opioid overdoses in the United States now involve synthetics (Ahmad et al., 2021). The unique physicochemical and pharmacological properties of synthetics described in this review are responsible for both the morbidity and mortality associated with their misuse as well as their widespread availability. This dramatic increase in the misuse of synthetics is often referred to as the "3rd wave" (Pardo et al., 2019; Volkow and Blanco, 2020) of the opioid epidemic. Among the consequences resulting from misuse of these potent opioids is the need for higher doses of the competitive antagonist, naloxone, to reverse an overdose. The development of more effective reversal agents such as those described in this review is an essential component of a tripartite strategy (Volkow and Collins, 2017) to reduce the biopsychosocial impact of opioid misuse in the "synthetic era".

Massachusetts Justice Community Opioid Innovation Network (MassJCOIN).

A major driver of the U.S. opioid crisis is limited access to effective medications for opioid use disorder (MOUD) that reduce overdose risks. Traditionally, jails and prisons in the U.S. have not initiated or maintained MOUD for incarcerated individuals with OUD prior to their return to the community, which places them at high risk for fatal overdose. A 2018 law (Chapter 208) made Massachusetts (MA) the first state to mandate that five county jails deliver all FDA-approved MOUDs (naltrexone [NTX], buprenorphine [BUP], and methadone). Chapter 208 established a 4-year pilot program to expand access to all FDA-approved forms of MOUD at five jails, with two more MA jails voluntarily joining this initiative. The law stipulates that MOUD be continued for individuals receiving it prior to detention and be initiated prior to release among sentenced individuals where appropriate. The jails must also facilitate continuation of MOUD in the community on release. The Massachusetts Justice Community Opioid Innovation Network (MassJCOIN) partnered with these seven diverse jails, the MA Department of Public Health, and community treatment providers to conduct a Type 1 hybrid effectiveness-implementation study of Chapter 208. We will: (1) Perform a longitudinal treatment outcome study among incarcerated individuals with OUD who receive NTX, BUP, methadone, or no MOUD in jail to examine postrelease MOUD initiation, engagement, and retention, as well as fatal and nonfatal opioid overdose and recidivism; (2) Conduct an implementation study to understand systemic and contextual factors that facilitate and impede delivery of MOUDs in jail and community care coordination, and strategies that optimize MOUD delivery in jail and for coordinating care with community partners; (3) Calculate the cost to the correctional system of implementing MOUD in jail, and conduct an economic evaluation from state policy-maker and societal perspectives to compare the value of MOUD prior to release from jail to no MOUD among matched controls. MassJCOIN made significant progress during its first six months until the COVID-19 pandemic began in March 2020. Participating jail sites restricted access for nonessential personnel, established other COVID-19 mitigation policies, and modified MOUD programming. MassJCOIN adapted research activities to this new reality in an effort to document and account for the impacts of COVID-19 in relation to each aim. The goal remains to produce findings with direct implications for policy and practice for OUD in criminal justice settings.