Rise and regional disparities in buprenorphine utilization in the United States.

PURPOSE: Buprenorphine is an opioid partial agonist used to treat opioid use disorder. While several policy changes have attempted to increase buprenorphine availability, access remains well below optimal levels. This study characterized how buprenorphine utilization in the United States has changed over time and whether there are regional disparities in distribution of the medication. METHODS: The amount of buprenorphine distributed from 2007 to 2017 was obtained from the Drug Enforcement Administration's Automated Reports and Consolidated Ordering System. Data were expressed as the percent change and milligrams per person in each state. The formulations and cost for prescriptions covered by Medicaid (2008 to 2018) were also examined. RESULTS: Buprenorphine distributed to pharmacies increased about 7-fold (476.8 to 3179.9 kg) while the quantities distributed to hospitals grew 5-fold (18.6 to 97.6 kg) nationally from 2007 to 2017. Buprenorphine distribution per person was almost 20-fold higher in Vermont (40.4 mg/person) relative to South Dakota (2.1 mg/person). There was a strong association between the number of physicians authorized to prescribe buprenorphine and distribution per state (r[49] = +0.94, P < .0005). The buprenorphine/naloxone sublingual film (Suboxone) was the predominant formulation (92.6% of 0.31 million Medicaid prescriptions) in 2008 but accounted for less than three-fifth (57.3% of 6.56 million prescriptions) in 2018. CONCLUSIONS: Although buprenorphine availability has substantially increased over the last decade, distribution was very nonhomogeneous across the United States.

Quantification of Conflicts of Interest in an Online Point-of-Care Clinical Support Website.

Online medical reference websites are utilized by health care providers to enhance their education and decision making. However, these resources may not adequately reveal pharmaceutical-author interactions and their potential conflicts of interest (CoIs). This investigation: (1) evaluates the correspondence of two well-utilized CoI databases: the Centers for Medicare and Medicaid Services Open Payments (CMSOP) and ProPublica's Dollars for Docs (PDD) and (2) quantifies CoIs among authors of a publicly available point of care clinical support website which is used to inform evidence-based medicine decisions. Two data sources were used: the hundred most common drugs and the top fifty causes of death. These topics were entered into a freely available database. The authors (N = 139) were then input into CMSOP and PDD and compensation and number of payments were determined for 2013-2015. The subset of highly compensated authors that also reported "Nothing to disclose" were further examined. There was a high degree of similarity between CMSOP and PDD for compensation (R2 ≥ 0.998) and payment number (R2 ≥ 0.992). The amount received was 1.4% higher in CMSOP ($4,059,194) than in PDD ($4,002,891). The articles where the authors had received the greatest compensation were in neurology (Parkinson's Disease = $1,810,032), oncology (Acute Lymphoblastic Leukemia = $616,727), and endocrinology (Type I Diabetes = $377,388). Two authors reporting "Nothing to disclose" received appreciable and potentially relevant compensation. CMSOP and PDD produced almost identical results. CoIs were common among authors but self-reporting may be an inadequate reporting mechanism. Recommendations are offered for improving the CoI transparency of pharmaceutical-author interactions in point-of-care electronic resources.

Focused Ultrasound Hyperthermia for Targeted Drug Release from Thermosensitive Liposomes: Results from a Phase I Trial.

Purpose To demonstrate the feasibility and safety of using focused ultrasound planning models to determine the treatment parameters needed to deliver volumetric mild hyperthermia for targeted drug delivery without real-time thermometry. Materials and Methods This study was part of the Targeted Doxorubicin, or TARDOX, phase I prospective trial of focused ultrasound-mediated, hyperthermia-triggered drug delivery to solid liver tumors ( ClinicalTrials.gov identifier NCT02181075). Ten participants (age range, 49-68 years; average age, 60 years; four women) were treated from March 2015 to March 2017 by using a clinically approved focused ultrasound system to release doxorubicin from lyso-thermosensitive liposomes. Ultrasonic heating of target tumors (treated volume: 11-73 cm3 [mean ± standard deviation, 50 cm3 ± 26]) was monitored in six participants by using a minimally invasive temperature sensor; four participants were treated without real-time thermometry. For all participants, CT images were used with a patient-specific hyperthermia model to define focused ultrasound treatment plans. Feasibility was assessed by comparing model-prescribed focused ultrasound powers to those implemented for treatment. Safety was assessed by evaluating MR images and biopsy specimens for evidence of thermal ablation and monitoring adverse events. Results The mean difference between predicted and implemented treatment powers was -0.1 W ± 17.7 (n = 10). No evidence of focused ultrasound-related adverse effects, including thermal ablation, was found. Conclusion In this 10-participant study, the authors confirmed the feasibility of using focused ultrasound-mediated hyperthermia planning models to define treatment parameters that safely enabled targeted, noninvasive drug delivery to liver tumors while monitored with B-mode guidance and without real-time thermometry. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Dickey and Levi-Polyachenko in this issue.

Trends in the medical supply of fentanyl and fentanyl analogues: United States, 2006 to 2017.

Fentanyl is an important opioid for pain management, but also has exceptional potential for misuse. Seven states have implemented opioid prescribing laws. The objectives of this study were to: 1) characterize the temporal pattern of fentanyl, fentanyl analogue, and other opioid use over the past decade, and 2) determine whether opioid prescribing laws impacted fentanyl use in the US. Drug weights were obtained from the US Automated Reports of Consolidated Orders System (June 2018), a comprehensive publically available resource, from 2006 to 2017 for fentanyl, sufentanil, remifentanil, alfentanil, other prescription opioids, and analyzed by presence of a state opioid prescribing law. Fentanyl, corrected for population, was reduced from 2016 to 2017 (-17.9%) and these decreases significantly exceeded the changes in hydrocodone (-12.3%), oxycodone (-10.1%), morphine (-13.3%), or codeine (-8.8%). Fentanyl showed a particularly large decline in Maine, a state with a strong opioid prescribing law. There was a 3.5 fold difference in fentanyl (µg per capita) in Alaska (488.2) relative to Oregon (1718.4). Hospital use of remifentanil and sufentanil tripled from 2006 to 2017. Although all states experienced a 2016 to 2017 decline in fentanyl, and this reduction was larger than many other prescription opioids, the rate of decline varied over three-fold between states. Strong state laws may account for a portion of the variance in fentanyl and other opioid reductions. The population health risks of fentanyl and fentanyl analogues warrants ongoing vigilance.

Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial.

BACKGROUND: Previous preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound. METHODS: We did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment. FINDINGS: Between March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 µg/g (SD 0·93) immediately after drug infusion to 8·56 µg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3-4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred. INTERPRETATION: The combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy. FUNDING: Oxford Biomedical Research Centre, National Institute for Health Research.

High-intensity focused ultrasonic ablation of sacral chordoma is feasible: a series of four cases and details of a national clinical trial.

High-intensity focused ultrasound describes the use of high-intensity focused ultrasound (HIFU) to ablate tumours without requiring an incision or other invasive procedure. This technique has been trialled on a range of tumours including uterine fibroids, prostate, liver and renal cancer. We describe our experience of using HIFU to ablate sacral chordoma in four patients with advanced tumours. Patients were treated under general anaesthetic or sedation using an ultrasound-guided HIFU device. HIFU therapy was associated with a reduction in tumour volume over time in three patients for whom follow up scans were available. Tumour necrosis was reliably demonstrated in two of the three patients. We have established a national trial to assess if HIFU may improve long-term outcome from sacral chordoma, details are given.

Prescription Opioid Distribution after the Legalization of Recreational Marijuana in Colorado.

There have been dynamic changes in prescription opioid use in the US but the state level policy factors contributing to these are incompletely understood. We examined the association between the legalization of recreational marijuana and prescription opioid distribution in Colorado. Utah and Maryland, two states that had not legalized recreational marijuana, were selected for comparison. Prescription data reported to the Drug Enforcement Administration for nine opioids used for pain (e.g., fentanyl, morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone) and two primarily for opioid use disorder (OUD, methadone and buprenorphine) from 2007 to 2017 were evaluated. Analysis of the interval pre (2007-2012) versus post (2013-2017) marijuana legalization revealed statistically significant decreases for Colorado (P < 0.05) and Maryland (P < 0.01), but not Utah, for pain medications. There was a larger reduction from 2012 to 2017 in Colorado (-31.5%) than the other states (-14.2% to -23.5%). Colorado had a significantly greater decrease in codeine and oxymorphone than the comparison states. The most prevalent opioids by morphine equivalents were oxycodone and methadone. Due to rapid and pronounced changes in prescription opioid distribution over the past decade, additional study with more states is needed to determine whether cannabis policy was associated with reductions in opioids used for chronic pain.

Dynamic changes in prescription opioids from 2006 to 2017 in Texas.

BACKGROUND: The US is experiencing an epidemic of opioid overdoses which may be at least partially due to an over-reliance on opioid analgesics in the treatment of chronic non-cancer pain and subsequent escalation to heroin or illicit fentanyl. As Texas was reported to be among the lowest in the US for opioid use and misuse, further examination of this state is warranted. MATERIALS AND METHODS: This study was conducted to quantify prescription opioid use in Texas. Data was obtained from the publicly available US Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) which monitors controlled substances transactions from manufacture to commercial distribution. Data for 2006-2017 from Texas for ten prescription opioids including eight primarily used to relieve pain (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, morphine, oxycodone, oxymorphone) and two (buprenorphine and methadone) for the treatment of an Opioid Use Disorder (OUD) were examined. RESULTS: The change in morphine mg equivalent (MME) of all opioids (+23.3%) was only slightly greater than the state's population gains (21.1%). Opioids used to treat an OUD showed pronounced gains (+90.8%) which were four-fold faster than population growth. Analysis of individual agents revealed pronounced elevations in codeine (+387.5%), hydromorphone (+106.7%), and oxycodone (+43.6%) and a reduction in meperidine (-80.3%) in 2017 relative to 2006. Methadone in 2017 accounted for a greater portion (39.5%) of the total MME than hydrocodone, oxycodone, morphine, hydromorphone, oxymorphone, and meperidine, combined. There were differences between urban and rural areas in the changes in hydrocodone and buprenorphine. CONCLUSIONS: Collectively, these findings indicate that continued vigilance is needed in Texas to appropriately treat pain and an OUD while minimizing the potential for prescription opioid diversion and misuse. Texas may lead the US in a return to pre-opioid epidemic prescription levels.

Descriptive, observational study of pharmaceutical and non-pharmaceutical arrests, use, and overdoses in Maine.

OBJECTIVES: The Maine Diversion Alert Program grants healthcare providers access to law enforcement data on drug charges. The objectives of this report were to analyse variations in drug charges by demographics and examine recent trends in arrests, prescriptions of controlled substances and overdoses. DESIGN: Observational. SETTING: Arrests, controlled prescription medication distribution and overdoses in Maine. PARTICIPANTS: Drug arrestees (n=1272) and decedents (n=2432). PRIMARY OUTCOME MEASURES: Arrestees were analysed by sex and age. Substances involved in arrests were reported by schedule (I-V or non-controlled prescription) and into opioids, stimulants or other classes. Controlled substances reported to the Drug Enforcement Administration (2007-2017) were evaluated. Drug-induced deaths (2007-2017) reported to the medical examiner were examined by the substance(s) identified. RESULTS: Males were more commonly arrested for stimulants and schedule II substances. More than two-thirds of arrests involved individuals under the age of 40. Individuals age >60 were elevated for oxycodone arrests. Over three-fifths (63.38%) of arrests involved schedule II-IV substances. Opioids accounted for almost half (44.6%) of arrests followed by stimulants (32.5%) and sedatives (9.1%). Arrests involving buprenorphine exceeded those for oxycodone, hydrocodone, methadone, tramadol and morphine, combined. Prescriptions for hydrocodone (-56.0%) and oxycodone (-46.9%) declined while buprenorphine increased (+58.1%) between 2012 and 2017. Deaths from 2007 to 2017 tripled. Acetylfentanyl and furanylfentanyl were the most common fentanyl analogues identified. CONCLUSIONS: Although the overall profile of those arrested for drug crimes in 2017 involve males, age <40 and heroin, exceptions (oxycodone for older adults) were observed. Most prescription opioids are decreasing while deaths involving opioids continue to increase in Maine.

Opioid distribution trends (2006-2017) in the US Territories.

BACKGROUND: The US mainland is experiencing an epidemic of opioid overdoses. Unfortunately, the US Territories (Guam, Puerto Rico, and the Virgin Islands) have often been overlooked in opioid pharmacoepidemiology research. This study examined common prescription opioids over the last decade. METHODS: The United States Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) was used to report on ten medical opioids: buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, and oxymorphone, by weight from 2006 to 2017. Florida and Hawaii were selected as comparison areas. RESULTS: Puerto Rico had the greatest Territorial oral morphine mg equivalent (MME) per capita (421.5) which was significantly higher (p < .005) than the Virgin Islands (139.2) and Guam (118.9) but significantly lower than that of Hawaii (794.6) or Florida (1,509.8). Methadone was the largest opioid by MMEs in 2017 in most municipalities, accounting for 41.1% of the total in the Virgin Islands, 37.9% in Florida, 36.6% in Hawaii but 80.8% in Puerto Rico. Puerto Rico and Florida showed pronounced differences in the distribution patterns by pharmacies, hospitals, and narcotic treatment programs for opioids. CONCLUSIONS: Continued monitoring of the US Territories is needed to provide a balance between appropriate access to these important agents for cancer related and acute pain while also minimizing diversion and avoiding the opioid epidemic which has adversely impacted the US mainland.

A Quantitative and Narrative Evaluation of Goodman and Gilman's Pharmacological Basis of Therapeutics.

Goodman and Gilman's The Pharmacological Basis of Therapeutics (GGPBT) has been a cornerstone in the education of pharmacists, physicians, and pharmacologists for decades. The objectives of this study were to describe and evaluate the 13th edition of GGPBT on bases including: (1) author characteristics; (2) recency of citations; (3) conflict of interest (CoI) disclosure; (4) expert evaluation of chapters. Contributors' (N = 115) sex, professional degrees, and presence of undisclosed potential CoI-as reported by the Center for Medicare and Medicaid's Open Payments (2013-2017)-were examined. The year of publication of citations was extracted relative to Katzung's Basic and Clinical Pharmacology (KatBCP), and DiPiro's Pharmacotherapy: A Pathophysiologic Approach (DiPPAPA). Content experts provided thorough chapter reviews. The percent of GGPBT contributors that were female (20.9%) was equivalent to those in KatBCP (17.0%). Citations in GGPBT (11.5 ± 0.2 years) were significantly older than those in KatBCP (10.4 ± 0.2) and DiPPAPA (9.1 ± 0.1, p < 0.0001). Contributors to GGPBT received USD 3 million in undisclosed remuneration (Maximum author = USD 743,718). In contrast, DiPPAPA made CoI information available. Reviewers noted several strengths but also some areas for improvement. GGPBT will continue to be an important component of the biomedical curriculum. Areas of improvement include a more diverse authorship, improved conflict of interest transparency, and a greater inclusion of more recent citations.

Trends in use of prescription stimulants in the United States and Territories, 2006 to 2016.

BACKGROUND: Stimulants are considered the first-line treatment for Attention Deficit Hyperactivity Disorder (ADHD) in the US and they are used in other indications. Stimulants are also diverted for non-medical purposes. Ethnic and regional differences in ADHD diagnosis and in stimulant use have been identified in earlier research. The objectives of this report were to examine the pharmacoepidemiological pattern of these controlled substances over the past decade and to conduct a regional analysis. METHODS: Data (drug weights) reported to the US Drug Enforcement Administration's Automation of Reports and Consolidated Orders System for four stimulants (amphetamine, methylphenidate, lisdexamfetamine, and methamphetamine) were obtained from 2006 to 2016 for Unites States/Territories. Correlations between state level use (mg/person) and Hispanic population were completed. RESULTS: Amphetamine use increased 2.5 fold from 2006 to 2016 (7.9 to 20.0 tons). Methylphenidate use, at 16.5 tons in 2006, peaked in 2012 (19.4 tons) and subsequently showed a modest decline (18.6 tons in 2016). The consumption per municipality significantly increased 7.6% for amphetamine and 5.5% for lisdexamfetamine but decreased 2.7% for methylphenidate (all p < .0005) from 2015 to 2016. Pronounced regional differences were also observed. Lisdexamfetamine use in 2016 was over thirty-fold higher in the Southern US (43.8 mg/person) versus the Territories (1.4 mg/person). Amphetamine use was about one-third lower in the West (48.1 mg/person) relative to the Northeastern (75.4 mg/person, p < .05) or the Midwestern (69.9 mg/person, p ≤ .005) states. States with larger Hispanic populations had significantly lower methylphenidate (r(49) = -0.63), lisdexamfetamine (B, r(49) = -0.49), and amphetamine (r(49) = -0.43) use. CONCLUSIONS: Total stimulant usage doubled in the last decade. There were dynamic changes but also regional disparities in the use of stimulant medications. Future research is needed to better understand the reasons for the sizable regional and ethnic variations in use of these controlled substances.

Heterogeneous Tissue Characterization Using Ultrasound: A Comparison of Fractal Analysis Backscatter Models on Liver Tumors.

Assessment of tumor tissue heterogeneity via ultrasound has recently been suggested as a method for predicting early response to treatment. The ultrasound backscattering characteristics can assist in better understanding the tumor texture by highlighting the local concentration and spatial arrangement of tissue scatterers. However, it is challenging to quantify the various tissue heterogeneities ranging from fine to coarse of the echo envelope peaks in tumor texture. Local parametric fractal features extracted via maximum likelihood estimation from five well-known statistical model families are evaluated for the purpose of ultrasound tissue characterization. The fractal dimension (self-similarity measure) was used to characterize the spatial distribution of scatterers, whereas the lacunarity (sparsity measure) was applied to determine scatterer number density. Performance was assessed based on 608 cross-sectional clinical ultrasound radiofrequency images of liver tumors (230 and 378 representing respondent and non-respondent cases, respectively). Cross-validation via leave-one-tumor-out and with different k-fold methodologies using a Bayesian classifier was employed for validation. The fractal properties of the backscattered echoes based on the Nakagami model (Nkg) and its extend four-parameter Nakagami-generalized inverse Gaussian (NIG) distribution achieved best results-with nearly similar performance-in characterizing liver tumor tissue. The accuracy, sensitivity and specificity of Nkg/NIG were 85.6%/86.3%, 94.0%/96.0% and 73.0%/71.0%, respectively. Other statistical models, such as the Rician, Rayleigh and K-distribution, were found to not be as effective in characterizing subtle changes in tissue texture as an indication of response to treatment. Employing the most relevant and practical statistical model could have potential consequences for the design of an early and effective clinical therapy.

Quantification of ultrasonic texture intra-heterogeneity via volumetric stochastic modeling for tissue characterization.

Intensity variations in image texture can provide powerful quantitative information about physical properties of biological tissue. However, tissue patterns can vary according to the utilized imaging system and are intrinsically correlated to the scale of analysis. In the case of ultrasound, the Nakagami distribution is a general model of the ultrasonic backscattering envelope under various scattering conditions and densities where it can be employed for characterizing image texture, but the subtle intra-heterogeneities within a given mass are difficult to capture via this model as it works at a single spatial scale. This paper proposes a locally adaptive 3D multi-resolution Nakagami-based fractal feature descriptor that extends Nakagami-based texture analysis to accommodate subtle speckle spatial frequency tissue intensity variability in volumetric scans. Local textural fractal descriptors - which are invariant to affine intensity changes - are extracted from volumetric patches at different spatial resolutions from voxel lattice-based generated shape and scale Nakagami parameters. Using ultrasound radio-frequency datasets we found that after applying an adaptive fractal decomposition label transfer approach on top of the generated Nakagami voxels, tissue characterization results were superior to the state of art. Experimental results on real 3D ultrasonic pre-clinical and clinical datasets suggest that describing tumor intra-heterogeneity via this descriptor may facilitate improved prediction of therapy response and disease characterization.