The impact of hydrocodone rescheduling on utilization, abuse, misuse, and overdose deaths.

PURPOSE: To evaluate the impact of increased federal restrictions on hydrocodone combination product (HCP) utilization, misuse, abuse, and overdose death. METHODS: We assessed utilization, misuse, abuse, and overdose death trends involving hydrocodone versus select opioid analgesics (OAs) and heroin using descriptive and interrupted time-series (ITS) analyses during the nine quarters before and after the October 2014 rescheduling of HCPs from a less restrictive (CIII) to more restrictive (CII) category. RESULTS: Hydrocodone dispensing declined >30% over the study period, and declines accelerated after rescheduling. ITS analyses showed that immediately postrescheduling, quarterly hydrocodone dispensing decreased by 177M dosage units while codeine, oxycodone, and morphine dispensing increased by 49M, 62M, and 4M dosage units, respectively. Postrescheduling, hydrocodone-involved misuse/abuse poison center (PC) case rates had a statistically significant immediate drop but a deceleration of preperiod declines. There were small level increases in codeine-involved PC misuse/abuse and overdose death rates immediately after HCP's rescheduling, but these were smaller than level decreases in rates for hydrocodone. Heroin-involved PC case rates and overdose death rates increased across the study period, with exponential increases in PC case rates beginning 2015. CONCLUSIONS: HCP rescheduling was associated with accelerated declines in hydrocodone dispensing, only partially offset by smaller increases in codeine, oxycodone, and morphine dispensing. The net impact on hydrocodone and other OA-involved misuse/abuse and fatal overdose was unclear. We did not detect an immediate impact on heroin abuse or overdose death rates; however, the dynamic nature of the crisis and data limitations present challenges to causal inference.

Repeated or Continuous Medically Supervised Ketamine Administration Associated with Hepatobiliary Adverse Events: A Retrospective Case Series.

INTRODUCTION: Emerging off-label medical uses of ketamine for the treatment of persistent conditions such as depression and chronic pain often require repeated administration. Cases reported by other countries suggest that long-term and repeated exposure to ketamine may be associated with several risks, including but not limited to hepatobiliary damage. OBJECTIVE: We aimed (1) to characterize the association between repeated administration of ketamine for off-label medical use and hepatobiliary events and (2) to describe recent trends in the use of ketamine across different clinical settings. METHODS: We conducted a retrospective case series analysis, utilizing reports identified from the US Food and Drug Administration Adverse Event Reporting System database as well as the medical literature. We included all cases reported through July 2018 describing both repeated exposure to ketamine in a hospital or ambulatory setting and a hepatobiliary adverse event. We excluded cases describing ketamine abuse. We identified adverse hepatobiliary events using the Medical Dictionary for Regulatory Activities (MedDRA®) and summarized various case characteristics including: patient demographics, route of ketamine administration, dose, time to onset of event, type of event, and pre-existing risk factors for hepatobiliary disease. To assess trends in the demand for ketamine, we used IQVIA, National Sales Perspectives™ to provide the nationally estimated number of vials sold for ketamine from the manufacturer to all US channels of distribution from 2013 through 2017. RESULTS: We identified 14 unique cases that met selection criteria with 21 hepatobiliary adverse events including liver enzyme elevation in all cases, biliary dilation with liver cirrhosis (n = 1), biliary dilation with cholangitis (n = 1), and pericholeductal fibrosis (n = 1). Most cases received ketamine for the treatment of complex regional pain syndrome or chronic pain. In cases with a reported time to onset, the majority of events occurred within 4 days. The nationally estimated number of ketamine vials sold in the USA from manufacturers to various channels of distribution increased from 1.2 million in 2013 to 2.1 million in 2017. CONCLUSIONS: We report an association between repeated or continuous administration of ketamine and hepatobiliary adverse events. Increased awareness among clinicians may mitigate these adverse outcomes, especially in the context of growing ketamine sales.

Drug availability adjustments in population-based studies of prescription opioid abuse.

PURPOSE: Population-based prescription opioid abuse studies in which one drug is compared to another, or drugs are compared across time, often account for the availability of those drugs in the community. The objective of this investigation is to assess consistency in the relative abuse ratios (RARs) across different approaches for adjusting for drug availability. METHODS: For the years 2004 through 2010, RARs for each of four prescription opioids (hydrocodone, oxycodone, hydromorphone, and morphine) were calculated using negative binomial regression. Measures of abuse (outcome) were misuse/abuse-related emergency department visits obtained from the Drug Abuse Warning Network. Measures of drug availability (offsets) were drug utilization estimates obtained from IMS Health. Separate regression models were run using each of five measures of drug utilization: unique patients (URDD), prescriptions dispensed (RX), tablets dispensed (TD), kilograms (KGs) sold, and morphine-equivalents (MEs) of kilograms sold. These results were compared for consistency. RESULTS: Aside from oxycodone-combination products, across molecules, RARs adjusted by RXs, TDs, and URDDs were generally similar to each other while RARs adjusted by KGs and MEs were different. For example, compared to hydrocodone, oxycodone had statistically significantly increased RARs of 3.6 (95%CI: 2.0-6.5), 3.5 (95%CI: 1.9-6.4), and 2.7 (95%CI: 1.5-5.0) when adjusted by URDDs, RXs, and TDs, respectively, but not when adjusted by KGs or MEs. CONCLUSIONS: Different drug utilization adjustment approaches may yield inconsistent RAR estimates in population-based prescription opioid abuse analyses. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Candidate metrics for evaluating the impact of prescriber education on the safe use of extended-release/long-acting (ER/LA) opioid analgesics.

OBJECTIVE: The objective of this study was to develop metrics to assess opioid prescribing behavior as part of the evaluation of the Extended-Release/Long-Acting (ER/LA) Opioid Analgesic Risk Evaluation and Mitigation Strategies (REMS). DESIGN: Candidate metrics were selected using published guidelines, examined using sensitivity analyses, and applied to cross-sectional rolling cohorts of Medicare patients prescribed with extended-release oxycodone (ERO) between July 2, 2006 and July 1, 2011. Potential metrics included prescribing opioid-tolerant-only ER/LA opioid analgesics to non-opioid-tolerant patients, prescribing early fills to patients, and ordering drug screens. RESULTS: Proposed definitions for opioid tolerance were seven continuous days of opioid usage of at least 30 mg oxycodone equivalents, within the 7 days (primary) or 30 days (secondary) prior to first opioid-tolerant-only ERO prescription. Forty-four percent of opioid-tolerant-only ERO episodes met the primary opioid tolerance definition; 56% met the secondary definition. Fills were deemed "early" if a prescription was filled before 70% (primary) or 50% (secondary) of the prior prescription's days' supply was to be consumed. Five percent (primary) and 2% (secondary) of episodes had more than or equal to two early fills during treatment. At least one drug screen was billed in 14% of episodes. Stratified analyses indicated that older patients were less likely to be opioid tolerant at the time of the first opioid-tolerant-only ERO prescription. CONCLUSIONS: Investigators propose three metrics to monitor changes in prescribing behaviors for opioid analgesics that might be used to evaluate the ER/LA Opioid Analgesics REMS. Low frequencies of patients, particularly those >85 years, were likely to be opioid tolerant prior to receiving prescriptions for opioid-tolerant-only ERO.

Analysis of benzonatate overdoses among adults and children from 1969-2010 by the United States Food and Drug Administration.

STUDY OBJECTIVE: To augment the December 2010 United States Food and Drug Administration (FDA) Drug Safety Communication on accidental ingestion of benzonatate in children less than 10 years old by summarizing data on emergency department visits, benzonatate exposure, and reports of benzonatate overdoses from several data sources. DESIGN: Retrospective review of adverse-event reports and drug utilization data of benzonatate. DATA SOURCES: The FDA Adverse Event Reporting System (AERS) database (1969-2010), the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project (NEISS-CADES, 2004-2009), and the IMS commercial data vendor (2004-2009). PATIENTS: Any patient who reported an adverse event with benzonatate captured in the AERS or NEISS-CADES database or received a prescription for benzonatate according to the IMS commercial data vendor. MEASUREMENTS AND MAIN RESULTS: Postmarketing adverse events with benzonatate were collected from the AERS database, emergency department visits due to adverse events with benzonatate were collected from the NEISS-CADES database, and outpatient drug utilization data were collected from the IMS commercial data vendor. Of 31 overdose cases involving benzonatate reported in the AERS database, 20 had a fatal outcome, and five of these fatalities occurred from accidental ingestions in children 2 years of age and younger. The NEISS-CADES database captured emergency department visits involving 12 cases of overdose from accidental benzonatate ingestions in children aged 1-3 years. Signs and symptoms of overdose included seizures, cardiac arrest, coma, brain edema or anoxic encephalopathy, apnea, tachycardia, and respiratory arrest and occurred in some patients within 15 minutes of ingestion. Dispensed benzonatate prescriptions increased by approximately 52% from 2004 to 2009. CONCLUSION: Although benzonatate has a long history of safe use, accumulating cases of fatal overdose, especially in children, prompted the FDA to notify health care professionals about the risks of benzonatate overdose. Pharmacists may have a role in preventing benzonatate overdoses by counseling patients on signs and symptoms of benzonatate overdose, the need for immediate medical care, and safe storage and disposal of benzonatate.

Molecular and cellular characterization of expanded and cryopreserved human limbal epithelial stem cells reveal unique immunological properties.

Transplantation of ex vivo expanded autologous limbal stem cells into the diseased eye of patients with limbal stem cell deficiency (LSCD) has been in practice worldwide. However, isolation of limbal tissue from the normal eye of the patient with unilateral LSCD still remains a major concern for the donor. More importantly, autologous cell transplantation is not a viable option for patients with bilateral LSCD. The objective of the current study was to determine the expansion potential of human limbal epithelial stem cells (hLESCs) for their possible use in allo-transplantation. A total of six limbal biopsy samples were cultured and expanded in vitro up to passage level 1 (P-1), at which point the hLESCs were cryopreserved. Semi-quantitative RT-PCR and immunophenotypic analysis revealed that hLESCs obtained before and after cryopreservation retained the expression of major limbal epithelial stem cell markers such as p63, SSEA-4, ABCG2, cytokeratin 19 (CK19), integrin ß1 and vimentin. One notable difference was that while P-0 hLESCs expressed HLA-DR mRNA, no HLA-DR gene expression was observed with the expanded and cryopreserved samples. Human LESCs did not express costimulatory proteins CD80 or B7-DC but expressed significant levels of CD86, B7-H1 and HLA-ABC molecules on the cell surface. Treatment of hLESCs with IFN-γ induced the expression of HLA-DR, indoleamine 2,3-dioxygenase (IDO) and HLA-G on these cells. Cultured hLESCs were unable to stimulate allogeneic T cell proliferation in vitro even in the presence of pro-inflammatory cytokine, IFN-γ. These results indicate that cryopreserved hLESCs are non-immunogenic in nature and express negative immunoregulatory molecules which may be critical for their survival in an allogeneic environment.