Associations Between Early Chiropractic Care and Physical Therapy on Subsequent Opioid Use Among Persons With Low Back Pain in Arkansas.

Objective: The objective of this study was to estimate the association between early use of physical therapy (PT) or chiropractic care and incident opioid use and long-term opioid use in individuals with a low back pain (LBP) diagnosis. Methods: A retrospective cohort study was conducted using data from Arkansas All Payers' Claims Database. Adults with incident LBP diagnosed in primary care or emergency departments between July 1, 2013, and June 30, 2017, were identified. Participants were required to be opioid naïve in the 6-month baseline period and without cancer, cauda equina syndrome, osteomyelitis, lumbar fracture, and paraplegia/quadriplegia in the entire study period. PT and chiropractic treatment were documented over the ensuing 30 days starting on the date of LBP. Any opioid use and long-term opioid use (LTOU) in 1-year follow-up were assessed. Multivariable logistic regressions controlling for covariates were estimated. Results: A total of 40 929 individuals were included in the final sample, with an average age of 41 years and 65% being women. Only 5% and 6% received PT and chiropractic service, respectively, within the first 30 days. Sixty-four percent had incident opioid use, and 4% had LTOU in the follow-up period. PT was not associated with incident opioid use (odds ratio [OR], 1.07; 95% confidence interval [CI], 0.98-1.18) or LTOU (OR, 1.19; 95% CI, 0.97-1.45). Chiropractic care decreased the odds of opioid use (OR, 0.88; 95% CI, 0.80-0.97) and LTOU (OR, 0.56; 95% CI, 0.40-0.77). Conclusion: In this study we found that receipt of chiropractic care, though not PT, may have disrupted the need for opioids and, in particular, LTOU in newly diagnosed LBP.

Characteristics and Network Influence of Providers Involved in the Treatment of Patients With Chronic Back, Neck or Joint Pain in Arkansas.

Increasing emphasis on guidelines and prescription drug monitoring programs highlight the role of healthcare providers in pain treatment. Objectives of this study were to identify characteristics of key players and influence of opioid prescribers through construction of a referral network of patients with chronic pain. A retrospective cohort study was performed and patients with commercial or Medicaid coverage with chronic back, neck, or joint pain were identified using the Arkansas All-Payer Claims-Database. A social network comprised of providers connected by patient referrals based on 12-months of healthcare utilization following chronic pain was constructed. Network measures evaluated were indegree and eigen (referrals obtained), betweenness (involvement), and closeness centrality (reach). Outcomes included influence of providers, opioid prescribers, and brokerage status. Exposures included provider demographics, specialties and network characteristics. There were 51,941 chronic pain patients who visited 8,110 healthcare providers. Primary care providers showed higher betweenness and closeness whereas specialists had higher indegree. Opioid providers showed higher centrality compared to non-opioid providers, which decreased with increasing volume of opioid prescribing. Non-pharmacologic providers showed significant brokerage scores. Findings from this study such as primary care providers having better reach, non-central positions of high-volume prescribers and non-pharmacologic providers having higher brokerage can aid interventional physician detailing. PERSPECTIVE: Opioid providers held central positions in the network aiding provider-directed interventions. However, high-volume opioid providers were at the borders making them difficult targets for interventions. Primary care providers had the highest reach, specialists received the most referrals and non-pharmacological providers and specialists acted as brokers between non-opioid and opioid prescribers.

The impact of high-risk and chronic opioid use among commercially insured endometriosis patients on health care resource utilization and costs in the United States.

OBJECTIVES: Evaluate all-cause and endometriosis-related health care resource utilization and costs among newly diagnosed endometriosis patients with high-risk versus low-risk opioid use or patients with chronic versus non-chronic opioid use. METHODS: A retrospective analysis of IBM MarketScan® Commercial Claims data from 2009 to 2018 was performed for females aged 18 to 49 with newly diagnosed endometriosis (International Classification of Diseases, Ninth Edition code: 617.xx; International Classification of Diseases, Tenth Edition code: N80.xx). Two sub-cohorts were identified: high-risk (⩾1 day with ⩾90 morphine milligram equivalents per day or ⩾1-day concomitant benzodiazepine use) or chronic opioid utilization (⩾90-day supply prescribed or ⩾10 opioid prescriptions). High-risk or chronic utilization was evaluated during the 12-month assessment period after the index date. Index date was the first opioid prescription within 12 months following endometriosis diagnosis. All outcomes were assessed over 12-month post-assessment period while adjusting for demographic and clinical characteristics. RESULTS: Out of 61,019 patients identified, 18,239 had high-risk opioid use and 5001 chronic opioid use. Health care resource utilization drivers were outpatient visits and pharmacy fills, which were higher among high-risk versus low-risk patients (outpatient visits: 17.49 vs 15.51; pharmacy fills: 19.58 vs 16.88, p < 0.0001). Chronic opioid users had a higher number of outpatient visits (19.53 vs 15.00, p < 0.0001) and pharmacy fills (23.18 vs 16.43, p < 0.0001) compared to non-chronic opioid users. High-risk opioid users had significantly higher all-cause health care costs compared to low-risk opioid users (US$16,377 vs US$13,153; p < 0.0001). Chronic opioid users also had significantly higher all-cause health care costs compared to non-chronic opioid users (US$20,930 vs US$12,272; p < 0.0001). Similar patterns were observed among endometriosis-related HCRU, except pharmacy fills among high-risk and chronic sub-cohorts. CONCLUSION: This analysis demonstrates significantly higher all-cause and endometriosis-related health care resource utilization and total costs for high-risk opioid users compared to low-risk opioid users among newly diagnosed endometriosis patients over 1 year. Similar trends were observed for comparing chronic opioid users with non-chronic opioid users, except for endometriosis-related pharmacy fills and associated costs.

Healthcare Resource Use and Costs Associated with Opioid Initiation Among Patients with Newly Diagnosed Endometriosis with Commercial Insurance in the USA.

INTRODUCTION: To compare all-cause and endometriosis-related healthcare resource utilization (HCRU) and healthcare costs by service categories (outpatient, inpatient, emergency room [ER], pharmacy) among patients with newly diagnosed endometriosis using opioids compared to patients with endometriosis not using opioids. METHODS: A retrospective analysis of IBM® MarketScan® Commercial Claims data from 2009 to 2018 was performed for women aged 18-49 with newly diagnosed endometriosis (International Classification of Diseases (ICD)-9 code 617.xx; ICD-10 code N80.xx) over 24 months follow-up. Patients were stratified on the basis of opioid use within 12 months post first endometriosis diagnosis date. Patients with opioid use were 1:1 matched to patients without opioid use using propensity score matching. RESULTS: A total of 85,329 female patients with a new endometriosis diagnosis were identified and 48,470 patients (24,235 opioid and 24,235 non-opioid users) remained after inclusion-exclusion criteria and matching. Opioid patients had an estimated mean 30.33 outpatient visits, 29.59 pharmacy fills, 0.28 inpatient visits, 0.65 ER visits, and total length of stay (LOS) was 1.01 days. Non-opioid patients had an estimated mean 27.94 outpatient visits, 22.06 pharmacy fills, 0.23 inpatient visits, 0.42 ER visits, and total LOS was 0.82 days. On average, opioid patients had significantly greater all-cause HCRU compared to non-opioid patients (all p < 0.0001). Among endometriosis-related healthcare utilization, there were similar ER visits, but lower outpatient visits, inpatient visits, and total LOS and higher pharmacy fills among opioid and non-opioid patients. Estimated mean all-cause costs were higher among opioid ($26,755) vs. non-opioid ($19,302) users (p < 0.0001). A similar trend was observed for estimated mean endometriosis-related costs. CONCLUSION: This analysis observed significantly higher all-cause HCRU and costs for opioid users compared to non-opioid users among patients with newly diagnosed endometriosis. While observed endometriosis-related costs were significantly higher in opioid users compared to non-opioid users during a 24-month follow-up period, endometriosis-related HCRU varied by service categories for these two populations over this time period.

Cost-Effectiveness of Intranasal Naloxone Distribution to High-Risk Prescription Opioid Users.

OBJECTIVES: To determine the cost-effectiveness of pharmacy-based intranasal naloxone distribution to high-risk prescription opioid (RxO) users. METHODS: We developed a Markov model with an attached tree for pharmacy-based naloxone distribution to high-risk RxO users using 2 approaches: one-time and biannual follow-up distribution. The Markov structure had 6 health states: high-risk RxO use, low-risk RxO use, no RxO use, illicit opioid use, no illicit opioid use, and death. The tree modeled the probability of an overdose happening, the overdose being witnessed, naloxone being available, and the overdose resulting in death. High-risk RxO users were defined as individuals with prescription opioid doses greater than or equal to 90 morphine milligram equivalents (MME) per day. We used a monthly cycle length, lifetime horizon, and US healthcare perspective. Costs (2018) and quality-adjusted life-years (QALYs) were discounted 3% annually. Microsimulation was performed with 100 000 individual trials. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: One-time distribution of naloxone prevented 14 additional overdose deaths per 100 000 persons, with an incremental cost-effectiveness ratio (ICER) of $56 699 per QALY. Biannual follow-up distribution led to 107 additional lives being saved with an ICER of $84 799 per QALY compared with one-time distribution. Probabilistic sensitivity analyses showed that a biannual follow-up approach would be cost-effective 50% of the time at a willingness-to-pay (WTP) threshold of $100 000 per QALY. Naloxone effectiveness and proportion of overdoses witnessed were the 2 most influential parameters for biannual distribution. CONCLUSION: Both one-time and biannual follow-up naloxone distribution in community pharmacies would modestly reduce opioid overdose deaths and be cost-effective at a WTP of $100 000 per QALY.

The risk of varenicline-induced seizure among those who have attempted to quit smoking using pharmacotherapy.

OBJECTIVE: Varenicline is an effective smoking cessation agent; however, its use is limited because of black box warnings issued by regulatory agencies in the U.S. and Australia. The U.S. Food and Drug Administration updated the label for varenicline in 2015 to warn about the risk of varenicline-induced seizures. The objective of this study was to examine the risk of seizure associated with varenicline use. METHODS: A nested case-control study was performed using IMS LifeLink PharMetrics Plus administrative claims data (2009-2015). The outcome was presumptive seizures. All smokers making an attempt to quit smoking and having no recent seizure events were included in the nest. Cases and controls were matched (1:4) on age (±5 years), sex, index date (±30 days), event date, and duration of enrollment. An exposure period of 90 days preceding the event date was used. Chi-square tests were used to compare the characteristics of cases and controls. Conditional logistic regression was conducted to determine if an association between presumptive seizures and varenicline use exists. RESULTS: Our final sample was comprised of 1342 cases and 5368 controls. The adjusted analysis showed that odds of a seizure for patients with a varenicline prescription were 1.09 (confidence interval [CI] = 0.88-1.36) times those of patients with no varenicline exposure. CONCLUSIONS: This study did not find a significant association between varenicline and increased risk of presumptive seizures. These findings raise questions regarding the necessity for a warning label for increased risk of seizures associated with varenicline.

Claims for contraceptive services among young women filling chronic opioid prescriptions.

OBJECTIVE: To describe claims for contraceptive services among reproductive-aged women filling chronic opioid prescriptions. STUDY DESIGN: Using a large US commercial claims database, IMS Lifelink+, we identified women aged 15-44 years who filled chronic opioid prescriptions (defined as a 90-day supply of opioids without a 30-day gap over a 180-day time period) and had continuous pharmacy and medical enrollment for at least 90 days prior to and 180 days following their index opioid prescription. After excluding women with any claims for pregnancy-related services, we describe claims for contraceptive prescriptions. RESULTS: We identified 16,074 women with claims for chronic opioids who had filled an average of 135±28-day supply of opioids over a 180-day period. Of these, 23.4% (n=3759) had a claim for prescription contraception in the 90 days prior or 180 days following their index opioid claim. Of those who had claims for prescription contraception, 70% (n=2642) received oral contraceptives; only 2% had claims related to a long-acting reversible contraceptive (i.e., a contraceptive implant or intrauterine device). CONCLUSIONS: Commercially insured women filling chronic opioid prescriptions may have unmet needs for prescription contraception. IMPLICATIONS: Efforts are needed to ensure that the reproductive health needs of women filling chronic opioid prescriptions are met.

Efficacy and Safety of the Early Addition of Vasopressin to Norepinephrine in Septic Shock.

BACKGROUND: Delays in achievement of target mean arterial pressure (MAP) have been associated with increased mortality in patients with septic shock. Vasopressin may be added to norepinephrine to raise MAP or decrease norepinephrine dosage. The purpose of this study was to determine whether early initiation of vasopressin to norepinephrine resulted in a reduced time to target MAP compared to norepinephrine monotherapy. METHODS: This retrospective cohort study compared early addition of vasopressin within 4 hours of septic shock onset to norepinephrine versus initial norepinephrine monotherapy in medically, critically ill patients with septic shock admitted from May 2014 to October 2015. Time to goal MAP was compared using Student t test and examined with Kaplan-Meier curves. Changes in Sequential Organ Failure Assessment (SOFA) scores were evaluated with Wilcoxon rank sum test. RESULTS: Each group contained 48 patients. Mean arterial pressure (61.5 vs 58.6 mm Hg) and intravenous fluid volume received at vasopressor initiation (14.3 vs 25.2 hours, P = .014) were similar. Patients started on early vasopressin achieved and maintained goal MAP sooner (6.2 vs 9.9 hours, P = .023), experienced greater reductions in SOFA scores at 72 hours (-4 vs -1, P = .012), and had shorter hospital durations (343 vs 604 hours, P = .014). Not initiating early vasopressin trended toward an association with increased time to goal MAP (P = .067). CONCLUSION: Early initiation of vasopressin in patients with septic shock may achieve and maintain goal MAP sooner and resolve organ dysfunction at 72 hours more effectively than later or no initiation.

Discontinuation of Vasopressin Before Norepinephrine in the Recovery Phase of Septic Shock.

BACKGROUND: Guidance for the discontinuation of vasopressors in the recovery phase of septic shock is limited. Norepinephrine is more easily titrated; however, septic shock is a vasopressin deficient state, which exogenous vasopressin endeavors to resolve. Discontinuation of vasopressin before norepinephrine may result in clinically significant hypotension. METHODS: This retrospective, cohort study compared discontinuation of norepinephrine and vasopressin in medically, critically ill patients in the recovery phase of septic shock from May 2014 to June 2016. Difference in clinically significant hypotension after norepinephrine or vasopressin discontinuation was evaluated with χ2 test. Linear regression was performed, examining the effect of agent discontinuation on clinically significant hypotension. Baseline variables were examined for a bivariate relationship with clinically significant hypotension; those with P < .2 were included in the model. RESULTS: Vasopressin was discontinued first or last in 62 and 92 patients, respectively. Sequential Organ Failure Assessment scores at 72 hours (7.9 vs 7.6, P = .679) were similar. In unadjusted analysis, when vasopressin was discontinued first, more clinically significant hypotension developed (10.9% vs 67.8%, P < .001). There was no difference in intensive care unit (174 vs 216 hours, P = .178) or hospital duration (470 vs 473 hours, P = .977). In adjusted analyses, discontinuing vasopressin first was associated with increased clinically significant hypotension (odds ratio [OR]: 13.837, 95% confidence interval [CI]: 3.403-56.250, P < .001) but not in-hospital (OR: 0.659, 95% CI: 0.204-2.137, P = .488) or 28-day mortality (OR: 0.215, 95% CI: 0.037-1.246, P = .086). CONCLUSION: Adult patients receiving norepinephrine and vasopressin in the resolving phase of septic shock may be less likely to develop clinically significant hypotension if vasopressin is the final vasopressor discontinued.

Prospective Open-label Trial of Early Concomitant Vasopressin and Norepinephrine Therapy versus Initial Norepinephrine Monotherapy in Septic Shock.

PURPOSE: Delays in achieving target mean arterial pressure (MAP) are associated with increased morbidity and mortality in patients with septic shock. This trial was conducted to test the hypothesis that early concomitant treatment with vasopressin and norepinephrine reduces the time to achieve and maintain target MAP compared with initial norepinephrine monotherapy. METHODS: A single-center prospective open-label trial was conducted in patients with septic shock between November 2015 and June 2016 at a medical intensive care unit in an academic medical center. Initial norepinephrine monotherapy was initiated between November 2015 and February 2016. Between March and June 2016, vasopressin was initiated within 4 hours of norepinephrine. The primary outcome was time to achieving and maintaining MAP of 65 mm Hg for at least 4 hours that was compared between groups using the Student t test and examined using the Kaplan-Meier curve (Clinical Trials registration: NCT02454348). RESULTS: Eighty-two patients were included (41 in each group). Patients treated with early concomitant vasopressin and norepinephrine more frequently had a positive culture (59% vs 37%, p=0.05) and grew nonlactose fermenting gram-negative bacilli (34% vs 10%, p=0.01) compared with patients treated with norepinephrine monotherapy, respectively. The median time to achieve and maintain MAP occurred faster in the early concomitant vasopressin and norepinephrine group, at 5.7 hours (interquartile range [IQR] 1.7-10.3 hrs), compared with 7.6 hours (IQR 3.6-16.7 hrs, p=0.058) in the norepinephrine group. Durations of therapy for norepinephrine or vasopressin, amount of norepinephrine received in the first 24 hours, norepinephrine dosage when MAP was achieved and maintained, maximum norepinephrine dosage, and mortality were similar between groups. CONCLUSION: Patients treated with early concomitant vasopressin and norepinephrine achieved and maintained MAP of 65 mm Hg faster than those receiving initial norepinephrine monotherapy, suggesting that overcoming vasopressin deficiency sooner may reduce the time patients spend in the early phase of septic shock.

A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors.

NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time. These changes were similar to those produced by NMDAR mutants in which the ligand-binding domains (LBDs) are locked in the closed clamshell conformation by incorporating a disulfide bridge. Since the locked glutamate-binding clefts primarily contributes to receptor efficacy these results suggests that UBP684 binding may induce switch in conformation similar to glutamate LBD locked state. Consistent with this prediction UBP684 displayed greater potentiation of NMDARs with only the GluN1 LBD locked compared to NMDARs with only the GluN2 LBD locked. Docking studies suggest that UBP684 binds to the GluN1 and GluN2 LBD interface supporting its potential ability in stabilizing the LBD closed conformation. Together these studies identify a novel pharmacological mechanism of facilitating the function of NMDARs.

Generation of Functional Human Retinal Ganglion Cells with Target Specificity from Pluripotent Stem Cells by Chemically Defined Recapitulation of Developmental Mechanism.

Glaucoma is a complex group of diseases wherein a selective degeneration of retinal ganglion cells (RGCs) lead to irreversible loss of vision. A comprehensive approach to glaucomatous RGC degeneration may include stem cells to functionally replace dead neurons through transplantation and understand RGCs vulnerability using a disease in a dish stem cell model. Both approaches require the directed generation of stable, functional, and target-specific RGCs from renewable sources of cells, that is, the embryonic stem cells and induced pluripotent stem cells. Here, we demonstrate a rapid and safe, stage-specific, chemically defined protocol that selectively generates RGCs across species, including human, by recapitulating the developmental mechanism. The de novo generated RGCs from pluripotent cells are similar to native RGCs at the molecular, biochemical, functional levels. They also express axon guidance molecules, and discriminate between specific and nonspecific targets, and are nontumorigenic. Stem Cells 2017;35:572-585.

Essential Roles for ARID1B in Dendritic Arborization and Spine Morphology of Developing Pyramidal Neurons.

De novo truncating mutations in ARID1B, a chromatin-remodeling gene, cause Coffin-Siris syndrome, a developmental disorder characterized by intellectual disability and speech impairment; however, how the genetic elimination leads to cognitive dysfunction remains unknown. Thus, we investigated the neural functions of ARID1B during brain development. Here, we show that ARID1B regulates dendritic differentiation in the developing mouse brain. We knocked down ARID1B expression in mouse pyramidal neurons using in utero gene delivery methodologies. ARID1B knockdown suppressed dendritic arborization of cortical and hippocampal pyramidal neurons in mice. The abnormal development of dendrites accompanied a decrease in dendritic outgrowth into layer I. Furthermore, knockdown of ARID1B resulted in aberrant dendritic spines and synaptic transmission. Finally, ARID1B deficiency led to altered expression of c-Fos and Arc, and overexpression of these factors rescued abnormal differentiation induced by ARID1B knockdown. Our results demonstrate a novel role for ARID1B in neuronal differentiation and provide new insights into the origin of cognitive dysfunction associated with developmental intellectual disability. SIGNIFICANCE STATEMENT: Haploinsufficiency of ARID1B, a component of chromatin remodeling complex, causes intellectual disability. However, the role of ARID1B in brain development is unknown. Here, we demonstrate that ARID1B is required for neuronal differentiation in the developing brain, such as in dendritic arborization and synapse formation. Our findings suggest that ARID1B plays a critical role in the establishment of cognitive circuitry by regulating dendritic complexity. Thus, ARID1B deficiency may cause intellectual disability via abnormal brain wiring induced by the defective differentiation of cortical neurons.

Bidirectional Effect of Pregnenolone Sulfate on GluN1/GluN2A N-Methyl-D-Aspartate Receptor Gating Depending on Extracellular Calcium and Intracellular Milieu.

Pregnenolone sulfate (PS), one of the most commonly occurring neurosteroids in the central nervous system, influences the function of several receptors. PS modulates N-methyl-D-aspartate receptors (NMDARs) and has been shown to have both positive and negative modulatory effects on NMDAR currents generally in a subtype-selective manner. We assessed the gating mechanism of PS modulation of GluN1/GluN2A receptors transiently expressed in human embryonic kidney 293 cells using whole-cell and single-channel electrophysiology. Only a modest effect on the whole-cell responses was observed by PS in dialyzed (nonperforated) whole-cell recordings. Interestingly, in perforated conditions, PS was found to increase the whole-cell currents in the absence of nominal extracellular Ca(2+), whereas PS produced an inhibition of the current responses in the presence of 0.5 mM extracellular Ca(2+). The Ca(2+)-binding DRPEER motif and GluN1 exon-5 were found to be critical for the Ca(2+)-dependent bidirectional effect of PS. Single-channel cell-attached analysis demonstrated that PS primarily affected the mean open time to produce its effects: positive modulation mediated by an increase in duration of open time constants, and negative modulation mediated by a reduction in the time spent in a long-lived open state of the receptor. Further kinetic modeling of the single-channel data suggested that the positive and negative modulatory effects are mediated by different gating steps which may represent GluN2 and GluN1 subunit-selective conformational changes, respectively. Our studies provide a unique mechanism of modulation of NMDARs by an endogenous neurosteroid, which has implications for identifying state-dependent molecules.