The catalytic domains of all human KDM5 JmjC demethylases catalyse N-methyl arginine demethylation.

The demethylation of Nε -methyllysine residues on histones by Jumonji-C lysine demethylases (JmjC-KDMs) has been established. A subset of JmjC-KDMs has also been reported to have Nω -methylarginine residue demethylase (RDM) activity. Here, we describe biochemical screening studies, showing that the catalytic domains of all human KDM5s (KDM5A-KDM5D), KDM4E and, to a lesser extent, KDM4A/D, have both KDM and RDM activities with histone peptides. Ras GTPase-activating protein-binding protein 1 peptides were shown to be RDM substrates for KDM5C/D. No RDM activity was observed with KDM1A and the other JmjC-KDMs tested. The results highlight the potential of JmjC-KDMs to catalyse reactions other than Nε -methyllysine demethylation. Although our study is limited to peptide fragments, the results should help guide biological studies investigating JmjC functions.

Evaluating the use of prescription sequence symmetry analysis as a pharmacovigilance tool: A scoping review.

BACKGROUND: The (prescription) sequence symmetry analysis (PSSA) design has been used to identify potential prescribing cascade signals by assessing the prescribing sequence of an index drug relative to a marker drug presumed to treat an adverse drug event provoked by the index drug. OBJECTIVES: This review aimed to explore the use of the PSSA design as a pharmacovigilance tool with a particular focus on the breadth of identified signals and advances in PSSA methodology. METHODS: We searched Embase, PubMed/Medline, Google Scholar, Web of Science and grey literature to identify studies that used the PSSA methodology. Two reviewers independently extracted relevant data for each included article. Study characteristics including signals identified, exposure time window, stratified analyses, and use of controls were extracted. RESULTS: We identified 53 studies which reported original results obtained using PSSA methodology or quantified the validity of components of the PSSA design. Of those, nine studies provided validation metrics showing reasonable sensitivity and high specificity of PSSA to identify prescribing cascade signals. We identified 340 unique index drug - marker drug signals published in the PSSA literature, representing 281 unique index - marker pharmacological class dyads (i.e., unique fourth-level Anatomical Therapeutic Chemical [ATC] classification dyads). Commonly observed signals were identified for index drugs acting upon the nervous system (34%), cardiovascular system (21%), and blood and blood-forming organs (15%), and many marker drugs were related to the nervous system (25%), alimentary tract and metabolism (23%), cardiovascular system (17%), and genitourinary system and sex hormones (14%). Negative controls and positive controls were utilized in 21% and 13% of studies, respectively. CONCLUSIONS: The PSSA methodology has been used in 53 studies worldwide to detect and evaluate over 300 unique prescribing cascades signals. Researchers should consider sensitivity analyses incorporating negative and/or positive controls and additional time windows to evaluate time-varying biases when designing PSSA studies.

Co-utilization of opioids and nonbenzodiazepine hypnotic drugs in U.S. ambulatory care visits, 2006-2016.

OBJECTIVE(S): This study aimed to characterize the co-utilization of non-benzodiazepine sedative 'Z'-drugs with opioids at ambulatory care visits in the United States. DESIGN: A cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2016 was completed. SETTING AND PARTICIPANTS: Ambulatory care visits in the United States involving adult patients with an opioid prescription were included in the analysis. OUTCOME MEASURES: The primary outcome was initiation or continuation of a Z-drug (zolpidem, eszopiclone, or zaleplon) in a patient visit in conjunction with an opioid medication. RESULTS: The authors analyzed 564,090,296 visits (weighted from a sample of 28,773) with a reported opioid prescription. Co-utilization of opioids with Z-drugs fluctuated during the study period beginning at 4.0% in 2006 (95% CI 2.2%-5.7%), 6.3% in 2012 (3.7%-8.9%), and 4.7% in 2016 (2.8%-6.5%). Among all opioid visits in the study period, co-utilization with a Z-drug was not significantly different among female patients compared with male patients (5.26% vs. 4.63%, P = 0.26). Among visits with concomitant opioid and Z-drugs, 7.0% reported new initiation of both medications in the same visit. CONCLUSION: At ambulatory care visits between 2006 and 2016, co-utilization of opioids and Z-drugs fluctuated with some differences by sex. Major regulatory advisories and policy changes during this period may have contributed to these varying rates of utilization. Additional work is needed to identify predictors of co-utilization and downstream consequences more widely.

Changes in Schedule II oral opioid volume dispensed in a private health plan following Florida's Acute Pain Opioid Restriction Law.

BACKGROUND: Florida's House Bill 21 (HB21), implemented into law on July 1, 2018, limited opioid prescriptions for acute pain to a 3-day supply. While the law has been associated with a decrease in opioid prescribing for acute pain, its effect on opioid volume dispensed at the plan level remains unknown. OBJECTIVES: To assess the impact of HB21 on the total volume dispensed of oral Schedule II opioids. We evaluated the change from before to after the law's implementation in (1) total number of opioid units dispensed per month and (2) total morphine milligram equivalent (MMEs) dispensed per month. METHODS: Pharmacy claims from July 2017 to June 2019 were analyzed from a private health plan serving a large Florida employer. We summed the number of units and the total MMEs dispensed for each month per 1,000 enrollees. Units were defined as the total quantity of tablets/capsules dispensed for each Schedule II oral opioid prescription. We used interrupted time series (ITS) models, accounting for autocorrelation, to determine any immediate change after the policy implementation and to estimate trends before and after the policy. RESULTS: We identified 16,226 prescriptions of oral Scheduled II opioids dispensed to 6,315 enrollees over a 2-year period. The HB21 law was associated with an immediate but not statistically significant decrease of 110.25 units dispensed per 1,000 enrollees in the month after implementation (95% CI: -218.84, -1.67; P = 0.06). There was an immediate but not statistically significant decrease of 1,456.29 MMEs dispensed per 1,000 enrollees following HB21 implementation (95% CI: -2,983.87, 71.29; P = 0.07). There were no significant changes in the slopes of the trends for total number of opioid units and total MMEs dispensed after HB21. CONCLUSIONS: Despite substantial lower quantities, there were no significant immediate reductions in total opioid units and MMEs dispensed in the year following the implementation of HB21. Our findings can inform other health plans on the potential effect of such restrictive laws and policies in other states where preexisting declining trends might have a higher impact than restriction policies. Future studies are needed to evaluate long-term intended and unintended consequences, including effects on patients' access to care, resulting from this type of restrictive law. DISCLOSURES: No outside funding supported this study. The authors report no conflicts of interest. Preliminary results of this study were presented at the Virtual ISPOR 2020 Conference held May 18-20, 2020.

Chronic Opioid Therapy: A Scoping Literature Review on Evolving Clinical and Scientific Definitions.

The management of chronic noncancer pain (CNCP) with chronic opioid therapy (COT) is controversial. There is a lack of consensus on how COT is defined resulting in unclear clinical guidance. This scoping review identifies and evaluates evolving COT definitions throughout the published clinical and scientific literature. Databases searched included PubMed, Embase, and Web of Science. A total of 227 studies were identified from 8,866 studies published between January 2000 and July 2019. COT definitions were classified by pain population of application and specific dosage/duration definition parameters, with results reported according to PRISMA-ScR. Approximately half of studies defined COT as "days' supply duration >90 days" and 9.3% defined as ">120 days' supply," with other days' supply cut-off points (>30, >60, or >70) each appearing in <5% of total studies. COT was defined by number of prescriptions in 63 studies, with 16.3% and 11.0% using number of initiations or refills, respectively. Few studies explicitly distinguished acute treatment and COT. Episode duration/dosage criteria was used in 90 studies, with 7.5% by Morphine Milligram Equivalents + days' supply and 32.2% by other "episode" combination definitions. COT definitions were applied in musculoskeletal CNCP (60.8%) most often, and typically in adults aged 18 to 64 (69.6%). The usage of ">90 days' supply" COT definitions increased from 3.2 publications/year before 2016 to 20.7 publications/year after 2016. An increasing proportion of studies define COT as ">90 days' supply." The most recent literature trends toward shorter duration criteria, suggesting that contemporary COT definitions are increasingly conservative. PERSPECTIVE: This study summarized the most common, current definition criteria for chronic opioid therapy (COT) and recommends adoption of consistent definition criteria to be utilized in practice and research. The most recent literature trends toward shorter duration criteria overall, suggesting that COT definition criteria are increasingly stringent.

Effects of hydrocodone rescheduling on opioid use outcomes: A systematic review.

OBJECTIVE: To evaluate opioid prescribing, dispensing, and use in relation to hydrocodone-containing product (HCP) rescheduling. METHODS: Seven biomedical databases and grey literature sources were searched with keywords and database-specific controlled vocabulary relevant to HCP rescheduling for items published between January 2014 and July 2019. We included English-language quasi-experimental studies that assessed changes in HCP and other opioid prescribing, dispensing, utilization, and opioid-related health outcomes before and after HCP rescheduling. A data extraction sheet was created for this review. Two authors evaluated risk of bias for each included study. Two of 4 authors each independently extracted patient demographics and opioid-related outcomes from the included studies. Conflicts were resolved by a third author. RESULTS: All studies identified (n = 44) were quasi-experimental in design with 10 using an interrupted time series approach. A total of 24 studies reported a decrease in HCP prescribing by 3.1%-66.0%. Six studies reported a decrease in HCP days' supply or doses by 14.0%-80.8%. There was increased prescribing of oxycodone-containing products by 4.5%-13.9% in 5 studies, tramadol by 2.7%-53.0% in 9 studies, codeine-containing products by 0.8%-1352.9% in 8 studies). Five studies reported a decrease in morphine equivalents by at least 10%, whereas 2 studies reported an increase in morphine equivalents. Differences in populations, sample sizes, and approaches did not allow for a meta-analysis. Details regarding approach and findings were limited in published conference abstracts (n = 16). CONCLUSIONS: Hydrocodone rescheduling was associated with reductions in prescribing and use of HCPs but was also associated with increased prescribing and use of other opioids, both schedule II and nonschedule II.