Socioeconomic impact of treatment with biological disease-modifying antirheumatic drugs in Japanese patients with rheumatoid arthritis.

OBJECTIVES: We evaluate the socioeconomic impact of treatment with biological and targeted synthetic disease-modifying antirheumatic drugs in Japanese patients with rheumatoid arthritis. METHODS: We analysed data retrospectively from the prospective observational CorEvitas RA Japan Registry (March 2016-February 2020). Patients were categorised into paid workers (PWs) and home workers (HWs) and further based on drug classes. We assessed medication persistence, treatment outcomes, health care resource utilisation, and socioeconomic impact over 12 months, including direct (drugs and health care resource utilisation) and indirect (loss of productivity) costs. RESULTS: Overall, 187 PWs and 114 HWs were identified. Over 12 months, medication persistence was high, treatment outcomes improved, and outpatient visits reduced in both groups. Following treatment initiation, direct costs increased, whereas indirect (loss of productivity) costs decreased in both groups. The unadjusted socioeconomic impact [Japanese yen (JPY)] increased across all drug classes in PWs (range: 29,700-151,700) and HWs (range: -28,700 to 83,000). Adjusted change in monthly socioeconomic impact was JPY 29,700-138,900 for PWs and JPY -28,000 to 92,800 for HWs. CONCLUSIONS: In this study of Japanese patients with rheumatoid arthritis, the socioeconomic burden increased across patient groups and drug classes. The decrease in indirect (loss of productivity) costs partially offset the increase in direct costs.

Web-Based Discussion and Illicit Street Sales of Tapentadol and Oxycodone in Australia: Epidemiological Surveillance Study.

BACKGROUND: Opioid use disorder and its consequences are a persistent public health concern for Australians. Web activity has been used to understand the perception of drug safety and diversion of drugs in contexts outside of Australia. The anonymity of the internet offers several advantages for surveilling and inquiring about specific covert behaviors, such as diversion or discussion of sensitive subjects where traditional surveillance approaches might be limited. OBJECTIVE: This study aims to characterize the content of web posts and compare reports of illicit sales of tapentadol and oxycodone from sources originating in Australia. First, post content is evaluated to determine whether internet discussion encourages or discourages proper therapeutic use of the drugs. Second, we hypothesize that tapentadol would have lower street price and fewer illicit sales than oxycodone. METHODS: Web posts originating in Australia between 2017 and 2019 were collected using the Researched Abuse, Diversion, and Addiction-Related Surveillance System Web Monitoring Program. Using a manual coding process, unstructured post content from social media, blogs, and forums was categorized into topics of discussion related to the harms and behaviors that could lead to harm. Illicit sales data in a structured format were collected through a crowdsourcing website between 2016 and 2019 using the Researched Abuse, Diversion, and Addiction-Related Surveillance System StreetRx Program. In total, 2 multivariable regression models assessed the differences in illicit price and number of sales. RESULTS: A total of 4.7% (28/600) of tapentadol posts discussed an adverse event, whereas 10.27% (95% CI 9.32-11.21) of oxycodone posts discussed this topic. A total of 10% (60/600) of tapentadol posts discussed unsafe use or side effects, whereas 20.17% (95% CI 18.92-21.41) of oxycodone posts discussed unsafe use or side effects. There were 31 illicit sales reports for tapentadol (geometric mean price per milligram: Aus $0.12 [US $0.09]) and 756 illicit sales reports for oxycodone (Aus $1.28 [US $0.91]). Models detected no differences in the street price or number of sales between the drugs when covariates were included, although the potency of the pill significantly predicted the street price (P<.001) and availability predicted the number of sales (P=.03). CONCLUSIONS: Australians searching the web for opinions could judge tapentadol as safer than oxycodone because of the web post content. The illicit sales market for tapentadol was smaller than that of oxycodone, and drug potency and licit availability are likely important factors influencing the illicit market.

Increasing rates of buprenorphine diversion in the United States, 2002 to 2019.

PURPOSE: Recent reports suggest that buprenorphine is being diverted and used non-medically. However, no apparent studies have reported national-level data on buprenorphine diversion. METHODS: Case report data were drawn from a quarterly survey of prescription drug diversion completed by a national sample of law enforcement and regulatory agencies who engage in drug diversion investigations. Quarterly rates of buprenorphine diversion per 100 000 population and 100 000 prescriptions dispensed were calculated for the period 2002 through 2019. Population-based diversion rates were also calculated by U.S. region. RESULTS: In total, 9670 cases of diverted buprenorphine were reported across all 50 states and the District of Columbia during the study period. Buprenorphine diversion rates, per 100 000 population, were characterized by an accelerating increase over time; increases in diversion rates from 1st quarter 2002 through 4th quarter 2006 were not statistically significant, yet from 1st quarter 2007 through 4th quarter 2019, the rate of diversion cases increased by 0.0067 cases per 100 000 per quarter (p < 0.001). Buprenorphine diversion rates per 100 000 prescriptions dispensed indicated a gradual increase over time; from 3rd quarter 2010 through 4th quarter 2019, diversion rates showed a statistically significant increase of 0.28 cases (p = 0.037) per quarter on average. The Northeast was the only region that did not observe an increase in the average quarterly change in buprenorphine diversion rates after 2006. CONCLUSIONS: Findings from this study illustrate longitudinal national trends of increasing buprenorphine diversion. Continued systematic surveillance of this phenomenon is needed.

An evaluation of online discussion relating to nonmedical use of prescription opioids within the UK.

AIM: To identify and describe the nature of online discussion relating to prescription opioids within the UK. METHODS: We performed analysis of posts originating in the UK related to buprenorphine, hydrocodone, oxycodone and tramadol using Social Studio, a web-monitoring platform. The study included posts published between January 2014 and December 2016. The data were cleaned to produce a final dataset consisting only of substantive mentions, which were then categorised by defined themes. RESULTS: The final dataset included a total of 17 361 substantive mentions (2936 buprenorphine, 2894 hydrocodone, 3826 oxycodone and 7705 tramadol). The most common theme for all 4 drugs was sharing experience or opinion comprising over 90% of mentions for each drug, while discussion related to polysubstance use was present in >1/4 of mentions across drug substances. Mentions related to diversion were more common for hydrocodone and oxycodone (8.1% [6.3-10.1 95% confidence interval] and 7.8% [6.5-9.2], respectively) than buprenorphine or tramadol (4.1 and 3.9% [3.5-4.3], respectively). CONCLUSION: This investigation shows that there is substantial online discussion relating to a variety of nonmedical use (NMU) behaviours of prescription opioids within the UK, including for hydrocodone, which is not medically available. Web monitoring provides useful data and merits future investigation; this could include expansion to other categories of drugs and a more in-depth analysis of motivations behind NMU, both of which could add timely evidence regarding the current situation in the UK and help inform public health interventions for NMU of prescription drugs.

Postmarketing Analysis of Misuse, Abuse, and Diversion of Xtampza ER.

OBJECTIVE: To evaluate abuse, misuse, and diversion of Xtampza ER, an extended-release (ER) abuse-deterrent formulation (ADF) of oxycodone. METHODS: Abuse, misuse, and diversion of Xtampza ER were assessed using Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System data sources. Xtampza ER was compared with immediate-release (IR) oxycodone, other ADF ER products combined, and non-ADF ER products combined. RESULTS: Xtampza ER prescriptions increased 50-fold during the study period. In contrast, cases from poison centers, substance abuse treatment centers, and diversion were infrequent and did not increase. Adjusted for prescriptions dispensed, poison center exposures were greater for IR oxycodone (rate ratio [RR] = 2.3, P = 0.008), other ADF ER opioids (RR = 5.2, P < 0.001), and non-ADF ER opioids (RR = 2.5, P = 0.004) than for Xtampza ER. In Treatment Center Programs Combined, past-month abuse prevalence for other ADF ER opioids (odds ratio [OR] = 7.4, P < 0.001) and non-ADF ER opioids (OR = 2.0, P = 0.002) was greater than Xtampza ER; IR oxycodone was not significantly different (OR = 1.2, P = 0.349). In the Drug Diversion Program, rates for IR oxycodone (RR = 3.7, P = 0.003), other ADF ER opioids (RR = 4.2, P = 0.002), and non-ADF ER opioids (RR = 3.4, P = 0.007) were greater than Xtampza ER. Adjustment using morphine equivalents provided similar results, except that IR oxycodone in Treatment Center Programs Combined became higher than Xtampza ER. Nonoral abuse cases involving Xtampza ER were infrequent; Web monitoring data support findings that Xtampza ER is difficult to abuse nonorally. CONCLUSION: Xtampza ER abuse, misuse, and diversion and tampering are low relative to other prescription opioid analgesics. Abuse and diversion did not increase over the study period.

Online Conversation Monitoring to Understand the Opioid Epidemic: Epidemiological Surveillance Study.

BACKGROUND: Between 2016 and 2017, the national mortality rate involving opioids continued its escalation; opioid deaths rose from 42,249 to 47,600, bringing the public health crisis to a new height. Considering that 69% of adults in the United States use online social media sites, a resource that builds a more complete understanding of prescription drug misuse and abuse could supplement traditional surveillance instruments. The Food and Drug Administration has identified 5 key risks and consequences of opioid drugs-misuse, abuse, addiction, overdose, and death. Identifying posts that discuss these key risks could lead to novel information that is not typically captured by traditional surveillance systems. OBJECTIVE: The goal of this study was to describe the trends of online posts (frequency over time) involving abuse, misuse, addiction, overdose, and death in the United States and to describe the types of websites that host these discussions. Internet posts that mentioned fentanyl, hydrocodone, oxycodone, or oxymorphone were examined. METHODS: Posts that did not refer to personal experiences were removed, after which 3.1 million posts remained. A stratified sample of 61,000 was selected. Unstructured data were classified into 5 key risks by manually coding for key outcomes of misuse, abuse, addiction, overdose, and death. Sampling probabilities of the coded posts were used to estimate the total post volume for each key risk. RESULTS: Addiction and misuse were the two most commonly discussed key risks for hydrocodone, oxycodone, and oxymorphone. For fentanyl, overdose and death were the most discussed key risks. Fentanyl had the highest estimated number of misuse-, overdose-, and death-related mentions (41,808, 42,659, and 94,169, respectively). Oxycodone had the highest estimated number of abuse- and addiction-related mentions (3548 and 12,679, respectively). The estimated volume of online posts for fentanyl increased by more than 10-fold in late 2017 and 2018. The odds of discussing fentanyl overdose (odds ratios [OR] 4.32, 95% CI 2.43-7.66) and death (OR 5.05, 95% CI 3.10-8.21) were higher for social media, while the odds of discussing fentanyl abuse (OR 0.10, 95% CI 0.04-0.22) and addiction (OR 0.24, 95% CI 0.15-0.38) were higher for blogs and forums. CONCLUSIONS: Of the 5 FDA-defined key risks, fentanyl overdose and death has dominated discussion in recent years, while discussion of oxycodone, hydrocodone, and oxymorphone has decreased. As drug-related deaths continue to increase, an understanding of the motivations, circumstances, and consequences of drug abuse would assist in developing policy responses. Furthermore, content was notably different based on media origin, and studies that exclusively use either social media sites (such as Twitter) or blogs and forums could miss important content. This study sets out sustainable, ongoing methodology for surveilling internet postings regarding these drugs.

The diversion of nonscheduled psychoactive prescription medications in the United States, 2002 to 2017.

PURPOSE: Systematic studies of the diversion of nonscheduled drugs, except for gabapentin, are not apparent. We searched diversion case reports of all other nonscheduled psychoactive prescription drugs in the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System. METHODS: Case report data are drawn from a quarterly survey of prescription drug diversion completed by a national sample of law enforcement and regulatory agencies. Rates of diversion per 100 000 population were calculated for each year from 2002 to 2017 for prescription medications with greater than 400 reported cases during the period. RESULTS: Cyclobenzaprine, quetiapine, and trazodone met criteria for analysis. We found a significant and steady increase in the diversion of each drug over the period. The 2017 annual rates of diversion per 100 000 population for the three medications range from 0.0428 to 0.0726. Although these rates of diversion are much lower than the rate for total opioid analgesics, they are all more than five times higher in 2017 compared with 2002. While diversion rates for opioids have decreased in recent years, rates for cyclobenzaprine, quetiapine, and trazodone have continued to increase. CONCLUSIONS: A common attribute of the three nonscheduled drugs studied here is that all are used for the treatment and/or self-treatment of opioid withdrawal symptoms, and the increasing diversion of these drugs may be related to the ongoing opioid epidemic and to increasing levels of control over pharmaceutical opioid availability in the United States. Prescribers need to be aware of illicit markets for these medications and prescribe to their patients with appropriate caution.

Consistency Between Opioid-Related Mortality Trends Derived From Poison Center and National Vital Statistics System, United States, 2006-2016.

OBJECTIVES: To determine the association between poison center opioid exposure calls and National Vital Statistics System (NVSS) deaths. METHODS: We categorized Centers for Disease Control and Prevention NVSS mortality and the Researched Abuse, Diversion and Addiction-Related Surveillance System poison center program cases from 2006 to 2016 by International Classification of Diseases, Tenth Revision, codes (heroin [T40.1]; natural or semisynthetic opioids [T40.2]; methadone [T40.3]; synthetic opioids, other than methadone [T40.4]). We scaled rates by 100 000 population and calculated Pearson correlation coefficients. Sensitivity analysis excluded polysubstance cases involving either heroin or synthetic opioids as well as natural and semisynthetic opioids. RESULTS: The NVSS mortality and poison center program exposure rates showed similar trends from 2006 to 2012, and diverged after 2012 for all opioids combined, natural and semisynthetic opioids, and synthetic opioids (r = -0.37, -0.12, and 0.30, respectively). Sensitivity analysis with removal of heroin or synthetic opioid polysubstance deaths markedly improved correlations for all opioids combined and natural and semisynthetic opioids (r = 0.87 and 0.36, respectively). CONCLUSIONS: The NVSS mortality and poison center exposure rates showed similar trends from 2006 to 2012 then diverged, with sensitivity analysis suggesting polysubstance cases also involving heroin or illicit fentanyl as the cause. Public Health Implications. The NVSS and poison center program may provide complementary data when trends diverge. Public health interventions must include both licit and illicit opioids for maximal impact.

Law enforcement-derived data on gabapentin diversion and misuse, 2002-2015: diversion rates and qualitative research findings.

PURPOSE: Recent limited epidemiologic and case reports suggest that gabapentin is being misused, especially among prescription opioid misusers. However, no apparent studies have reported data from law enforcement on the diversion and misuse of gabapentin. METHODS: Case report data are drawn from a quarterly survey of prescription drug diversion completed by a national sample of law enforcement and regulatory agencies who engage in drug diversion investigations. Rates of gabapentin diversion per 100 000 population were calculated for each quarter from 2002 through 2015. Qualitative data are drawn from a brief questionnaire completed by a subsample of survey respondents and were organized and presented by theme. RESULTS: In total, 407 new cases of diverted gabapentin were reported during the time period, with diversion rates steadily increasing from zero cases in the first 2 quarters of 2002 to a high of 0.027 cases per 100 000 population in the fourth quarter of 2015. Qualitative data suggest that gabapentin is being misused in conjunction with prescription opioids and that gabapentin and heroin are being combined and consumed together. Law enforcement reporters found these drug use trends to be contributing to gabapentin diversion. CONCLUSIONS: The recent increase in gabapentin diversion appears to be related to the opioid epidemic, based on law enforcement descriptions of gabapentin being misused in combination with opioids. Yet epidemiological data related to this finding is limited and research conducted among gabapentin misusers is needed to understand this problem in more depth. Greater monitoring of gabapentin abuse and diversion appear warranted.

Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants.

Leber congenital amaurosis 9 (LCA9) is an autosomal recessive retinal degeneration condition caused by mutations in the NAD(+) biosynthetic enzyme NMNAT1. This condition leads to early blindness but no other consistent deficits have been reported in patients with NMNAT1 mutations despite its central role in metabolism and ubiquitous expression. To study how these mutations affect NMNAT1 function and ultimately lead to the retinal degeneration phenotype, we performed detailed analysis of LCA-associated NMNAT1 mutants, including the expression, nuclear localization, enzymatic activity, secondary structure, oligomerization, and promotion of axonal and cellular integrity in response to injury. In many assays, most mutants produced results similar to wild type NMNAT1. Indeed, NAD(+) synthetic activity is unlikely to be a primary mechanism underlying retinal degeneration as most LCA-associated NMNAT1 mutants had normal enzymatic activity. In contrast, the secondary structure of many NMNAT1 mutants was relatively less stable as they lost enzymatic activity after heat shock, whereas wild type NMNAT1 retains significant activity after this stress. These results suggest that LCA-associated NMNAT1 mutants are more vulnerable to stressful conditions that lead to protein unfolding, a potential contributor to the retinal degeneration observed in this syndrome.

The Effect of Central Nervous System Penetration Effectiveness of Highly Active Antiretroviral Therapy on Neuropsychological Performance and Neuroimaging in HIV Infected Individuals.

The incidence of HIV-associated dementia has been greatly reduced in the era of highly active antiretroviral therapy (HAART); however milder forms of cognitive impairment persist. It remains uncertain whether HAART regimens with a high degree of central nervous system penetration effectiveness (CPE) exert beneficial neurological outcomes in HIV-infected (HIV+) individuals on stable treatment. Sixty-four HIV-infected adults on HAART were assigned a CPE score using a published ranking system and divided into high (≥7; n = 35) and low (<7; n = 29) CPE groups. All participants completed neuropsychological testing in addition to structural neuroimaging. Neuropsychological tests included measures known to be sensitive to HIV with values converted into standardized scores (NPZ-4) based on published normative scores. A semi-automated methodology was utilized to assess brain volumetrics within cortical (grey and white matter) and subcortical (thalamus, caudate, putamen) regions of interest. Analyses assessed NPZ-4 and brain volumetric differences between HIV+ individuals with high and low CPE scores. No significant differences in brain integrity were observed between the two groups. Long-term HAART regimens with a high degree of CPE were not associated with significantly improved neuropsychological or neuroimaging outcomes in HIV+ adults. Results suggest that alternate mechanisms may potentially contribute to better neurological outcomes in the era of HAART.

A clear and present danger: endogenous ligands of Toll-like receptors.

Neurologic disease promoted by microbial pathogens, sterile injury, or neurodegeneration rapidly induces innate immunity in adjacent healthy tissue, which in turn contributes extensively to neurologic injury. With more recent focus on innate immune processes, it appears that necrotic, but not apoptotic, death mechanisms provoke inflammatory responses likely due to the release or production of endogenous ligands that activate resident immune cells of the central nervous system. These ligands comprise a diverse set of proteins, nucleic acids, and glycosaminoglycans, including heat shock proteins, HMGB1, RNA, DNA, hyaluronan, and heparin sulfate, that stimulate innate immune mechanisms largely through Toll-like receptors (TLRs). The blockade of interactions between endogenous ligands and TLRs may enable neuroprotective therapeutic strategies for a variety of neurologic diseases.