Heroin use onset among nonmedical prescription opioid users in the club scene.

PubMed

Surratt, Hilary L; Kurtz, Steven P; Buttram, Mance; Levi-Minzi, Maria A; Pagano, Maria E; Cicero, Theodore J

2017-10-01

Nonmedical prescription opioid use (NMPOU) is well documented among participants in the club scene, yet prior studies have not examined transition to heroin use. We prospectively examined heroin initiation among a sample of young adults with drug involvement associated with participation in the club scene, to understand factors that influence transition from NMPOU to heroin and to identify opportunities for intervention. Data were drawn from a randomized trial that enrolled 750 Miami-based club and prescription drug users through respondent driven sampling, and tested the efficacy of assessment interventions in reducing risk. Participants reported current substance use at baseline, 3, 6, and 12 month follow-ups. We examined predictors of heroin initiation among participants reporting NMPOU at baseline, with no lifetime history of heroin use (N=323). The mean age was 25.0 years; 67.5% met DSM-IV criteria for substance dependence. About 1 in 13 participants (7.7%) initiated heroin use at follow-up. In univariable comparisons, frequent LSD use, history of drug overdose, high frequency NMPOU, using oral tampering methods, and endorsing a primary medical source for prescription opioids were associated with greater likelihood of heroin initiation. LSD use, oral tampering, and primary medical source were significant predictors in a Cox regression model. Heroin initiation of 7.7% suggests a high level of vulnerability for transition among young adult NMPO users in the club scene. The importance of oral tampering methods in the trajectory of NMPOU may indicate a need to further examine the role of abuse deterrent formulations in prevention efforts. Copyright © 2017 Elsevier B.V. All rights reserved.

Ephemeral profiles of prescription drug and formulation tampering: evolving pseudoscience on the Internet.

PubMed

Cone, Edward J

2006-06-01

The magnitude of non-therapeutic use, or misuse of prescription pharmaceuticals now rivals that of illicit drug abuse. Drug and formulation tampering enables misusers to administer higher doses by intended and non-intended routes. Perceived motives appear to be a combination of interests in achieving a faster onset and enhancing psychoactive effects. Narcotic analgesics, stimulants, and depressants are widely sought, examined, and tampered with for recreational use. This review examines tampering methods reported on the Internet for selected pharmaceutical products. The Internet provides broad and varied guidance on tampering methods that are specific to drug classes and unique formulations. Instructions are available on crushing, separating, purifying and chemically altering specific formulations to allow changes in dosage, route of administration, and time course of effects. Many pharmaceutical formulations contain features that serve as "barriers" to tampering. The nature and effectiveness of formulation barriers vary widely with many being overcome by adventurous misusers. Examples of successes and failures in tampering attempts are frequently described on Internet sites that support recreational drug use. Successful tampering methods that have widespread appeal evolve into recipes and become archived on multiple websites. Examples of tampering methods include: (1) how to separate narcotic drugs (codeine, hydrocodone, oxycodone) from excipients and non-desirable actives (aspirin, acetaminophen, ibuprofen); (2) overcoming time-release formulations (beads, layers, matrices); (3) removal of active drug from high-dose formulations (patches, pills); (4) alteration of dosage forms for alternate routes of administration. The development of successful formulations that inhibit or prevent drug/formulation tampering with drugs of abuse should take into consideration the scope and practice of tampering methods available to recreational drug users on the Internet.

NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.

PubMed

Miyazaki, Takahiro; Choi, Irene Y; Rubas, Werner; Anand, Neel K; Ali, Cherie; Evans, Juli; Gursahani, Hema; Hennessy, Marlene; Kim, Grace; McWeeney, Daniel; Pfeiffer, Juergen; Quach, Phi; Gauvin, David; Riley, Timothy A; Riggs, Jennifer A; Gogas, Kathleen; Zalevsky, Jonathan; Doberstein, Stephen K

2017-10-01

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Ensuring safe access to medication for palliative care while preventing prescription drug abuse: innovations for American inner cities, rural areas, and communities overwhelmed by addiction

PubMed Central

Francoeur, Richard B

2011-01-01

This article proposes and develops novel components of community-oriented programs for creating and affording access to safe medication dispensing centers in existing retail pharmacies and in permanent or travelling pharmacy clinics that are guarded by assigned or off-duty police officers. Pharmacists at these centers would work with police, medical providers, social workers, hospital administrators, and other professionals in: planning and overseeing the safe storage of controlled substance medications in off-site community safe-deposit boxes; strengthening communication and cooperation with the prescribing medical provider; assisting the prescribing medical provider in patient monitoring (checking the state prescription registry, providing pill counts and urine samples); expanding access to lower-cost, and in some cases, abuse-resistant formulations of controlled substance medications; improving transportation access for underserved patients and caregivers to obtain prescriptions; and integrating community agencies and social networks as resources for patient support and monitoring. Novel components of two related community-oriented programs, which may be hosted outside of safe medication dispensing centers, are also suggested and described: (1) developing medication purchasing cooperatives (ie, to help patients, families, and health institutions afford the costs of medications, including tamper-or abuse-resistant/deterrent drug formulations); and (2) expanding the role of inner-city methadone maintenance treatment programs in palliative care (ie, to provide additional patient monitoring from a second treatment team focusing on narcotics addiction, and potentially, to serve as an untapped source of opioid medication for pain that is less subject to abuse, misuse, or diversion). PMID:22312232

Ensuring safe access to medication for palliative care while preventing prescription drug abuse: innovations for American inner cities, rural areas, and communities overwhelmed by addiction.

PubMed

Francoeur, Richard B

2011-01-01

This article proposes and develops novel components of community-oriented programs for creating and affording access to safe medication dispensing centers in existing retail pharmacies and in permanent or travelling pharmacy clinics that are guarded by assigned or off-duty police officers. Pharmacists at these centers would work with police, medical providers, social workers, hospital administrators, and other professionals in: planning and overseeing the safe storage of controlled substance medications in off-site community safe-deposit boxes; strengthening communication and cooperation with the prescribing medical provider; assisting the prescribing medical provider in patient monitoring (checking the state prescription registry, providing pill counts and urine samples); expanding access to lower-cost, and in some cases, abuse-resistant formulations of controlled substance medications; improving transportation access for underserved patients and caregivers to obtain prescriptions; and integrating community agencies and social networks as resources for patient support and monitoring. Novel components of two related community-oriented programs, which may be hosted outside of safe medication dispensing centers, are also suggested and described: (1) developing medication purchasing cooperatives (ie, to help patients, families, and health institutions afford the costs of medications, including tamper-or abuse-resistant/deterrent drug formulations); and (2) expanding the role of inner-city methadone maintenance treatment programs in palliative care (ie, to provide additional patient monitoring from a second treatment team focusing on narcotics addiction, and potentially, to serve as an untapped source of opioid medication for pain that is less subject to abuse, misuse, or diversion).

A Secure and Robust Approach to Software Tamper Resistance

NASA Astrophysics Data System (ADS)

Ghosh, Sudeep; Hiser, Jason D.; Davidson, Jack W.

Software tamper-resistance mechanisms have increasingly assumed significance as a technique to prevent unintended uses of software. Closely related to anti-tampering techniques are obfuscation techniques, which make code difficult to understand or analyze and therefore, challenging to modify meaningfully. This paper describes a secure and robust approach to software tamper resistance and obfuscation using process-level virtualization. The proposed techniques involve novel uses of software check summing guards and encryption to protect an application. In particular, a virtual machine (VM) is assembled with the application at software build time such that the application cannot run without the VM. The VM provides just-in-time decryption of the program and dynamism for the application's code. The application's code is used to protect the VM to ensure a level of circular protection. Finally, to prevent the attacker from obtaining an analyzable snapshot of the code, the VM periodically discards all decrypted code. We describe a prototype implementation of these techniques and evaluate the run-time performance of applications using our system. We also discuss how our system provides stronger protection against tampering attacks than previously described tamper-resistance approaches.

Changes in drug use patterns reported on the web after the introduction of ADF OxyContin: findings from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Web Monitoring Program.

PubMed

Vosburg, Suzanne K; Haynes, Colleen; Besharat, Andrea; Green, Jody L

2017-09-01

This qualitative study summarizes information that individuals shared online about use of OxyContin following the August 2010 introduction of the abuse deterrent formulation (ADF). The primary objective was to study online posts that endorsed continued use of OxyContin or a switch from OxyContin to another formulation of oxycodone or another substance altogether following the introduction of the ADF. A secondary objective was to determine whether posts revealed that the ADF led to cessation of OxyContin use. Data were collected with the Researched Abuse, Diversion, and Addiction-Related Surveillance System Web Monitoring Program, an online surveillance system that collects and organizes posts about prescription drugs from social media websites, blogs, and forums from 3Q2009 to 4Q2014 using a commercially available web platform. Posts were categorized by whether they conveyed a switch to drugs other than reformulated OxyContin or a continuation of reformulated OxyContin abuse. "Switch posts" primarily discussed switching to immediate-release opioids. "Continue abusing" posts identified tampering strategies for alternate routes of administration, oral use, and continued use although post authors were generally unhappy with the experience. No reference to OxyContin cessation as a function of the introduction of the ADF was found; however, discontinued use was discussed. Web Monitoring data are useful for capturing cross sections of Internet conversation reflecting reactions to new drug formulations. These data support the notion that users will gravitate to non-ADFs generally, and to immediate-release non-ADF opioid formulations, specifically, as long as these options remain on the market. Copyright © 2017 John Wiley & Sons, Ltd.

A Randomized Controlled Trial of the Effects of Online Pain Management Education on Primary Care Providers.

PubMed

Trudeau, Kimberlee J; Hildebrand, Cristina; Garg, Priyanka; Chiauzzi, Emil; Zacharoff, Kevin L

2017-04-01

To improve pain management practices, we developed an online interactive continuing education (CE) program for primary care providers (PCPs). This program follows the flow of clinical decision-making through simulated cases at critical pain treatment points along the pain treatment continuum. A randomized controlled trial was conducted to test the efficacy of this program. Participants were randomized to either the experimental condition or the control condition (online, text-based CE program). A total of 238 primary care providers were recruited through hospitals, professional newsletters, and pain conferences. Participants in both conditions reported significantly improved scores on knowledge (KNOW-PAIN 50), attitudes (CAOS), and pain practice behaviors (PPBS) scales over the four-month study. The experimental condition showed significantly greater change over time on the tamper-resistant formulations (TRFs) of opioids and dosing CAOS subscale compared with the control condition. Post hoc comparisons suggested that participants in the experimental condition were less likely to endorse use of opioid TRFs over time compared with the control condition. Exploratory analyses for potential moderators indicated a significant three-way interaction with time, condition, and discipline (i.e., physician vs other) for the impediments and concerns attitudes subscale and the early refill behaviors subscale. Post hoc comparisons indicated that physicians in the experimental condition exhibited the greatest change in attitudes and the nonphysicians exhibited the greatest change in reported behaviors in response to requests for early refills. Findings suggest online CE programs may positively impact PCPs' knowledge, attitudes, and pain practice behaviors but provide minimal evidence for the value of including interactivity. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Current status and evolving role of abuse-deterrent opioids in managing patients with chronic pain.

PubMed

Webster, Lynn; St Marie, Barbara; McCarberg, Bill; Passik, Steven D; Panchal, Sunil J; Voth, Eric

2011-01-01

Opioids are widely used for the treatment of patients with chronic pain; yet, the increase in their abuse, misuse, and diversion is an ongoing focus of regulatory, governmental, and legal scrutiny. As a consequence, clinicians are faced with numerous challenges in an effort to use opioids in appropriate patients with pain while minimizing the potential for opioid abuse, misuse, and diversion. Policies and programs such as state prescription monitoring programs, which have been in existence for decades, are but one attempt to address some of the issues regarding the prescribing of opioids. Another is a risk evaluation and mitigation strategy for opioids under consideration by the US Food and Drug Administration. At the clinical level, a universal precautions and risk management package that includes risk assessment and patient monitoring is a recommended approach. This approach can also include the use of abuse-deterrent and abuse-resistant formulations designed to reduce the nonmedical use of opioids. Several of these opioid formulations have been approved or should soon be on the market for use in the United States; however, their role and other questions regarding their use remain unanswered. The authors offer their clinical perspective on several of these key questions.

21 CFR 800.12 - Contact lens solutions and tablets; tamper-resistant packaging.

Code of Federal Regulations, 2010 CFR

2010-04-01

...-resistant retail packages, there is the opportunity for the malicious adulteration of these products with... confidence in the security of the packages of over-the-counter (OTC) health care products. The Food and Drug... used to make such a solution for retail sale that is not packaged in a tamper-resistant package and...

21 CFR 800.12 - Contact lens solutions and tablets; tamper-resistant packaging.

Code of Federal Regulations, 2011 CFR

2011-04-01

...-resistant retail packages, there is the opportunity for the malicious adulteration of these products with... confidence in the security of the packages of over-the-counter (OTC) health care products. The Food and Drug... used to make such a solution for retail sale that is not packaged in a tamper-resistant package and...

21 CFR 800.12 - Contact lens solutions and tablets; tamper-resistant packaging.

Code of Federal Regulations, 2012 CFR

2012-04-01

...-resistant retail packages, there is the opportunity for the malicious adulteration of these products with... confidence in the security of the packages of over-the-counter (OTC) health care products. The Food and Drug... used to make such a solution for retail sale that is not packaged in a tamper-resistant package and...

21 CFR 800.12 - Contact lens solutions and tablets; tamper-resistant packaging.

Code of Federal Regulations, 2013 CFR

2013-04-01

...-resistant retail packages, there is the opportunity for the malicious adulteration of these products with... confidence in the security of the packages of over-the-counter (OTC) health care products. The Food and Drug... used to make such a solution for retail sale that is not packaged in a tamper-resistant package and...

21 CFR 800.12 - Contact lens solutions and tablets; tamper-resistant packaging.

Code of Federal Regulations, 2014 CFR

2014-04-01

...-resistant retail packages, there is the opportunity for the malicious adulteration of these products with... confidence in the security of the packages of over-the-counter (OTC) health care products. The Food and Drug... used to make such a solution for retail sale that is not packaged in a tamper-resistant package and...

Scoring the best deal: Quantity discounts and street price variation of diverted oxycodone and oxymorphone.

PubMed

Lebin, Jacob A; Murphy, David L; Severtson, Stevan Geoffrey; Bau, Gabrielle E; Dasgupta, Nabarun; Dart, Richard C

2018-05-15

Diverted prescription opioids are significant contributors to drug overdose mortality. Street price has been suggested as an economic metric of the diverted prescription opioid black market. This study examined variables that may influence the street price of diverted oxycodone and oxymorphone. A cross-sectional study was conducted utilizing data from the previously validated, crowdsourcing website StreetRx. Street price reports of selected oxycodone and oxymorphone products, between August 22, 2014 and June 30, 2016, were considered for analysis. Geometric means and 95% confidence intervals were calculated comparing prices per milligram of drug in US dollars. Univariate and multivariable regressions were used to examine the influence of dosage strength, drug formulation, and bulk purchasing on street price. A total of 5611 oxycodone and 1420 oxymorphone reports were analyzed. Across various dosages and formulations, geometric mean prices per milligram ranged between $0.12 and $1.07 for oxycodone and $0.73 and $2.90 for oxymorphone. For a 2-fold increase in dosage strength, there is a 24.0% (95% CI: -28.1%, -19.6%, P < 0.001) and a 22.5% (95% CI: -24.2%, -20.8%, P < 0.001) decrease on average in price per milligram for oxycodone and oxymorphone, respectively. Lower potency, high dosage strength, crush-resistant opioids, and those purchased in bulk were significantly cheaper. Street prices for diverted oxycodone and oxymorphone are influenced by multiple factors including potency, dosage, formulation, and bulk purchasing. Buyers who purchase large quantities of low potency, large dosage, crush-resistant formulation prescription opioids can expect to achieve the lowest price. Copyright © 2018 John Wiley & Sons, Ltd.

21 CFR 700.25 - Tamper-resistant packaging requirements for cosmetic products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... cosmetic products. 700.25 Section 700.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.25 Tamper-resistant packaging requirements for cosmetic products. (a) General. Because most cosmetic liquid...

21 CFR 700.25 - Tamper-resistant packaging requirements for cosmetic products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... cosmetic products. 700.25 Section 700.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.25 Tamper-resistant packaging requirements for cosmetic products. (a) General. Because most cosmetic liquid...

21 CFR 700.25 - Tamper-resistant packaging requirements for cosmetic products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... cosmetic products. 700.25 Section 700.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.25 Tamper-resistant packaging requirements for cosmetic products. (a) General. Because most cosmetic liquid...

21 CFR 700.25 - Tamper-resistant packaging requirements for cosmetic products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... cosmetic products. 700.25 Section 700.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.25 Tamper-resistant packaging requirements for cosmetic products. (a) General. Because most cosmetic liquid...

21 CFR 700.25 - Tamper-resistant packaging requirements for cosmetic products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Tamper-resistant packaging requirements for cosmetic products. 700.25 Section 700.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... of cosmetic product packages. The Food and Drug Administration has the authority and responsibility...

Conductive fabric seal

DOEpatents

Livesay, Ronald Jason; Mason, Brandon William; Kuhn, Michael Joseph; Rowe, Nathan Carl

2017-04-04

Disclosed are several examples of a system and method for detecting if an article is being tampered with. Included is a covering made of a substrate that is coated with a layer of an electrically conductive material that forms an electrically conductive surface having an electrical resistance. The covering is configured to at least partially encapsulate the article such that the article cannot be tampered with, without modifying the electrical resistance of the electrically conductive surface of the covering. A sensing device is affixed to the electrically conductive surface of the covering and the sensing device monitors the condition of the covering by producing a signal that is indicative of the electrical resistance of the electrically conductive surface of the covering. A measured electrical resistance that differs from a nominal electrical resistance is indicative of a covering that is being tampered with and an alert is communicated to an observer.

Conductive fabric seal

DOEpatents

Livesay, Ronald Jason; Mason, Brandon William; Kuhn, Michael Joseph; Rowe, Nathan Carl

2015-10-13

Disclosed are several examples of a system and method for detecting if an article is being tampered with. Included is a covering made of a substrate that is coated with a layer of an electrically conductive material that forms an electrically conductive surface having an electrical resistance. The covering is configured to at least partially encapsulate the article such that the article cannot be tampered with, without modifying the electrical resistance of the electrically conductive surface of the covering. A sensing device is affixed to the electrically conductive surface of the covering and the sensing device monitors the condition of the covering by producing a signal that is indicative of the electrical resistance of the electrically conductive surface of the covering. A measured electrical resistance that differs from a nominal electrical resistance is indicative of a covering that is being tampered with and an alert is communicated to an observer.

Security Management of Electronic Data Interchange

DTIC Science & Technology

1993-06-01

48 6. Signatures by Tamper-Resistent Electronic seal .................................. 49 7. Resolution of Disputes...Trademark by RSA). Secure communication is not possible without any pi eu uous relationship between parties. Electronic mail may be sealed in a...public key certification. [Ref. 321 6. Signatures by Tamper-Resistent Electronic seal There is a separation between encryption and decryption in a public

Development and validation of an Opioid Attractiveness Scale: a novel measure of the attractiveness of opioid products to potential abusers

PubMed Central

Butler, Stephen F; Benoit, Christine; Budman, Simon H; Fernandez, Kathrine C; McCormick, Cynthia; Venuti, Synne Wing; Katz, Nathaniel

2006-01-01

Background The growing trends in opioid abuse, assessment of the abuse liability of prescription opioid products, and growing efforts by the pharmaceutical industry to develop 'abuse-resistant' formulations highlight a need to understand the features that make one product more 'attractive' than another to potential abusers. We developed a scale to measure the 'attractiveness' of prescription opioids to potential abusers, and used the scale to measure the relative attractiveness of 14 opioid analgesic products. Methods First, the concept of attractiveness was empirically defined with a group of prescription opioid abusers and experts in opioid abuse using a process called Concept Mapping. Abuse liability consisted of two components: factors intrinsic to the drug formulation (e.g., speed of onset, duration) and factors extrinsic to drug formulation (e.g., availability, availability of alternatives, cost). A 17-item Opioid Attractiveness Scale (OAS) was constructed, focusing on factors intrinsic to the drug product. Results A total of 144 individuals participated in tests of validity and reliability. Internal consistency was excellent (Cronbach's α = 0.85–0.94). Drug rankings based on OAS scores achieved good inter-rater agreement (Kendall's W 0.37, p < 0.001). Agreement on drug OAS scores between the developmental sample and a confirmation sample was good (IntraClass Correlations [ICC] of 0.65–0.69). Global ratings of overall attractiveness of the 14 selected opioid products by substance abuse counselors corresponded with the rankings based on OAS ratings of the abuser group. Finally, substance abuse counselors completed the OAS, yielding a high level of correspondence with ratings by the abuser group (ICC = 0.83, p = 0.002). The OAS differentiated attractiveness among 14 selected pharmaceutical opioid products. OxyContin, Dilaudid, and Percocet were ranked highest (most attractive); Talwin NX and Duragesic were ranked lowest (least attractive). Conclusion An initial examination of the psychometric properties of the OAS suggests that it is a valid and reliable scale. The OAS may be useful in providing important guidance on product features that are attractive to potential abusers. PMID:16457713

Development and validation of an Opioid Attractiveness Scale: a novel measure of the attractiveness of opioid products to potential abusers.

PubMed

Butler, Stephen F; Benoit, Christine; Budman, Simon H; Fernandez, Kathrine C; McCormick, Cynthia; Venuti, Synne Wing; Katz, Nathaniel

2006-02-02

The growing trends in opioid abuse, assessment of the abuse liability of prescription opioid products, and growing efforts by the pharmaceutical industry to develop 'abuse-resistant' formulations highlight a need to understand the features that make one product more 'attractive' than another to potential abusers. We developed a scale to measure the 'attractiveness' of prescription opioids to potential abusers, and used the scale to measure the relative attractiveness of 14 opioid analgesic products. First, the concept of attractiveness was empirically defined with a group of prescription opioid abusers and experts in opioid abuse using a process called Concept Mapping. Abuse liability consisted of two components: factors intrinsic to the drug formulation (e.g., speed of onset, duration) and factors extrinsic to drug formulation (e.g., availability, availability of alternatives, cost). A 17-item Opioid Attractiveness Scale (OAS) was constructed, focusing on factors intrinsic to the drug product. A total of 144 individuals participated in tests of validity and reliability. Internal consistency was excellent (Cronbach's alpha = 0.85-0.94). Drug rankings based on OAS scores achieved good inter-rater agreement (Kendall's W 0.37, p < 0.001). Agreement on drug OAS scores between the developmental sample and a confirmation sample was good (IntraClass Correlations [ICC] of 0.65-0.69). Global ratings of overall attractiveness of the 14 selected opioid products by substance abuse counselors corresponded with the rankings based on OAS ratings of the abuser group. Finally, substance abuse counselors completed the OAS, yielding a high level of correspondence with ratings by the abuser group (ICC = 0.83, p = 0.002). The OAS differentiated attractiveness among 14 selected pharmaceutical opioid products. OxyContin, Dilaudid, and Percocet were ranked highest (most attractive); Talwin NX and Duragesic were ranked lowest (least attractive). An initial examination of the psychometric properties of the OAS suggests that it is a valid and reliable scale. The OAS may be useful in providing important guidance on product features that are attractive to potential abusers.

In Vitro Drug Release After Crushing: Evaluation of Xtampza® ER and Other ER Opioid Formulations.

PubMed

Mayock, Stephen P; Saim, Said; Fleming, Alison B

2017-12-01

Extended-release (ER) opioids are associated with high rates of abuse. Recreational opioid users often manipulate ER formulations to achieve a high plasma concentration in a short amount of time, resulting in a more rapid and intense high. Patients may also manipulate ER tablets to facilitate swallowing, without recognizing that manipulation could increase release rate. The goal of this study was to assess the ability of oxycodone DETERx (Xtampza ® ER, Collegium Pharmaceutical, Inc., Canton, MA, USA) and other commercially available ER opioid formulations with and without physicochemical abuse-deterrent characteristics to be manipulated by crushing in an in vitro setting. In vitro dissolution techniques were used to compare the opioid release from a variety of ER opioid formulations. Dissolution was assessed for intact and crushed dosage forms. Opioid release was quantified using high-performance liquid chromatography. Intact formulations exhibited drug release rates characteristic of 12- or 24-h dosage forms. After crushing using commonly available household tools, only Xtampza ER maintained ER of opioid. Xtampza ER maintained its ER characteristics after crushing, unlike many other commercially available opioid formulations, including some formulated with abuse-deterrent properties. As such, Xtampza ER may be less appealing to abusers and offer a margin of safety for patients who manipulate dosage forms to facilitate swallowing.

"Tampering to Death": A Fatal Codeine Intoxication Due to a Homemade Purification of a Medical Formulation.

PubMed

Fais, Paolo; Pigaiani, Nicola; Cecchetto, Giovanni; Montisci, Massimo; Gottardo, Rossella; Viel, Guido; Pascali, Jennifer Paola; Tagliaro, Franco

2017-11-01

Many homemade tamper processes of medical codeine formulations are available on selected "forums" on the Internet, where recreational codeine users claim to be able to purify codeine by removing additives, such as acetaminophen, to avoid or limit adverse effects. In this work, it is reported and discussed a fatal case of codeine intoxication. The findings of objects such as jars, filters, and tablets, and amounts of unknown liquid material at the death scene investigation suggested a fatal codeine intoxication after the tampering procedure called "cold water extraction." Toxicological results obtained from the analysis of both the nonbiological material and the body fluids of the decedent integrated with the information collected at the death scene investigation confirmed the above-mentioned hypothesis. This report underlines the importance of a tight interconnection between criminalistics and legal medicine to strengthen the identification of the cause of death and the reconstruction of the event. © 2017 American Academy of Forensic Sciences.

Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations.

PubMed

Walter, Carmen; Knothe, Claudia; Lötsch, Jörn

2016-07-01

Abuse-deterrent formulations (ADFs) are technologically sophisticated pharmaceutical formulations that impede manipulation and extraction of opioids and/or provoke unpleasant effects when they are taken in excessive quantity. This is implemented by creating physical barriers, inseparably combining the opioid with an opioid antagonist or adding aversive agents to the formulation. These pharmaceutical changes may potentially alter the pharmacokinetics and consequently the pharmacodynamics of the opioid. In this review, comparative evidence on pharmacokinetic differences between abuse-deterrent and classical formulations of the same opioids is summarized; furthermore, pharmacodynamic differences, with a focus on analgesia and abuse-related symptoms, are addressed. Most of the 12 studies comparing opioid pharmacokinetics have judged the physically intact ADF as being bioequivalent to the corresponding classical formulation. Pharmacokinetic differences have, however, been reported with physically manipulated ADFs and have ranged from moderate deviations from bioequivalence to complete changes in the pharmacokinetic profile (e.g. from a sustained-release formulation to a fast-release formulation). Pharmacodynamic effects were assessed in 14 comparative studies, which reported that intact ADFs usually provided clinically equivalent analgesia and clear advantages with respect to their addiction potential. However, withdrawal symptoms could be induced by the ADFs, although rarely and, in particular, when the ADFs had been physically altered. This evidence suggests that opioid ADFs are a working concept resulting in mostly minor pharmacokinetic and pharmacodynamic differences in comparison with classical formulations; however, they may deviate from this equivalence when physically altered.

Tagging RDT&E. Volume 1. Technology Assessment and Development Reports

DTIC Science & Technology

1994-03-01

weapon system component could have a unique, counterfeit and transfer resistant, and tamper indicating identifier (or tag), inspectors could...the random nature of the reflective surfaces on each particle, the tag is highly resistant to counterfeiting . Sym t, n- BDM Jnvolvement RPT Sandia...layers) that tampering has occurred. A reflective particle (RP) disk was added by PNL to increase the difficulty of counterfeiting the tag and to make

Reformulation of controlled-release oxycodone and pharmacy dispensing patterns near the US-Canada border.

PubMed

Gomes, Tara; Paterson, J Michael; Juurlink, David N; Dhalla, Irfan A; Mamdani, Muhammad M

2012-01-01

In August 2010, a tamper-resistant formulation of controlled-release oxycodone (OxyContin-OP) was introduced in the United States but not in Canada. Our objective was to determine whether introduction of OxyContin-OP in the United States influenced prescription volumes for the original controlled-release oxycodone formulation (OxyContin) at Canadian pharmacies near the international border. We conducted a population-based, serial, cross-sectional study of prescriptions dispensed from pharmacies in the 3 cities with the highest volume of US-Canada border crossings in Ontario: Niagara Falls, Windsor and Sarnia. We analyzed data on all outpatient prescriptions for OxyContin dispensed by Canadian pharmacies near each border crossing between 2010 Apr. 1 and 2012 Feb. 29. We calculated and compared monthly prescription rates, adjusted per 1000 population and stratified by tablet strength. The number of tablets dispensed near 4 border crossings in the 3 Canadian cities remained stable over the study period. However, the rate of dispensing at pharmacies near the Detroit-Windsor Tunnel increased roughly 4-fold between August 2010 and February 2011, from 505 to 1969 tablets per 1000 population. By April 2011, following warnings to prescribers and pharmacies regarding drug-seeking behaviour, the dispensing rate declined to 1683 tablets per 1000 population in this area. By November 2011, the rate had returned to levels observed in early 2010. Our analyses suggest that 242 075 excess OxyContin tablets were dispensed near the Detroit-Windsor Tunnel between August 2010 and October 2011. Prescribing of the original formulation of controlled-release oxycodone rose substantially near a major international border crossing following the introduction of a tamper-resistant formulation in the United States. It is possible that the restriction of this finding to the area surrounding the Detroit-Windsor Tunnel reflects specific characteristics of this border crossing, including its high traffic volume, direct access to the downtown core and drug-trafficking patterns in the Detroit area. Our findings highlight the potential impact of cross-border differences in medication availability on drug-seeking behaviour.

Tamper-Resistant Mobile Health Using Blockchain Technology

PubMed Central

2017-01-01

Background Digital health technologies, including telemedicine, mobile health (mHealth), and remote monitoring, are playing a greater role in medical practice. Safe and accurate management of medical information leads to the advancement of digital health, which in turn results in a number of beneficial effects. Furthermore, mHealth can help lower costs by facilitating the delivery of care and connecting people to their health care providers. Mobile apps help empower patients and health care providers to proactively address medical conditions through near real-time monitoring and treatment, regardless of the location of the patient or the health care provider. Additionally, mHealth data are stored in servers, and consequently, data management that prevents all forms of manipulation is crucial for both medical practice and clinical trials. Objective The aim of this study was to develop and evaluate a tamper-resistant mHealth system using blockchain technology, which enables trusted and auditable computing using a decentralized network. Methods We developed an mHealth system for cognitive behavioral therapy for insomnia using a smartphone app. The volunteer data collected with the app were stored in JavaScript Object Notation format and sent to the blockchain network. Thereafter, we evaluated the tamper resistance of the data against the inconsistencies caused by artificial faults. Results Electronic medical records collected using smartphones were successfully sent to a private Hyperledger Fabric blockchain network. We verified the data update process under conditions where all the validating peers were running normally. The mHealth data were successfully updated under network faults. We further ensured that any electronic health record registered to the blockchain network was resistant to tampering and revision. The mHealth data update was compatible with tamper resistance in the blockchain network. Conclusions Blockchain serves as a tamperproof system for mHealth. Combining mHealth with blockchain technology may provide a novel solution that enables both accessibility and data transparency without a third party such as a contract research organization. PMID:28747296

Child-resistant and tamper-resistant packaging: A systematic review to inform tobacco packaging regulation.

PubMed

Jo, Catherine L; Ambs, Anita; Dresler, Carolyn M; Backinger, Cathy L

2017-02-01

We aimed to investigate the effects of special packaging (child-resistant, adult-friendly) and tamper-resistant packaging on health and behavioral outcomes in order to identify research gaps and implications for packaging standards for tobacco products. We searched seven databases for keywords related to special and tamper-resistant packaging, consulted experts, and reviewed citations of potentially relevant studies. 733 unique papers were identified. Two coders independently screened each title and abstract for eligibility. They then reviewed the full text of the remaining papers for a second round of eligibility screening. Included studies investigated a causal relationship between type of packaging or packaging regulation and behavioral or health outcomes and had a study population composed of consumers. Studies were excluded on the basis of publication type, if they were not peer-reviewed, and if they had low external validity. Two reviewers independently coded each paper for study and methodological characteristics and limitations. Discrepancies were discussed and resolved. The review included eight studies: four assessing people's ability to access the contents of different packaging types and four evaluating the impact of packaging requirements on health-related outcomes. Child-resistant packaging was generally more difficult to open than non-child-resistant packaging. Child-resistant packaging requirements have been associated with reductions in child mortality. Child-resistant packaging holds the expectation to reduce tobacco product poisonings among children under six. Published by Elsevier Inc.

Child-resistant and tamper-resistant packaging: A systematic review to inform tobacco packaging regulation

PubMed Central

Jo, Catherine L.; Ambs, Anita; Dresler, Carolyn M.; Backinger, Cathy L.

2017-01-01

Objective We aimed to investigate the effects of special packaging (child-resistant, adult-friendly) and tamper-resistant packaging on health and behavioral outcomes in order to identify research gaps and implications for packaging standards for tobacco products. Methods We searched seven databases for keywords related to special and tamper-resistant packaging, consulted experts, and reviewed citations of potentially relevant studies. 733 unique papers were identified. Two coders independently screened each title and abstract for eligibility. They then reviewed the full text of the remaining papers for a second round of eligibility screening. Included studies investigated a causal relationship between type of packaging or packaging regulation and behavioral or health outcomes and had a study population composed of consumers. Studies were excluded on the basis of publication type, if they were not peer-reviewed, and if they had low external validity. Two reviewers independently coded each paper for study and methodological characteristics and limitations. Discrepancies were discussed and resolved. Results The review included eight studies: four assessing people’s ability to access the contents of different packaging types and four evaluating the impact of packaging requirements on health-related outcomes. Child-resistant packaging was generally more difficult to open than non-child-resistant packaging. Child-resistant packaging requirements have been associated with reductions in child mortality. Conclusions Child-resistant packaging holds the expectation to reduce tobacco product poisonings among children under six. PMID:27939602

Assessment of extended-release opioid analgesics for the treatment of chronic pain.

PubMed

Gudin, Jeffrey A

2013-03-01

Approximately 3.8 million patients annually receive extended-release (ER) or long-acting opioid prescriptions in the outpatient setting, around half of which are written by primary care physicians. Compared with short-acting, immediate-release (IR) formulations, ER and oral long-acting opioid analgesics are associated with clinical advantages, such as extended periods of time during which drug plasma levels are within the therapeutic range, decreased peak-to-trough fluctuations, and prolonged analgesia over the dosing period. Additionally, ER opioids offer a more convenient, less frequent dosing regimen to chronic pain patients who are often taking several concomitant medications. The increased utilization of ER opioids has been accompanied by a rise in the misuse and abuse of these formulations. Certain pharmacokinetic parameters (e.g., longer time to maximum drug plasma concentration, lower maximum drug plasma concentration) may decrease the abuse potential of intact ER opioids by limiting the positive subjective and reinforcing effects relative to IR formulations. Putative abuse-deterrent formulations have also recently been introduced to impede physical manipulation of these formulations, or reduce the harm resulting from such behavior. Such formulations may represent an incremental advance to reduce non-oral forms of abuse. This article reviews the pharmacokinetic profiles and abuse-deterrent features of newer ER opioid analgesics for the treatment of moderate to severe chronic pain.

Tamper indicating gold nanocup plasmonic films

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeVetter, Brent M.; Bernacki, Bruce E.; Bennett, Wendy D.

The spectral signature of nanoplasmonic films are both robust and tailorable with optical responses ranging from the visible to the near-infrared. We present the development of flexible, elastomeric nanoplasmonic films consisting of periodic arrays of gold nanocups as tamper indicating films. Gold nanocups have polarization-sensitive optical properties that may be manufactured into films that offer unique advantages for tamper indication. These flexible films can be made quickly and at low-cost using commercially available monodisperse polystyrene nanospheres through self-assembly followed by plasma etching, metal deposition, and lift-off from a sacrificial substrate. Polarization- and angle-dependent optical spectroscopic measurements were performed to characterizemore » the fabricated films. Furthermore, using polarization-sensitive hyperspectral imaging, we demonstrate how these films can be applied to tamper indication and counterfeit resistance applications.« less

Tamper indicating gold nanocup plasmonic films

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeVetter, Brent M.; Bernacki, Bruce E.; Bennett, Wendy D.

2017-02-13

The spectral signature of nanoplasmonic films are both robust and tailorable with optical responses ranging from the visible to the near-infrared. We present the development of flexible, elastomeric nanoplasmonic films consisting of periodic arrays of gold nanocups as tamper indicating films. Gold nanocups have polarization-sensitive optical properties that may be manufactured into films that offer unique advantages for tamper indication. These flexible films can be made quickly and at low-cost using commercially available monodisperse polystyrene nanospheres through self-assembly followed by plasma etching, metal deposition, and lift-off from a sacrificial substrate. Polarization- and angle-dependent optical spectroscopic measurements were performed to characterizemore » the fabricated films. Using polarization-sensitive hyperspectral imaging, we demonstrate how these films can be applied to tamper indication and counterfeit resistance applications.« less

Research design considerations for clinical studies of abuse-deterrent opioid analgesics: IMMPACT recommendations

PubMed Central

Turk, Dennis C.; O’Connor, Alec B.; Dworkin, Robert H.; Chaudhry, Amina; Katz, Nathaniel P.; Adams, Edgar H.; Brownstein, John S.; Comer, Sandra D.; Dart, Richard; Dasgupta, Nabarun; Denisco, Richard A.; Klein, Michael; Leiderman, Deborah B.; Lubran, Robert; Rappaport, Bob A.; Zacny, James P.; Ahdieh, Harry; Burke, Laurie B.; Cowan, Penney; Jacobs, Petra; Malamut, Richard; Markman, John; Michna, Edward; Palmer, Pamela; Peirce-Sandner, Sarah; Potter, Jennifer S.; Raja, Srinivasa N.; Rauschkolb, Christine; Roland, Carl L.; Webster, Lynn R.; Weiss, Roger D.; Wolf, Kerry

2013-01-01

Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Due to the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs in order to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability; (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation; (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse; and (4) post-marketing epidemiological studies. PMID:22770841

Pharmacokinetics of hydrocodone extended-release tablets formulated with different levels of coating to achieve abuse deterrence compared with a hydrocodone immediate-release/acetaminophen tablet in healthy subjects.

PubMed

Darwish, Mona; Bond, Mary; Tracewell, William; Robertson, Philmore; Yang, Ronghua

2015-01-01

A hydrocodone extended-release (ER) formulation employing the CIMA(®) Abuse-Deterrence Technology platform was developed to provide resistance against rapid release of hydrocodone when tablets are comminuted or taken with alcohol. This study evaluated the pharmacokinetics of three hydrocodone ER tablet prototypes with varying levels of polymer coating to identify the prototype expected to have the greatest abuse deterrence potential based on pharmacokinetic characteristics that maintain systemic exposure to hydrocodone comparable to that of a commercially available hydrocodone immediate-release (IR) product. In this four-period crossover study, healthy subjects aged 18-45 years were randomized to receive a single intact, oral 45-mg tablet of one of three hydrocodone ER prototypes (low-, intermediate-, or high-level coating) or an intact, oral tablet of hydrocodone IR/acetaminophen (APAP) 10/325 mg every 6 h until four tablets were administered, with each of the four treatments administered once over the four study periods. Dosing periods were separated by a minimum 5-day washout. Naltrexone 50 mg was administered to block opioid receptors. Blood samples for pharmacokinetic assessments were collected predose and through 72 h postdose. Parameters assessed included maximum observed plasma hydrocodone concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve from time 0 to infinity (AUC(0-∞)). Mean C(max) values were 49.2, 32.6, and 28.4 ng/mL for the low-, intermediate-, and high-level coating hydrocodone ER tablet prototypes, respectively, and 37.3 ng/mL for the hydrocodone IR/APAP tablet; respective median t(max) values were 5.9, 8.0, 8.0, and 1.0 h. Total systemic exposure to hydrocodone (AUC(0-∞)) was comparable between hydrocodone ER tablet prototypes (640, 600, and 578 ng·h/mL, respectively) and hydrocodone IR/APAP (581 ng·h/mL). No serious adverse events or deaths were reported. The most common adverse events included headache (26%) and nausea (18%). All three hydrocodone ER tablet prototypes (low-, intermediate-, and high-level polymer coating) demonstrated ER pharmacokinetic characteristics. The hydrocodone ER tablet prototype with the high-level coating was selected for development because of its comparable exposure to the hydrocodone IR/APAP formulation and potentially increased ability to resist rapid drug release upon product tampering because of a higher polymer coating level. All study medications were well tolerated in healthy naltrexone-blocked volunteers.

Routes of abuse of prescription opioid analgesics: a review and assessment of the potential impact of abuse-deterrent formulations.

PubMed

Gasior, Maciej; Bond, Mary; Malamut, Richard

2016-01-01

Prescription opioid analgesics are an important treatment option for patients with chronic pain; however, misuse, abuse and diversion of these medications are a major global public health concern. Prescription opioid analgesics can be abused via intended and non-intended routes of administration, both intact or after manipulation of the original formulation to alter the drug-delivery characteristics. Available data indicate that ingestion (with or without manipulation of the prescribed formulation) is the most prevalent route of abuse, followed by inhalation (snorting, smoking and vaping) and injection. However, reported routes of abuse vary considerably between different formulations. A number of factors have been identified that appear to be associated with non-oral routes of abuse, including a longer duration of abuse, younger age, male sex and a rural or socially deprived location. The development of abuse-deterrent formulations of prescription opioid analgesics is an important step toward reducing abuse of these medications. Available abuse-deterrent formulations aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or even aversive. There are currently five opioid analgesics with a Food and Drug Administration abuse-deterrent label, and a number of other products are under review. A growing body of evidence suggests that introduction of abuse-deterrent opioid analgesics in the USA has been associated with decreased rates of abuse of these formulations. The availability of abuse-deterrent formulations therefore appears to represent an important step toward curbing the epidemic of abuse of prescription opioid analgesics, while ensuring the availability of effective pain medications for patients with legitimate medical need.

Tamper-Resistant Mobile Health Using Blockchain Technology.

PubMed

Ichikawa, Daisuke; Kashiyama, Makiko; Ueno, Taro

2017-07-26

Digital health technologies, including telemedicine, mobile health (mHealth), and remote monitoring, are playing a greater role in medical practice. Safe and accurate management of medical information leads to the advancement of digital health, which in turn results in a number of beneficial effects. Furthermore, mHealth can help lower costs by facilitating the delivery of care and connecting people to their health care providers. Mobile apps help empower patients and health care providers to proactively address medical conditions through near real-time monitoring and treatment, regardless of the location of the patient or the health care provider. Additionally, mHealth data are stored in servers, and consequently, data management that prevents all forms of manipulation is crucial for both medical practice and clinical trials. The aim of this study was to develop and evaluate a tamper-resistant mHealth system using blockchain technology, which enables trusted and auditable computing using a decentralized network. We developed an mHealth system for cognitive behavioral therapy for insomnia using a smartphone app. The volunteer data collected with the app were stored in JavaScript Object Notation format and sent to the blockchain network. Thereafter, we evaluated the tamper resistance of the data against the inconsistencies caused by artificial faults. Electronic medical records collected using smartphones were successfully sent to a private Hyperledger Fabric blockchain network. We verified the data update process under conditions where all the validating peers were running normally. The mHealth data were successfully updated under network faults. We further ensured that any electronic health record registered to the blockchain network was resistant to tampering and revision. The mHealth data update was compatible with tamper resistance in the blockchain network. Blockchain serves as a tamperproof system for mHealth. Combining mHealth with blockchain technology may provide a novel solution that enables both accessibility and data transparency without a third party such as a contract research organization. ©Daisuke Ichikawa, Makiko Kashiyama, Taro Ueno. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 26.07.2017.

Legal liability perspectives on abuse-deterrent opioids in the treatment of chronic pain.

PubMed

Brushwood, David B; Rich, Ben A; Coleman, John J; Bolen, Jennifer; Wong, Winston

2010-12-01

Abuse-deterrent opioid analgesic formulations can help reduce the risk of opioid diversion and abuse. Not all opioid analgesics are available as both extended- and immediate-release dosage forms in abuse-deterrent formulations. Clinicians may have to balance the clinical benefit of a product that does not use abuse-deterrent technology versus the regulatory benefit of using a product with this technology. There is the possibility that a health care professional may be held legally liable when a product without abuse-deterrent qualities is used and a person suffers harm that would not have occurred had an abuse-deterrent formulation been provided. This article reviews legal precedents that inform an understanding of the need to reduce malpractice exposure by identifying patients who are at high risk of opioid diversion and/or abuse and considering the use of an abuse-deterrent formulation for these patients.

Research design considerations for clinical studies of abuse-deterrent opioid analgesics: IMMPACT recommendations.

PubMed

Turk, Dennis C; O'Connor, Alec B; Dworkin, Robert H; Chaudhry, Amina; Katz, Nathaniel P; Adams, Edgar H; Brownstein, John S; Comer, Sandra D; Dart, Richard; Dasgupta, Nabarun; Denisco, Richard A; Klein, Michael; Leiderman, Deborah B; Lubran, Robert; Rappaport, Bob A; Zacny, James P; Ahdieh, Harry; Burke, Laurie B; Cowan, Penney; Jacobs, Petra; Malamut, Richard; Markman, John; Michna, Edward; Palmer, Pamela; Peirce-Sandner, Sarah; Potter, Jennifer S; Raja, Srinivasa N; Rauschkolb, Christine; Roland, Carl L; Webster, Lynn R; Weiss, Roger D; Wolf, Kerry

2012-10-01

Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Because of the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability, (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation, (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse, and (4) postmarketing epidemiological studies. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Buprenorphine implants in medical treatment of opioid addiction.

PubMed

Chavoustie, Steven; Frost, Michael; Snyder, Ole; Owen, Joel; Darwish, Mona; Dammerman, Ryan; Sanjurjo, Victoria

2017-08-01

Opioid use disorder is a chronic, relapsing disease that encompasses use of both prescription opioids and heroin and is associated with a high annual rate of overdose deaths. Medical treatment has proven more successful than placebo treatment or psychosocial intervention, and the partial µ-opioid receptor agonist and κ-opioid receptor antagonist buprenorphine is similar in efficacy to methadone while offering lower risk of respiratory depression. However, frequent dosing requirements and potential for misuse and drug diversion contribute to significant complications with treatment adherence for available formulations. Areas covered: This review describes the development of and preliminary data from clinical trials of an implantable buprenorphine formulation. Efficacy and safety data from comparative studies with other administrations of buprenorphine, including tablets and sublingual film, will be described. Key premises of the Risk Evaluation and Mitigation Strategy program for safely administering buprenorphine implants, which all prescribing physicians must complete, are also discussed. Expert commentary: Long-acting implantable drug formulations that offer consistent drug delivery and lower risk of misuse, diversion, or accidental pediatric exposure over traditional formulations represent a promising development for the effective treatment of opioid use disorder.

Current Impact and Application of Abuse-Deterrent Opioid Formulations in Clinical Practice.

PubMed

Lee, Ya-Han; Brown, Daniel L; Chen, Hsiang-Yin

2017-11-01

Abuse-deterrent formulations (ADFs) represent one novel strategy for curbing the potential of opioid abuse. We aim to compare and contrast the characteristics and applications of current abuse-deterrent opioid products in clinical practice. Literature searches were conducted in databases (Pubmed Medline, International Pharmaceutical Abstracts, Google Scholar) and official reports. Relevant data were screened and organized into: 1) epidemiology of opioid abuse, 2) mitigation strategies for reducing opioid abuse, 3) development of ADFs, and 4) clinical experience with these formulations. Increasing trends of opioid abuse and misuse have been reported globally. There are 5 types of abuse-deterrent opioid products: physical chemical barrier, combined agonist/antagonist, sequestered aversive agent, prodrug, and novel delivery system. The advantages and disadvantages of the 5 options are discussed in this review. A total of 9 products with abuse-deterrent labels have been approved by the Food and Drug Administration (FDA). The rates of abuse, diversion, and overdose deaths of these new products are also discussed. A framework for collecting in-time data on the efficacy, benefit and risk ratio, and cost-effectiveness of these new products is suggested to facilitate their optimal use. The present review did not utilize systematic review standards or meta-analytic techniques, given the large heterogeneity of data and outcomes reviewed. ADFs provide an option for inhibiting the abuse or misuse of oral opioid products by hindering extraction of the active ingredient, preventing alternative routes of administration, or causing aversion. Their relatively high costs, uncertain insurance policies, and limited data on pharmacoeconomics warrant collaborative monitoring and assessment by government agencies, pharmaceutical manufacturers, and data analysis services to define their therapeutic role in the future. Opioid abuse, abuse-deterrent formulations, ADF, post-marketing, FDA guidance, cost impact, abuse liking, physician attitude, generic abuse-deterrent formulation, clinical application.

Protocol: changes in rates of opioid overdose and poisoning events in an integrated health system following the introduction of a formulation of OxyContin® with abuse-deterrent properties.

PubMed

Janoff, Shannon L; Perrin, Nancy A; Coplan, Paul M; Chilcoat, Howard D; Campbell, Cynthia I; Green, Carla A

2016-05-14

Addiction, overdoses and deaths resulting from prescription opioids have increased dramatically over the last decade. In response, several manufacturers have developed formulations of opioids with abuse-deterrent properties. For many of these products, the Food and Drug Administration (FDA) recognized the formulation with labeling claims and mandated post-marketing studies to assess the abuse-deterrent effects. In response, we assess differences in rates of opioid-related overdoses and poisonings prior to and following the introduction of a formulation of OxyContin® with abuse-deterrent properties. To assess effects of this formulation, electronic medical record (EMR) data from Kaiser Permanente Northwest (KPNW) and Kaiser Permanente Northern California (KPNC) are linked to state death data and compared to chart audits. Overdose and poisoning events will be categorized by intentionality and number of agents involved, including illicit drugs and alcohol. Using 6-month intervals over a 10-year period, trends will be compared in rates of opioid-related overdoses and poisoning events associated with OxyContin® to rates of events associated with other oxycodone and opioid formulations. Qualitative interviews with patients and relatives of deceased patients will be conducted to capture circumstances surrounding events. This study assesses and tracks changes in opioid-related overdoses and poisoning events prior to and following the introduction of OxyContin® with abuse-deterrent properties. Public health significance is high because these medications are designed to reduce abuse-related behaviors that lead to important adverse outcomes, including overdoses and deaths.

Richard P. Feynman and the Feynman Diagrams

Science.gov Websites

available in full-text and on the Web. Documents: A Theorem and Its Application to Finite Tampers, DOE Fermi-Thomas Theory; DOE Technical Report, April 28, 1947 Mathematical Formulation of the Quantum Theory

Experience with an extended-release opioid formulation designed to reduce abuse liability in a community-based pain management clinic

PubMed Central

Rubino, Daniel

2011-01-01

Context With the growing public health concern over rising rates of opioid abuse, physicians have a responsibility to incorporate safeguards into their practice to minimize the potential for opioid misuse, abuse, and diversion. Patient-specific treatment regimens should include steps to monitor treatment success with regard to optimal pain management as well as inappropriate use of opioids and other substances. Opioid formulations designed to be less attractive for abuse are also being developed. While future studies are needed to determine the impact of such formulations in addressing the issue of opioid misuse in the community as a whole, the experience of practitioners who have utilized these formulations can highlight the practical steps to incorporate such formulations into the everyday patient-care setting. Purpose The purpose of this report is to describe experience in managing patients with chronic, moderate-to-severe pain using morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT) (EMBEDA®, King Pharmaceuticals® Inc, Bristol, TN, which was acquired by Pfizer Inc, New York, NY, in March 2011), a formulation designed with features to deter abuse/misuse, in a community-based pain management clinic. Case presentations Case reports demonstrating a clinical management plan for assessment, initial interview procedures, explanation/discussion of proposed therapies, patients’ treatment goals, conversion to MS-sNT, and titration and treatment outcomes are provided. Results The management approach yielded successful outcomes including pain relief, improved quality of life, treatment satisfaction, and patient acceptance of a formulation designed to deter abuse/misuse. Discussion The cases presented demonstrate that the communication accompanying complete pretreatment assessment, goal-setting and expectations, and attention to individual patient needs can enable optimization of pain-related outcomes, resulting in improved quality of life for patients and fostering patient acceptance of formulations designed to help address opioid abuse/misuse issues in the community at large. PMID:22069367

Choosing a Bait Station Product for Household Use

EPA Pesticide Factsheets

Information on tamper-resistant, weather-resistant, and other products that meet EPA safety standards and can help consumers control household rodents while greatly reducing accidental exposure to children, pets, and non-target wildlife.

The role of abuse-deterrent formulations in countering opioid misuse and abuse.

PubMed

Nguyen, V; Raffa, R B; Taylor, R; Pergolizzi, J V

2015-12-01

Pain is a prevalent, and due to the ageing population, increasing medical problem. Opioids are frequently prescribed to meet the unmet medical need. Unfortunately, with the increase in the legitimate use of opioids, there has been a corresponding increase in abuse. A practical way to retain the pain relief afforded by opioids while decreasing opportunities for abuse is to make it more difficult to extract the opioid from the product or to make it less desirable to do so by designing an abuse-deterrent formulation (ADF). We provide a brief overview of the strategies and early evidence related to opioid ADFs. Published and unpublished literature, websites, and other sources were searched for current opioid formulation options, including immediate-release and extended-release products. Each was summarized, reviewed and assessed. The strategies that have been used to design the current opioid ADFs involve one or more of four approaches: a physical barrier; incorporation of an opioid receptor antagonist (e.g. naloxone) that self-limits opioid action when taken in excess amount; inclusion of a noxious agent that is released during inappropriate use; or a pro-drug. Legitimate use of opioid analgesics carries with it certain risks, including the risk of abuse. The new ADFs utilize four major strategies and provide innovative additions to the armamentarium. They likely will become an important part of a comprehensive approach to limiting, although not eliminating, opioid misuse and abuse. © 2015 John Wiley & Sons Ltd.

Opioid use and harms associated with a sustained-release tapentadol formulation: a postmarketing study protocol

PubMed Central

Larance, Briony; Farrell, Michael; Cairns, Rose; Buckley, Nicholas; Degenhardt, Louisa

2018-01-01

Introduction It has been argued that tapentadol may pharmacologically have lower abuse potential than other pharmaceutical opioids currently available. However, there has been no comprehensive triangulation of data regarding use and harms associated with this formulation. A sustained-release formulation (SRF) of tapentadol (Palexia) was released in Australia in 2011 and listed for public subsidy in 2013. We summarise here the methods of a postmarketing study which will measure postintroduction: (1) population level availability, (2) extramedical use and diversion, (3) attractiveness for extramedical use and (4) associated harms, of tapentadol compared against other pharmaceutical opioids. Methods and analysis We evaluated key sources on pharmaceutical use and harms in Australia. This review indicateddata from four sources that disaggregate pharmaceutical opioid formulations and capture tapentadol SRF could be triangulated. These data sources comprised: (1) national pharmaceutical opioid community sales data from 2011 to 2017, (2) national pharmaceutical opioid poisonings reported to Poison Information Centres (PICs) from 2011 to 2017, (3) number of vendors on online marketplaces listing pharmaceutical opioids for sale and (4) data on pharmaceutical opioid extramedical use, attractiveness and harms from interviews with people who regularly inject drugs in Australia. Ethics and dissemination Ethics approval is not required for use of pharmaceutical sales data. Ethics approval has been obtained for use of national pharmaceutical opioid poisonings reported to PICs (LNR/16/SCHN/44) and for use of online marketplace data and interview data from people who inject drugs (HC12086). Key findings will be published mid-2018 in a peer-reviewed academic journal, and presented at various conferences and professional meetings. PMID:29574444

Opioids with abuse-deterrent properties: A regulatory and technological overview.

PubMed

Haddox, J David

Three concurrent public health problems coexist in the United States: endemic nonmedical use/misuse of opioid analgesics, epidemic overdose fatalities involving opioid analgesics, and endemic chronic pain in adults. These intertwined issues comprise an opioid crisis that has spurred the development of formulations of opioids with abuse-deterrent properties and label claims (OADP). To reduce abuse and misuse of prescription opioids, the federal Food and Drug Administration (FDA) has issued a formal Guidance to drug developers that delineates four categories of testing to generate data sufficient for a description of a product's abuse-deterrent properties, along with associated claims, in its Full Prescribing Information (FPI). This article reviews the epidemiology of the crisis as background for the development of OADP, summarizes the FDA Guidance for Industry regarding abuse-deterrent technologies, and provides an overview of some technologies that are currently employed or are under study for incorporation into OADP. Such technologies include physical and chemical barriers to abuse, combined formulations of opioid agonists and antagonists, inclusion of aversive agents, use of delivery systems that deter abuse, development of new molecular entities and prodrugs, and formulation of products that include some combination of these approaches. Opioids employing these novel technologies are one part of a comprehensive intervention strategy that can deter abuse of prescription opioid analgesics without creating barriers to the safe use of prescription opioids. The maximal public health contribution of OADP will probably occur only when all opioids have FDA-recognized abuse-deterrent properties and label claims.

Abuse and Diversion of Immediate Release Opioid Analgesics as Compared to Extended Release Formulations in the United States

PubMed Central

Iwanicki, Janetta L.; Severtson, S. Geoff; McDaniel, Heather; Rosenblum, Andrew; Fong, Chunki; Cicero, Theodore J.; Ellis, Matthew S.; Kurtz, Steven P.; Buttram, Mance E.; Dart, Richard C.

2016-01-01

Background Therapeutic use and abuse of prescription opioids in the United States increased substantially between 1990 and 2010. The Centers for Disease Control estimated deaths related to pharmaceutical opioids reached nearly 19,000 in 2014. Of prescription opioids sold, 10% are extended release (ER) and 90% immediate release (IR). However, most regulations and interventions have focused on decreasing ER abuse. Our objective was to compare rates of abuse and diversion of ER and IR opioid analgesics over time using multiple surveillance programs. Methods Rates of abuse and diversion of ER and IR opioid formulations were compared using data from four surveillance programs in the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS®) System. Data were evaluated from 2009 through 2015, and Poisson regression used to compare IR and ER opioid cases over time. Results From 2009 to 2015, IR opioids were prescribed at a rate 12 to 16 times higher than ER. In the Poison Center Program, population-adjusted rates of Intentional Abuse for IR were 4.6 fold higher than ER opioids (p<0.001). In the Drug Diversion Program, population-adjusted rates of diversion were 6.1 fold higher for IR than ER opioids (p<0.001). In the Opioid Treatment Program, population-adjusted rates of endorsements for abuse were 1.6 fold higher for IR opioids than ER (p = 0.002). In the Survey of Key Informants' Patients Program, population-adjusted rates of endorsements for abuse were 1.5 fold higher for IR opioids than ER (p<0.001). Conclusions Between 2009 and 2015, IR opioids were prescribed at a much higher rate than ER opioids. Results from four surveillance programs show population-adjusted rates of prescription opioid abuse were markedly higher for IR than ER medications. For the greatest public health benefit, future interventions to decrease prescription opioid abuse should focus on both IR and ER formulations. PMID:27936038

Abuse and Diversion of Immediate Release Opioid Analgesics as Compared to Extended Release Formulations in the United States.

PubMed

Iwanicki, Janetta L; Severtson, S Geoff; McDaniel, Heather; Rosenblum, Andrew; Fong, Chunki; Cicero, Theodore J; Ellis, Matthew S; Kurtz, Steven P; Buttram, Mance E; Dart, Richard C

2016-01-01

Therapeutic use and abuse of prescription opioids in the United States increased substantially between 1990 and 2010. The Centers for Disease Control estimated deaths related to pharmaceutical opioids reached nearly 19,000 in 2014. Of prescription opioids sold, 10% are extended release (ER) and 90% immediate release (IR). However, most regulations and interventions have focused on decreasing ER abuse. Our objective was to compare rates of abuse and diversion of ER and IR opioid analgesics over time using multiple surveillance programs. Rates of abuse and diversion of ER and IR opioid formulations were compared using data from four surveillance programs in the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS®) System. Data were evaluated from 2009 through 2015, and Poisson regression used to compare IR and ER opioid cases over time. From 2009 to 2015, IR opioids were prescribed at a rate 12 to 16 times higher than ER. In the Poison Center Program, population-adjusted rates of Intentional Abuse for IR were 4.6 fold higher than ER opioids (p<0.001). In the Drug Diversion Program, population-adjusted rates of diversion were 6.1 fold higher for IR than ER opioids (p<0.001). In the Opioid Treatment Program, population-adjusted rates of endorsements for abuse were 1.6 fold higher for IR opioids than ER (p = 0.002). In the Survey of Key Informants' Patients Program, population-adjusted rates of endorsements for abuse were 1.5 fold higher for IR opioids than ER (p<0.001). Between 2009 and 2015, IR opioids were prescribed at a much higher rate than ER opioids. Results from four surveillance programs show population-adjusted rates of prescription opioid abuse were markedly higher for IR than ER medications. For the greatest public health benefit, future interventions to decrease prescription opioid abuse should focus on both IR and ER formulations.

Opioid use and harms associated with a sustained-release tapentadol formulation: a postmarketing study protocol.

PubMed

Peacock, Amy; Larance, Briony; Farrell, Michael; Cairns, Rose; Buckley, Nicholas; Degenhardt, Louisa

2018-03-23

It has been argued that tapentadol may pharmacologically have lower abuse potential than other pharmaceutical opioids currently available. However, there has been no comprehensive triangulation of data regarding use and harms associated with this formulation. A sustained-release formulation (SRF) of tapentadol (Palexia) was released in Australia in 2011 and listed for public subsidy in 2013. We summarise here the methods of a postmarketing study which will measure postintroduction: (1) population level availability, (2) extramedical use and diversion, (3) attractiveness for extramedical use and (4) associated harms, of tapentadol compared against other pharmaceutical opioids. We evaluated key sources on pharmaceutical use and harms in Australia. This review indicateddata from four sources that disaggregate pharmaceutical opioid formulations and capture tapentadol SRF could be triangulated. These data sources comprised: (1) national pharmaceutical opioid community sales data from 2011 to 2017, (2) national pharmaceutical opioid poisonings reported to Poison Information Centres (PICs) from 2011 to 2017, (3) number of vendors on online marketplaces listing pharmaceutical opioids for sale and (4) data on pharmaceutical opioid extramedical use, attractiveness and harms from interviews with people who regularly inject drugs in Australia. Ethics approval is not required for use of pharmaceutical sales data. Ethics approval has been obtained for use of national pharmaceutical opioid poisonings reported to PICs (LNR/16/SCHN/44) and for use of online marketplace data and interview data from people who inject drugs (HC12086). Key findings will be published mid-2018 in a peer-reviewed academic journal, and presented at various conferences and professional meetings. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Research design strategies to evaluate the impact of formulations on abuse liability.

PubMed

McColl, Shelley; Sellers, Edward M

2006-06-01

Scheduling of a chemical drug substance under the Controlled Substances Act (CSA) includes an evaluation of preclinical and clinical safety, and experimental abuse liability studies, as well as information on diversion and overdose. Formulations that mitigate abuse liability, dependence potential and public health risks (e.g., altered absorption rate and tamperability, long half-life, pro-drugs and combination products) are amenable to preclinical and clinical studies to compare their abuse potential to reference compounds. For new formulations (NF) as marketed agents, direct comparison to the immediate release (IR) formulation of the reference compound is typically needed across the full range of potential studies. While the public health advantage of formulation changes in the marketplace can be conceptualized in behavioral economic terms, generating persuasive data is challenging. Study complexity increases because of additional conditions (e.g., placebo, 2-3 doses of the IR formulation, 2-3 doses of the new formulation, and 2-3 doses of the unscheduled or negative control drug), larger sample sizes (study power driven by the comparison of the new formulation versus the IR or placebo), and associated increases in study duration. However, the use of single maximal doses of well-characterized controls can reduce the number of study arms, and using incomplete block designs can reduce study duration. Less typical experimental approaches may also be useful, such as human choice or discrimination procedures, or pre-marketing consumer studies among experienced drug tamperers. New formulations that demonstrate a substantial difference from marketed or reference products have a potential marketing advantage and should require less onerous risk management. Post-marketing epidemiological data demonstrating the lack of abuse will carry the most weight from a public health and physician perspective.

10 CFR 73.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... this part. Intrusion alarm means a tamper indicating electrical, electromechanical, electrooptical... manipulation resistant, electromechanical device which provides the same function as a built-in combination...

10 CFR 73.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... this part. Intrusion alarm means a tamper indicating electrical, electromechanical, electrooptical... manipulation resistant, electromechanical device which provides the same function as a built-in combination...

A Case for Tamper-Resistant and Tamper-Evident Computer Systems

DTIC Science & Technology

2007-02-01

such as Kerberos is hard to apply [2] B . Gassend, G. Sub, D. Clarke, M. Dijk, and S. Devadas . Caches and Hash Trees for Efficient Memory Integrity...the block’s data from DRAM. For authentication, Merkle [14] G. Suh, D. Clarke, B . Gassend, M. van Dijk, and S. Devadas . Efficient Memory Integrity...wwi4serverwatch.com/news/article.php/ tion where a data block is encrypted or decrypted through an XOR 1399451, 2000. [11] B . Rogers, Y. Solihin

Enhanced tamper indicator

DOEpatents

Garcia, Anthony R.; Johnston, Roger G.

2003-07-08

The present invention provides an apparatus and method whereby the reliability and tamper-resistance of tamper indicators can be improved. A flexible connector may be routed through a latch for an enclosure such as a door or container, and the free ends of the flexible connector may be passed through a first locking member and firmly attached to an insert through the use of one or more attachment members such as set screws. A second locking member may then be assembled in interlocking relation with the first locking member to form an interlocked assembly around the insert. The insert may have one or more sharp projections extending toward the first or second locking member so that any compressive force applied in an attempt to disassemble the interlocked assembly results in permanent, visible damage to the first or second locking member.

Evaluating the abuse potential of opioids and abuse-deterrent -opioid formulations: A review of clinical study methodology.

PubMed

Setnik, Beatrice; Schoedel, Kerri A; Levy-Cooperman, Naama; Shram, Megan; Pixton, Glenn C; Roland, Carl L

With the development of opioid abuse-deterrent formulations (ADFs), there is a need to conduct well-designed human abuse potential studies to evaluate the effectiveness of their deterrent properties. Although these types of studies have been conducted for many years, largely to evaluate inherent abuse potential of a molecule and inform drug scheduling, methodological approaches have varied across studies. The focus of this review is to describe current "best practices" and methodological adaptations required to assess abuse-deterrent opioid formulations for regulatory submissions. A literature search was conducted in PubMed® to review methodological approaches (study conduct and analysis) used in opioid human abuse potential studies. Search terms included a combination of "opioid," "opiate," "abuse potential," "abuse liability," "liking," AND "pharmacodynamic," and only studies that evaluated single doses of opioids in healthy, nondependent individuals with or without prior opioid experience were included. Seventy-one human abuse potential studies meeting the prespecified criteria were identified, of which 21 studies evaluated a purported opioid ADF. Based on these studies, key methodological considerations were reviewed and summarized according to participant demographics, study prequalification, comparator and dose selection, route of administration and drug manipulation, study blinding, outcome measures and training, safety, and statistical analyses. The authors recommend careful consideration of key elements (eg, a standardized definition of a "nondependent recreational user"), as applicable, and offer key principles and "best practices" when conducting human abuse potential studies for opioid ADFs. Careful selection of appropriate study conditions is dependent on the type of ADF technology being evaluated.

Outbreaks of infections associated with drug diversion by US health care personnel.

PubMed

Schaefer, Melissa K; Perz, Joseph F

2014-07-01

To summarize available information about outbreaks of infections stemming from drug diversion in US health care settings and describe recommended protocols and public health actions. We reviewed records at the Centers for Disease Control and Prevention related to outbreaks of infections from drug diversion by health care personnel in US health care settings from January 1, 2000, through December 31, 2013. Searches of the medical literature published during the same period were also conducted using PubMed. Information compiled included health care setting(s), infection type(s), specialty of the implicated health care professional, implicated medication(s), mechanism(s) of diversion, number of infected patients, number of patients with potential exposure to blood-borne pathogens, and resolution of the investigation. We identified 6 outbreaks over a 10-year period beginning in 2004; all occurred in hospital settings. Implicated health care professionals included 3 technicians and 3 nurses, one of whom was a nurse anesthetist. The mechanism by which infections were spread was tampering with injectable controlled substances. Two outbreaks involved tampering with opioids administered via patient-controlled analgesia pumps and resulted in gram-negative bacteremia in 34 patients. The remaining 4 outbreaks involved tampering with syringes or vials containing fentanyl; hepatitis C virus infection was transmitted to 84 patients. In each of these outbreaks, the implicated health care professional was infected with hepatitis C virus and served as the source; nearly 30,000 patients were potentially exposed to blood-borne pathogens and targeted for notification advising testing. These outbreaks revealed gaps in prevention, detection, and response to drug diversion in US health care facilities. Drug diversion is best prevented by health care facilities having strong narcotics security measures and active monitoring systems. Appropriate response includes assessment of harm to patients, consultation with public health officials when tampering with injectable medication is suspected, and prompt reporting to enforcement agencies. Published by Elsevier Inc.

What's holding back abuse-deterrent opioid formulations? Considering 12 U.S. stakeholders.

PubMed

Pergolizzi, Joseph V; Taylor, Robert; LeQuang, Jo Ann; Raffa, Robert B

2018-06-01

There is no greater public health threat at this time in America than the opioid abuse crisis, and a systematic, level-headed, coherent, and unified approach is needed. Among the many things that have been proposed to help reduce opioid abuse is the development of opioid analgesic products in abuse-deterrent formulations (ADFs). This seems to make perfect sense. Areas covered: In this article, the viewpoints of 12 stakeholders (physicians, pain patients, payers, manufacturers, regulators, law enforcement, hospitals, first responders, elected officials, rehabilitation centers, opioid addicts, and the general public) were considered in terms of how ADF opioids are regarded and might contribute potential impediments to more widespread use. This is a narrative review based on the literature. Stakeholders were not surveyed directly. Expert opinion: Although abuse-deterrent technology for opioid analgesics has been available for several years, ADFs have not gained widespread acceptance. ADF products serve an important but limited purpose, but their incremental costs may serve as a 'mixed message' for many of the stakeholders concerned about cost containment.

Establishing "abuse-deterrence equivalence" for generic abuse-deterrent opioid formulations: A proposed development framework.

PubMed

Setnik, Beatrice; Cone, Edward J

2016-01-01

Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent formulations of novel drugs and formulations; however, they do not address "abuse-deterrence equivalence" for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.

Remotely Monitored Sealing Array Software

DOE Office of Scientific and Technical Information (OSTI.GOV)

2012-09-12

The Remotely Monitored Sealing Array (RMSA) utilizes the Secure Sensor Platform (SSP) framework to establish the fundamental operating capabilities for communication, security, power management, and cryptography. In addition to the SSP framework the RMSA software has unique capabilities to support monitoring a fiber optic seal. Fiber monitoring includes open and closed as well as parametric monitoring to detect tampering attacks. The fiber monitoring techniques, using the SSP power management processes, allow the seals to last for years while maintaining the security requirements of the monitoring application. The seal is enclosed in a tamper resistant housing with software to support activemore » tamper monitoring. New features include LED notification of fiber closure, the ability to retrieve the entire fiber optic history via translator command, separate memory storage for fiber optic events, and a more robust method for tracking and resending failed messages.« less

Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update.

PubMed

Soyka, Michael

2015-02-01

Opioid dependence is a severe medical disorder with a high psychiatric and somatic comorbidity and mortality rate. The opioid agonist methadone, mixed agonist-antagonist buprenorphine and the combination of buprenorphine with the opioid antagonist naloxone are the first-line maintenance treatments for opioid dependence. Risk of diversion and accidental intoxications, especially in children, are of great concern. To lower these risks, a novel buprenorphine-naloxone film has been developed and introduced in the USA and Australia. This review evaluates the available preclinical and clinical data on the novel buprenorphine-naloxone film for treatment of opioid dependence. Literature was identified through a comprehensive PubMed search. Data sources also included official FDA information and material made public by the manufacturer. Few preclinical and clinical data on safety and efficacy have been published. The pharmacological differences between the novel film and the conventional buprenorphine/naloxone are small. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal. The spectrum of adverse events seems to be similar to that of the conventional sublingual tablet. Recent data show that patients prefer the novel film over the conventional sublingual tablet. Emerging surveillance data indicate a lower risk of accidental poisoning in children compared with the conventional formulation. Further clinical and preclinical data are needed to explore additional possible advantages of the new formulation.

The effect of an abuse‐deterrent opioid formulation (OxyContin) on opioid abuse‐related outcomes in the postmarketing setting

PubMed Central

Chilcoat, HD; Butler, SF; Sellers, EM; Kadakia, A; Harikrishnan, V; Haddox, JD; Dart, RC

2016-01-01

An extended‐release opioid analgesic (OxyContin, OC) was reformulated with abuse‐deterrent properties to deter abuse. This report examines changes in abuse through oral and nonoral routes, doctor‐shopping, and fatalities in 10 studies 3.5 years after reformulation. Changes in OC abuse from 1 year before to 3 years after OC reformulation were calculated, adjusted for prescription changes. Abuse of OC decreased 48% in national poison center surveillance systems, decreased 32% in a national drug treatment system, and decreased 27% among individuals prescribed OC in claims databases. Doctor‐shopping for OC decreased 50%. Overdose fatalities reported to the manufacturer decreased 65%. Abuse of other opioids without abuse‐deterrent properties decreased 2 years later than OC and with less magnitude, suggesting OC decreases were not due to broader opioid interventions. Consistent with the formulation, decreases were larger for nonoral than oral abuse. Abuse‐deterrent opioids may mitigate abuse and overdose risks among chronic pain patients. PMID:27170195

Evolving Role of Local Anesthetics in Managing Postsurgical Analgesia.

PubMed

Golembiewski, Julie; Dasta, Joseph

2015-06-01

Opioid analgesics, the cornerstone of effective postsurgical pain management, may be associated with risk of opioid-related adverse drug events (ADEs) that may complicate the postsurgical experience. Perioperative multimodal analgesic regimens have the potential to improve postsurgical pain control and may permit use of lower analgesic doses and reduce the incidence of opioid-related ADEs. Utility of traditional local anesthetic formulations to provide analgesia over the entire postsurgical period is limited by their short duration of action. Liposome bupivacaine, a liposomal formulation of bupivacaine indicated for single-dose administration into the surgical site to produce postsurgical analgesia, was evaluated in multiple surgical models as part of multimodal analgesic regimens and was found in clinical trials to provide postsurgical analgesia for up to 72 hours. Here, we provide an overview of the available multimodal analgesic options and recent recommendations for optimal postsurgical pain management. A review of the literature was conducted, and results from recent clinical trials are included. The use of a multimodal analgesic regimen, including liposome bupivacaine, can extend the time to first postsurgical opioid use, may reduce postsurgical opioid consumption, and reduce hospital length of stay and costs compared with an opioid-only analgesic regimen. Use of multimodal analgesic regimens is a practical way to achieve good postsurgical analgesia while minimizing reliance on opioids and associated adverse events. Taken as a whole, evidence from the clinical studies of liposome bupivacaine suggests this local anesthetic formulation may be a useful component of multimodal analgesic regimens for managing postsurgical pain in select patients, with the potential to reduce opioid use and opioid-related ADEs in the postsurgical setting. As with bupivacaine, appropriate use of liposome bupivacaine to optimize clinical effects, economic implications, and patient tolerability will depend on appropriate patient selection, practitioner training, and institutional protocols. As a component of a multimodal analgesic regimen, liposome bupivacaine represents a new approach to extending the duration of postsurgical analgesia. Further studies across a range of surgical settings should help clarify the most appropriate roles for this prolonged-release formulation of bupivacaine. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Abuse-deterrent formulations of prescription opioid analgesics in the management of chronic noncancer pain.

PubMed

Hale, Martin E; Moe, Derek; Bond, Mary; Gasior, Maciej; Malamut, Richard

2016-10-01

Misuse, abuse and diversion of prescription opioid analgesics represent a global public health concern. The development of abuse-deterrent formulations (ADFs) of prescription opioid analgesics is an important step toward reducing abuse and diversion of these medications, as well as potentially limiting medical consequences when misused or administered in error. ADFs aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or aversive. However, opioid ADFs may still be abused via the intended route of administration by increasing the dose and/or dosing frequency. The science of abuse deterrence and the regulatory landscape are still relatively new and evolving. This paper reviews the current status of opioid ADFs, with particular focus on different approaches that can be used to deter abuse, regulatory considerations and implications for clinical management.

New Formulations of Methylphenidate for the Treatment of Attention-Deficit/Hyperactivity Disorder: Pharmacokinetics, Efficacy, and Tolerability.

PubMed

Cortese, Samuele; D'Acunto, Giulia; Konofal, Eric; Masi, Gabriele; Vitiello, Benedetto

2017-02-01

Psychostimulants are the recommended first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD). Methylphenidate is one of the most commonly used psychostimulants worldwide. Given that immediate-release and/or tablet/capsule formulations may decrease adherence to methylphenidate treatment, several drug companies have been developing novel long-acting and/or liquid/chewable formulations that may improve adherence as well as (for long-acting formulations) reduce abuse potential, decrease stigma associated with multiple administrations per day, and decrease the potential for adverse effects related to dosage peak. Here, we review the pharmacokinetics, efficacy, and tolerability of novel formulations of methylphenidate that are in development or have been approved by the US FDA or European Medicines Agency (EMA) in the last 5 years. We searched the websites of the FDA, EMA, ClinicalTrials.gov, and the pertinent drug companies. We also searched PubMed, Ovid databases (MEDLINE, PsycINFO, Embase + Embase classic), and ISI Web of Knowledge (Web of Science [Science Citation Index Expanded], Biological Abstracts, Biosis, Food Science and Technology Abstracts) to retrieve any additional pertinent information. We found data from trials for the following compounds: (1) methylphenidate extended-release oral suspension (MEROS; NWP06, Quillivant™); (2) methylphenidate extended-release chewable capsules (NWP09, QuilliChew ER™); (3) methylphenidate hydrochloride extended-release capsules (Aptensio XR™); (4) methylphenidate extended-release orally disintegrating tablets (XR-ODT; NT-0102, Cotempla™); (5) ORADUR technology (once-daily tamper-resistant formulation) methylphenidate sustained release (SR); and (6) methylphenidate modified-release (HLD-200; Bejorna™). Overall, available evidence based on trials suggests these compounds have good efficacy and tolerability. Future research should further explore the effectiveness and tolerability of these new formulations as well as their potential to improve adherence to treatment in the 'real world' via pragmatic trials.

Twenty‐five years of prescription opioid use in Australia: a whole‐of‐population analysis using pharmaceutical claims

PubMed Central

Karanges, Emily A.; Blanch, Bianca; Buckley, Nicholas A.

2016-01-01

Aim The aim of this paper is to investigate 25‐year trends in community use of prescribed opioid analgesics in Australia, and to map these trends against major changes to opioid registration and subsidy. Methods We obtained dispensing data from 1990 to 2014 from two sources: dispensing claims processed under Australia's national drug subsidy programme, the Pharmaceutical Benefits Scheme, including under co‐payment records from 2012; and estimates of non‐subsidized medicine use from a survey of Australian pharmacies (until 2011). Utilization was expressed in defined daily doses (DDD)/1000 population/day. Results Opioid dispensing increased almost four‐fold between 1990 and 2014, from 4.6 to 17.4 DDD/1000 pop/day. In 1990, weak, short‐acting or orally administered opioids accounted for over 90% of utilization. Use of long‐acting opioids increased over 17‐fold between 1990 and 2000, due primarily to the subsidy of long‐acting morphine and increased use of methadone for pain management. Between 2000 and 2011, oxycodone, fentanyl, buprenorphine, tramadol and hydromorphone use increased markedly. Use of strong opioids, long‐acting and transdermal preparations also increased, largely following the subsidy of various opioids for noncancer pain. In 2011, the most dispensed opioids were codeine (41.1% of total opioid use), oxycodone (19.7%) and tramadol (16.1%); long‐acting formulations comprised approximately half, and strong opioids 40%, of opioid dispensing. Conclusions Opioid utilization in Australia is increasing, although these figures remain below levels reported in the US and Canada. The increased use of opioids was largely driven by the subsidy of long‐acting formulations and opioids for the treatment of noncancer pain. PMID:26991673

Extended-release intramuscular naltrexone (VIVITROL®): a review of its use in the prevention of relapse to opioid dependence in detoxified patients.

PubMed

Syed, Yahiya Y; Keating, Gillian M

2013-10-01

Naltrexone is a μ-opioid receptor antagonist that blocks the euphoric effects of heroin and prescription opioids. In order to improve treatment adherence, a once-monthly, intramuscular, extended-release formulation of naltrexone (XR-NTX) [VIVITROL(®)] has been developed, and approved in the USA and Russia for the prevention of relapse to opioid dependence, after opioid detoxification. The clinical efficacy of this formulation in patients with opioid dependence was demonstrated in a 24-week, randomized, double-blind, placebo-controlled, multicentre, phase III trial (ALK21-013; n = 250). In this trial, opioid-detoxified patients receiving XR-NTX 380 mg once every 4 weeks, in combination with psychosocial support, had a significantly higher median proportion of weeks of confirmed opioid abstinence during weeks 5-24, compared with those receiving placebo (primary endpoint). A significantly higher proportion of patients receiving XR-NTX achieved total confirmed abstinence during this period than those receiving placebo. XR-NTX was also associated with a significantly greater reduction in opioid craving and a significantly longer treatment retention period than placebo. XR-NTX was generally well tolerated in the phase III trial. The most common (incidence ≥5 %) treatment-emergent adverse events that also occurred more frequently with XR-NTX than with placebo were hepatic enzyme abnormalities, nasopharyngitis, insomnia, hypertension, influenza and injection-site pain. Thus, XR-NTX is a useful treatment option for the prevention of relapse to opioid dependence, following opioid detoxification.

Resisting Prescribed Opioids: A Qualitative Study of Decision Making in Patients Taking Opioids for Chronic Noncancer Pain.

PubMed

Paterson, Charlotte; Ledgerwood, Kay; Arnold, Carolyn; Hogg, Malcolm; Xue, Charlie; Zheng, Zhen

2016-04-01

Opioids are increasingly prescribed for chronic noncancer pain across the developed world. Clinical guidelines for management of these patients focus on over-use. However, research into other types of long-term medication indicates that many patients minimize drug use whenever possible. To identify the varying influences on patients' decisions about their use of prescribed opioids and explore whether concepts of resistance and minimization of intake apply to these patients. A multiprofessional team performed a qualitative interview study using the constant-comparative method. Patient's decision making was explored in depth and with a thematic analysis utilizing a published "Model of medicine-taking." A purposive sample of 20 participants drawn from two pain clinics in Melbourne, Australia. The sample was biased toward patients interested in nonmedication pain management options. Patients' needs to obtain relief from severe pain, maintain function, and minimize side effects could lead to under-use as well as over-use of prescribed opioids. In keeping with the published Model of medicine-taking, resistance to taking opioids was a common and important influence on behavior. In the face of severe chronic pain, many participants used a variety of strategies to evaluate, avoid, reduce, self-regulate, and replace opioids. Furthermore, participants perceived a resistance to opioids within the system and among some healthcare professionals. This sometimes adversely affected their adherence. Both patients and doctors exhibit aspects of resistance to the use of prescribed opioids for chronic noncancer pain, suggesting that this shared concern could be the basis of a productive therapeutic alliance to improve communication and shared decision making. Clinical guidelines for opioids use for chronic noncancer pain focus on over-use. Our qualitative interview study found that many patients resisted and minimized the use of opioids. Using a published "Model of medicine-taking," we identified various influences on patient decision making. Both patients and doctors had concerns about using opioids for chronic noncancer pain. These could be the basis of a productive therapeutic alliance to improve communication and shared decision making. © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

31 CFR 592.403 - Transshipment or transit through the United States.

Code of Federal Regulations, 2013 CFR

2013-07-01

... the shipment is sealed in a tamper-resistant container, accompanied by a Kimberley Process Certificate, and leaves the United States in the identical state in which it entered. The validation, recordkeeping...

31 CFR 592.403 - Transshipment or transit through the United States.

Code of Federal Regulations, 2014 CFR

2014-07-01

... the shipment is sealed in a tamper-resistant container, accompanied by a Kimberley Process Certificate, and leaves the United States in the identical state in which it entered. The validation, recordkeeping...

31 CFR 592.403 - Transshipment or transit through the United States.

Code of Federal Regulations, 2010 CFR

2010-07-01

... the shipment is sealed in a tamper-resistant container, accompanied by a Kimberley Process Certificate, and leaves the United States in the identical state in which it entered. The validation, recordkeeping...

31 CFR 592.403 - Transshipment or transit through the United States.

Code of Federal Regulations, 2011 CFR

2011-07-01

... the shipment is sealed in a tamper-resistant container, accompanied by a Kimberley Process Certificate, and leaves the United States in the identical state in which it entered. The validation, recordkeeping...

31 CFR 592.403 - Transshipment or transit through the United States.

Code of Federal Regulations, 2012 CFR

2012-07-01

... the shipment is sealed in a tamper-resistant container, accompanied by a Kimberley Process Certificate, and leaves the United States in the identical state in which it entered. The validation, recordkeeping...

On the designing of a tamper resistant prescription RFID access control system.

PubMed

Safkhani, Masoumeh; Bagheri, Nasour; Naderi, Majid

2012-12-01

Recently, Chen et al. have proposed a novel tamper resistant prescription RFID access control system, published in the Journal of Medical Systems. In this paper we consider the security of the proposed protocol and identify some existing weaknesses. The main attack is a reader impersonation attack which allows an active adversary to impersonate a legitimate doctor, e.g. the patient's doctor, to access the patient's tag and change the patient prescription. The presented attack is quite efficient. To impersonate a doctor, the adversary should eavesdrop one session between the doctor and the patient's tag and then she can impersonate the doctor with the success probability of '1'. In addition, we present efficient reader-tag to back-end database impersonation, de-synchronization and traceability attacks against the protocol. Finally, we propose an improved version of protocol which is more efficient compared to the original protocol while provides the desired security against the presented attacks.

Opioid-Induced Constipation and Bowel Dysfunction: A Clinical Guideline.

PubMed

Müller-Lissner, Stefan; Bassotti, Gabrio; Coffin, Benoit; Drewes, Asbjørn Mohr; Breivik, Harald; Eisenberg, Elon; Emmanuel, Anton; Laroche, Françoise; Meissner, Winfried; Morlion, Bart

2017-10-01

To formulate timely evidence-based guidelines for the management of opioid-induced bowel dysfunction. Constipation is a major untoward effect of opioids. Increasing prescription of opioids has correlated to increased incidence of opioid-induced constipation. However, the inhibitory effects of opioids are not confined to the colon, but also affect higher segments of the gastrointestinal tract, leading to the coining of the term "opioid-induced bowel dysfunction." A literature search was conducted using Medline, EMBASE, and EMBASE Classic, and the Cochrane Central Register of Controlled Trials. Predefined search terms and inclusion/exclusion criteria were used to identify and categorize relevant papers. A series of statements were formulated and justified by a comment, then labeled with the degree of agreement and their level of evidence as judged by the Strength of Recommendation Taxonomy (SORT) system. From a list of 10,832 potentially relevant studies, 33 citations were identified for review. Screening the reference lists of the pertinent papers identified additional publications. Current definitions, prevalence, and mechanism of opioid-induced bowel dysfunction were reviewed, and a treatment algorithm and statements regarding patient management were developed to provide guidance on clinical best practice in the management of patients with opioid-induced constipation and opioid-induced bowel dysfunction. In recent years, more insight has been gained in the pathophysiology of this "entity"; new treatment approaches have been developed, but guidelines on clinical best practice are still lacking. Current knowledge is insufficient regarding management of the opioid side effects on the upper gastrointestinal tract, but recommendations can be derived from what we know at present. © 2016 American Academy of Pain Medicine.

Injectable and implantable sustained release naltrexone in the treatment of opioid addiction

PubMed Central

Kunøe, Nikolaj; Lobmaier, Philipp; Ngo, Hanh; Hulse, Gary

2014-01-01

Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1–7 months have become available for clinical use and research. This qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood-borne diseases such as hepatitis or human immunodeficiency virus. There is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations of SRX with behavioural interventions, and to study at-risk groups such as prison inmates or opioid-addicted pregnant patients. The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction. PMID:23088328

Advances in the delivery of buprenorphine for opioid dependence

PubMed Central

Rosenthal, Richard N; Goradia, Viral V

2017-01-01

Opioid use disorders (OUDs) have long been a global problem, but the prevalence rates have increased over 20 years to epidemic proportions in the US, with concomitant increases in morbidity and all-cause mortality, but especially opioid overdose. These increases are in part attributable to a several-fold expansion in the prescription of opioid pain medications over the same time period. Opioid detoxification and psychosocial treatments alone have each not yielded sufficient efficacy for OUD, but μ-opioid receptor agonist, partial agonist, and antagonist medications have demonstrated the greatest overall benefit in OUD treatment. Buprenorphine, a μ-opioid receptor partial agonist, has been used successfully on an international basis for several decades in sublingual tablet and film preparations for the treatment of OUD, but the nature of formulation, which is typically self-administered, renders it susceptible to nonadherence, diversion, and accidental exposure. This article reviews the clinical trial data for novel buprenorphine delivery systems in the form of subcutaneous depot injections, transdermal patches, and subdermal implants for the treatment of OUD and discusses both the clinical efficacy of longer-acting formulations through increasing consistent medication exposure and their potential utility in reducing diversion. These new delivery systems also offer new dosing opportunities for buprenorphine and strategies for dosing intervals in the treatment of OUD. PMID:28894357

Advances in the delivery of buprenorphine for opioid dependence.

PubMed

Rosenthal, Richard N; Goradia, Viral V

2017-01-01

Opioid use disorders (OUDs) have long been a global problem, but the prevalence rates have increased over 20 years to epidemic proportions in the US, with concomitant increases in morbidity and all-cause mortality, but especially opioid overdose. These increases are in part attributable to a several-fold expansion in the prescription of opioid pain medications over the same time period. Opioid detoxification and psychosocial treatments alone have each not yielded sufficient efficacy for OUD, but μ-opioid receptor agonist, partial agonist, and antagonist medications have demonstrated the greatest overall benefit in OUD treatment. Buprenorphine, a μ-opioid receptor partial agonist, has been used successfully on an international basis for several decades in sublingual tablet and film preparations for the treatment of OUD, but the nature of formulation, which is typically self-administered, renders it susceptible to nonadherence, diversion, and accidental exposure. This article reviews the clinical trial data for novel buprenorphine delivery systems in the form of subcutaneous depot injections, transdermal patches, and subdermal implants for the treatment of OUD and discusses both the clinical efficacy of longer-acting formulations through increasing consistent medication exposure and their potential utility in reducing diversion. These new delivery systems also offer new dosing opportunities for buprenorphine and strategies for dosing intervals in the treatment of OUD.

Changes in misuse and abuse of prescription opioids following implementation of Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy.

PubMed

Bucher Bartelson, Becki; Le Lait, M Claire; Green, Jody L; Cepeda, M Soledad; Coplan, Paul M; Maziere, Jean-Yves; Wedin, Gregory P; Dart, Richard C

2017-09-01

An unintended consequence of extended-release (ER) and long-acting (LA) prescription opioids is that these formulations can be more attractive to abusers than immediate-release (IR) formulations. The US Food and Drug Administration recognized these risks and approved the ER/LA Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS), which has a goal of reducing opioid misuse and abuse and their associated consequences. The primary objective of this analysis is to determine whether ER/LA REMS implementation was associated with decreased reports of misuse and abuse. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS(R)) System Poison Center Program were utilized. Poison center cases are assigned a reason for exposure, a medical outcome, and a level of health care received. Rates adjusted for population and drug utilization were analyzed over time. RADARS System Poison Center Program data indicate a notable decrease in ER/LA opioid rates of intentional abuse and misuse as well as major medical outcomes or hospitalizations following implementation of the ER/LA REMS. While similar decreases were observed for the IR prescription opioid group, the decreasing rate for the ER/LA opioids exceeded the decreasing rates for the IR prescription opioids and was distinctly different than that for the prescription stimulants, indicating that the ER/LA REMS program may have had an additional effect on decreases in opioid abuse and intentional misuse beyond secular trends. Copyright © 2017 John Wiley & Sons, Ltd.

Options for Dealing With Rodent Infestations

EPA Pesticide Factsheets

After removing sources of food and water and shelter, your next options are rodent traps and poisons (rodenticides). Rat or mouse traps may be lethal (snap traps) or live (cage-type), and poison baits must be placed in tamper-resistant bait stations.

Opioid-Induced Constipation and Bowel Dysfunction: A Clinical Guideline

PubMed Central

Müller-Lissner, Stefan; Bassotti, Gabrio; Coffin, Benoit; Drewes, Asbjørn Mohr; Breivik, Harald; Eisenberg, Elon; Emmanuel, Anton; Laroche, Françoise; Meissner, Winfried; Morlion, Bart

2017-01-01

Abstract Objective To formulate timely evidence-based guidelines for the management of opioid-induced bowel dysfunction. Setting Constipation is a major untoward effect of opioids. Increasing prescription of opioids has correlated to increased incidence of opioid-induced constipation. However, the inhibitory effects of opioids are not confined to the colon, but also affect higher segments of the gastrointestinal tract, leading to the coining of the term “opioid-induced bowel dysfunction.” Methods A literature search was conducted using Medline, EMBASE, and EMBASE Classic, and the Cochrane Central Register of Controlled Trials. Predefined search terms and inclusion/exclusion criteria were used to identify and categorize relevant papers. A series of statements were formulated and justified by a comment, then labeled with the degree of agreement and their level of evidence as judged by the Strength of Recommendation Taxonomy (SORT) system. Results From a list of 10,832 potentially relevant studies, 33 citations were identified for review. Screening the reference lists of the pertinent papers identified additional publications. Current definitions, prevalence, and mechanism of opioid-induced bowel dysfunction were reviewed, and a treatment algorithm and statements regarding patient management were developed to provide guidance on clinical best practice in the management of patients with opioid-induced constipation and opioid-induced bowel dysfunction. Conclusions In recent years, more insight has been gained in the pathophysiology of this “entity”; new treatment approaches have been developed, but guidelines on clinical best practice are still lacking. Current knowledge is insufficient regarding management of the opioid side effects on the upper gastrointestinal tract, but recommendations can be derived from what we know at present. PMID:28034973

Maximizing value in opioid utilization: Is oxycodone immediate release a good option for pain management?

PubMed

Pergolizzi, Joseph V; Köknel Talu, Gül; Zmponga, Gianpetrio; Erdine, Serdar; Taylor, Robert; Ayan, Burak; Raffa, Robert B

2015-01-01

The modern approach to the management of pain involves optimizing all aspects of the process. This includes utilization of pharmacologic and non-pharmacologic modalities, consideration of patient characteristics, proper matching of the physiology of the pain with the analgesic's mechanism of action (pharmacodynamics, PD), and the onset and duration of action (pharmacokinetics, PK). No single agent or formulation satisfies all of the requirements for all patients. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective options for inflammatory pain and, as is acetaminophen, for mild pain. Specialized agents are helpful for particular pains, such as for migraine headache. Opioids remain the standard option for severe pain. Although they are generally a safe and effective option, opioids can produce dose-limiting adverse effects and have abuse potential. The goal of pain therapy is thus to achieve the maximum pain relief with the least amount of opioid exposure. Against this background of measured approach to the use of analgesics, an immediate release (IR) oral formulation of the established opioid oxycodone has been developed to provide rapid onset of action and rate of titration, both of which could maximize temporal matching of dose with pain level and reduce total exposure to drug. This article considers the option of an immediate release (IR) oral formulation for the management of pain.

Risk based In Vitro Performance Assessment of Extended Release Abuse Deterrent Formulations

PubMed Central

Xu, Xiaoming; Gupta, Abhay; Al-Ghabeish, Manar; Calderon, Silvia N.; Khan, Mansoor A.

2016-01-01

High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products. PMID:26784976

Dual-opioid therapy: changing the paradigm. Introduction.

PubMed

Nicholson, Bruce D

2012-03-01

Morphine sulfate and oxycodone hydrochloride are commonly used for pain management because of their pharmacologic profile, pharmacokinetics, and analgesic potency. However, opioids are associated with a significant adverse event (AE) burden that limits their use in both the acute and the chronic pain settings. Co-administration of opioids demonstrated synergistic analgesia and reduced side effects. Thus, dual-opioid therapy has the potential to enhance the positive analgesic benefits of opioids, while limiting the burden of opioid-related AEs. This symposium proceedings was based on presentations at the 13th World Congress on Pain in August 2010. This program will review the rationale for dual-opioid therapy based on preclinical findings and data from clinical studies showing the efficacy and tolerability profile of a dual-opioid formulation when used to treat acute postoperative pain. Wiley Periodicals, Inc.

Abuse-deterrent formulations, an evolving technology against the abuse and misuse of opioid analgesics.

PubMed

Schaeffer, Tammi

2012-12-01

The increased use of opioid pain medication has been mirrored by the increased misuse and abuse of these drugs. As part of a multidisciplinary approach to this epidemic, pharmaceutical companies, with the encouragement of the Food and Drug Administration, have increased the development of abuse-deterrent formulations. While all have the goal of treating pain while mitigating misuse and abuse, there are different technologies utilized to impart the abuse-deterrent properties. The goal of this paper is to review the basis of abuse-deterrent formulations, the different types and approaches of some of the abuse-deterrent products, and their current regulatory status in the USA.

The metamorphosis of hydromorphone.

PubMed

Reisfield, Gary M; Wilson, George R

2005-01-01

Hydromorphone, one of the oldest and most potent of opioids, is an effective alternative to morphine. With a variety of routes of administration, it has an efficacy similar to that of morphine. The FDA has recently approved the first commercially available extended-release formulation, a once-daily hydromorphone for the management of moderate to severe pain in opioid tolerant individuals with an anticipated extended period of use. The formulation exhibits less peak-to-trough fluctuation in plasma concentration, while providing analgesia statistically indistinguishable from its immediate-release counterpart. The manufacturer and the FDA have articulated a plan to minimize unskillful prescribing and abuse/diversion through education, supply-chain integrity, and surveillance. It is anticipated that Palladone will be a valuable addition to the limited armamentarium of extended-release opioids.

Injectable and implantable sustained release naltrexone in the treatment of opioid addiction.

PubMed

Kunøe, Nikolaj; Lobmaier, Philipp; Ngo, Hanh; Hulse, Gary

2014-02-01

Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1-7 months have become available for clinical use and research. This qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood-borne diseases such as hepatitis or human immunodeficiency virus. There is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations of SRX with behavioural interventions, and to study at-risk groups such as prison inmates or opioid-addicted pregnant patients. The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Tamper-indicating barcode and method

DOEpatents

Cummings, Eric B.; Even, Jr., William R.; Simmons, Blake A.; Dentinger, Paul Michael

2005-03-22

A novel tamper-indicating barcode methodology is disclosed that allows for detection of alteration to the barcode. The tamper-indicating methodology makes use of a tamper-indicating means that may be comprised of a particulate indicator, an optical indicator, a deformable substrate, and/or may be an integrated aspect of the barcode itself. This tamper-indicating information provides greater security for the contents of containers sealed with the tamper-indicating barcodes.

Assessment of Tapentadol API Abuse Liability With the Researched Abuse, Diversion and Addiction-Related Surveillance System.

PubMed

Vosburg, Suzanne K; Severtson, S Geoffrey; Dart, Richard C; Cicero, Theodore J; Kurtz, Steven P; Parrino, Mark W; Green, Jody L

2018-04-01

Tapentadol, a Schedule II opioid with a combination of µ-opioid activity and norepinephrine reuptake inhibition, is used for the management of moderate to severe acute and chronic pain. Its dual mechanism of action is thought to reduce opioid-related side effects that can complicate pain management. Since approval, tapentadol has been tracked across multiple outcomes suggesting abuse liability, and a pattern of relatively low, although not absent, abuse liability has been found. This retrospective cohort study further details the abuse liability of tapentadol as an active pharmaceutical ingredient (API) when immediate-release as well as extended-release formulations were on the market together (fourth quarter of 2011 to second quarter of 2016). Tapentadol (API) was compared with tramadol, hydrocodone, morphine, oxycodone, hydromorphone, and oxymorphone across Poison Center, Drug Diversion, and Treatment Center Programs Combined data streams from the Researched Abuse, Diversion and Addiction-Related Surveillance system. Findings suggest the public health burden related to tapentadol to date is low, but present. Event rates of abuse per population-level denominators were significantly lower than all other opioids examined. However, when adjusted for drug availability, event rates of abuse were lower than most Schedule II opioids studied, but were not the lowest. Disentangling these 2 sets of findings further by examining various opioid formulations, such as extended-release and the role of abuse-deterrent formulations, is warranted. This article presents the results from an examination of tapentadol API across the Researched Abuse, Diversion and Addiction-Related Surveillance System: a broad and carefully designed postmarketing mosaic. Data to date from Poison Center, Drug Diversion, and Treatment Centers combined suggest a low, but present public health burden related to tapentadol. Copyright © 2018. Published by Elsevier Inc.

Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality.

PubMed

Dasgupta, Nabarun; Funk, Michele Jonsson; Proescholdbell, Scott; Hirsch, Annie; Ribisl, Kurt M; Marshall, Steve

2016-01-01

Previous studies examining opioid dose and overdose risk provide limited granularity by milligram strength and instead rely on thresholds. We quantify dose-dependent overdose mortality over a large spectrum of clinically common doses. We also examine the contributions of benzodiazepines and extended release opioid formulations to mortality. Prospective observational cohort with one year follow-up. One year in one state (NC) using a controlled substances prescription monitoring program, with name-linked mortality data. Residential population of North Carolina (n = 9,560,234), with 2,182,374 opioid analgesic patients. Exposure was dispensed prescriptions of solid oral and transdermal opioid analgesics; person-years calculated using intent-to-treat principles. Outcome was overdose deaths involving opioid analgesics in a primary or additive role. Poisson models were created, implemented using generalized estimating equations. Opioid analgesics were dispensed to 22.8% of residents. Among licensed clinicians, 89.6% prescribed opioid analgesics, and 40.0% prescribed ER formulations. There were 629 overdose deaths, half of which had an opioid analgesic prescription active on the day of death. Of 2,182,374 patients prescribed opioids, 478 overdose deaths were reported (0.022% per year). Mortality rates increased gradually across the range of average daily milligrams of morphine equivalents. 80.0% of opioid analgesic patients also received benzodiazepines. Rates of overdose death among those co-dispensed benzodiazepines and opioid analgesics were ten times higher (7.0 per 10,000 person-years, 95 percent CI: 6.3, 7.8) than opioid analgesics alone (0.7 per 10,000 person years, 95 percent CI: 0.6, 0.9). Dose-dependent opioid overdose risk among patients increased gradually and did not show evidence of a distinct risk threshold. There is urgent need for guidance about combined classes of medicines to facilitate a better balance between pain relief and overdose risk. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. 2016. This work is written by US Government employees and is in the public domain in the US.

43 CFR 423.25 - Vandalism, tampering, and theft.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Vandalism, tampering, and theft. 423.25 Section 423.25 Public Lands: Interior Regulations Relating to Public Lands BUREAU OF RECLAMATION... of Conduct § 423.25 Vandalism, tampering, and theft. (a) You must not tamper or attempt to tamper...

Interpreting labels of abuse-deterrent opioid analgesics.

PubMed

Webster, Lynn R

To provide an overview of available abuse-deterrent opioids (ADOs) and the labeling text that describes abuse-deterrent (AD) properties. A nonsystematic review of ADO literature and regulatory documents guiding their development. A critical assessment and discussion of common routes of opioid abuse, AD methods and properties, US Food and Drug Administration (FDA) study requirements to achieve AD labeling, and brief guide to understanding AD labels. The FDA has issued guidance as incentive and direction to industry to develop ADOs as one component of a multi-pronged public-health strategy to combat opioid abuse and misuse. The guidance describes separate categories of premarket and postmarket studies and makes recommendations for claims that may be made based on study findings. Ten ADOs have FDA-approved labeling attesting to AD properties. Available formulations that fail to conform to FDA guidance in study and labeling recommendations cannot be considered ADO. Formulations with AD properties are expected to reduce risk compared to the same agents without AD properties but cannot prevent all abuse and adverse clinical outcomes.

Abuse-deterrent formulations approval reform: Will clinical correctness or real-world results be used to address the nation's opioid crisis: "Noninterference" as a new approval standard.

PubMed

Cohen, Dan

To further the public policy objectives of Congress and the country, legislators should now insist that abuse-deterrent formulations (ADFs) be deployed for every C-II opioid and stimulant. The need for these innovative technologies has never been greater. And to most efficiently incentivize innovators to develop and deploy the most effective and modern deterrents, a new and simpler regulatory approval standard for ADF should be adopted by the U.S. Food and Drug Administration. That standard, based on a concept of "Noninterference" increases the potential for a much earlier deployment of ADFs in a broad range of products and allows deterrence to play its most effective role in combatting the national opioid crisis.

23 CFR Appendix A to Part 1313 - Tamper Resistant Driver's License

Code of Federal Regulations, 2010 CFR

2010-04-01

...) Block graphics. (15) Security fonts and graphics with known hidden flaws. (16) Card stock, layer with colors. (17) Micro-graphics. (18) Retroflective security logos. (19) Machine readable technologies such... permit that has one or more of the following security features: (1) Ghost image. (2) Ghost graphic. (3...

Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability.

PubMed

Johnson, Franklin; Setnik, Beatrice

2011-01-01

Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain, contain pellets of extended-release morphine sulfate with a sequestered naltrexone core (MS-sNT). Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered with by crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessary to establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it is also necessary to demonstrate that product therapeutic integrity is maintained for patients. Data were reviewed from 3 studies to determine: 1) the quantity of naltrexone released when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar and pestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-induced subjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MS-sNT is taken as directed. The naltrexone bioavailability study compared naltrexone release from MS-sNTC with that from whole intact MS-sNT capsules (MS-sNTW) and an equal naltrexone solution (NS) dose. Equivalent bioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximum plasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated to infinity [AUC∞]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug liking and euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphine sulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safety of MS-sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safety assessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS). Naltrexone from MS-sNTC met criteria for equivalent bioavailability to NS. Although morphine relative bioavailability was similar for MS-sNTC and MSS, mean peak (Emax) visual analog scale (VAS) scores for drug liking and Cole/Addiction Research Center Inventory Stimulation-Euphoria were significantly reduced for MS-sNTC vs MSS (p < 0.001). In these 2 studies, a total of 6 participants had one measurement of plasma naltrexone after MS-sNTW that was above the lower limit of quantification. In the OL safety study, 72/93 participants (77%) had no quantifiable naltrexone concentrations. There was neither evidence of naltrexone accumulation for any participant nor any significant correlation with MS-sNT dose, age, or sex. Of 4 participants with the highest naltrexone concentrations, none had COWS scores consistent with moderate opioid withdrawal symptoms. Only 5 participants had COWS scores consistent with moderate opioid withdrawal; all 5 had not taken MS-sNT as directed. Study populations may not be fully representative of patients receiving opioid therapy for the management of chronic, moderate-to-severe pain and of opioid abusers. When MS-sNT capsules are crushed, all of the sequestered naltrexone (relative to oral NS) is released and immediately available to mitigate morphine-induced effects. When MS-sNT was crushed, the naltrexone released abated drug liking and euphoria relative to that from an equal dose of immediate-release morphine from MSS administration in a majority of participants. Naltrexone concentrations were low over a period of 12 months without evidence of accumulation, and there were no observable opioid withdrawal symptoms when MS-sNT was taken as directed.

Abuse-Deterrent Formulations and the Prescription Opioid Abuse Epidemic in the United States: Lessons Learned From OxyContin.

PubMed

Cicero, Theodore J; Ellis, Matthew S

2015-05-01

In an effort to reduce wide-scale abuse of the proprietary oxycodone hydrochloride formulation OxyContin, an abuse-deterrent formulation (ADF) was introduced in 2010. Although the reformulation produced an immediate drop in abuse rates, a definite ceiling effect appeared over time, beyond which no further decrease was seen. To examine the factors that led to the initial steep decline in OxyContin abuse and the substantial levels of residual abuse that have remained relatively stable since 2012. We used data from the ongoing Survey of Key Informants' Patients program, part of the Researched Abuse, Diversion and Addiction-Related Surveillance system that collects and analyzes postmarketing data on misuse and diversion of prescription opioid analgesics and heroin. For our survey study, patients with a DSM-V diagnosis of opioid use disorder and primary drug of abuse consisting of a prescription opioid or heroin (N = 10,784) at entry to 1 of 150 drug treatment programs in 48 states completed an anonymous structured survey of opioid abuse patterns (surveys completed from January 1, 2009, through June 30, 2014). A subset of these patients (n = 244) was interviewed to add context and expand on the structured survey. In addition to key demographic measures, past-month abuse of opioids was the primary measure in the structured surveys. In the interviews, the effect of the introduction of the ADF on drug-seeking behavior was examined. Reformulated OxyContin was associated with a significant reduction of past-month abuse after its introduction (45.1% [95% CI, 41.2%-49.1%] in January to June 2009 to 26.0% [95% CI, 23.6%-28.4%] in July to December 2012; P < .001; χ(2) = 230.83), apparently owing to a migration to other opioids, particularly heroin. However, this reduction leveled off, such that 25% to 30% of the sample persisted in endorsing past-month abuse from 2012 to 2014 (at study end [January to June 2014], 26.7% [95% CI, 23.7%-29.6%]). Among the 88 participants who indicated experience using pre-ADF and ADF OxyContin, this residual level of abuse reflects the following 3 phenomena: (1) a transition from nonoral routes of administration to oral use (38 participants [43%]); (2) successful efforts to defeat the ADF mechanism leading to a continuation of inhaled or injected use (30 participants [34%]); and (3) exclusive use of the oral route independent of formulation type (20 participants [23%]). Abuse-deterrent formulations can have the intended purpose of curtailing abuse, but the extent of their effectiveness has clear limits, resulting in a significant level of residual abuse. Consequently, although drug abuse policy should focus on limiting supplies of prescription analgesics for abuse, including ADF technology, efforts to reduce supply alone will not mitigate the opioid abuse problem in this country.

PRN 94-7: Label Improvement Program for the Revision of Use Directions for Commensal Rodenticides and Statement of the Agency's Policies on the Use of Rodenticide Bait Stations

EPA Pesticide Factsheets

This Notice requires registrants of certain pesticide products claimed to control commensal rodents and registered under FIFRA to revise the labeling of such products to bear certain statements concerning tamper-resistant bait stations.

Coverage of Medications That Treat Opioid Use Disorder and Opioids for Pain Management in Marketplace Plans, 2017.

PubMed

Huskamp, Haiden A; Riedel, Lauren E; Barry, Colleen L; Busch, Alisa B

2018-06-01

Efficacious medications to treat opioid use disorders (OUDs) have been slow to diffuse into practice, and insurance coverage limits may be one important barrier. To compare coverage for medications used to treat OUDs and opioids commonly prescribed for pain management in plans offered on the 2017 Health Insurance Marketplace exchanges. We identified a sample of 100 plans offered in urban and in rural counties on the 2017 Marketplaces, weighting by population. We accessed publicly available plan coverage information on healthcare.gov for states with a federally facilitated exchange, the state exchange website for state-based exchanges, and insurer websites. About 14% of plans do not cover any formulations of buprenorphine/naloxone. Plans were more likely to require prior authorization for any of the covered office-based buprenorphine or naltrexone formulations preferred for maintenance OUD treatment (ie, buprenorphine/naloxone, buprenorphine implants, injectable long-acting naltrexone) than of short-acting opioid pain medications (63.6% vs. 19.4%; P<0.0001). Only 10.6% of plans cover implantable buprenorphine, 26.1% cover injectable naltrexone, and 73.4% cover at least 1 abuse-deterrent opioid pain medication. Many Marketplace plans either do not cover or require prior authorization for coverage of OUD medications, and these restrictions are often more common for OUD medications than for short-acting opioid pain medications. Regulators tasked with enforcement of the Mental Health Parity and Addiction Equity Act, which requires that standards for formulary design for mental health and substance use disorder drugs be comparable to those for other medications, should focus attention on formulary coverage of OUD medications.

Tampered Region Localization of Digital Color Images Based on JPEG Compression Noise

NASA Astrophysics Data System (ADS)

Wang, Wei; Dong, Jing; Tan, Tieniu

With the availability of various digital image edit tools, seeing is no longer believing. In this paper, we focus on tampered region localization for image forensics. We propose an algorithm which can locate tampered region(s) in a lossless compressed tampered image when its unchanged region is output of JPEG decompressor. We find the tampered region and the unchanged region have different responses for JPEG compression. The tampered region has stronger high frequency quantization noise than the unchanged region. We employ PCA to separate different spatial frequencies quantization noises, i.e. low, medium and high frequency quantization noise, and extract high frequency quantization noise for tampered region localization. Post-processing is involved to get final localization result. The experimental results prove the effectiveness of our proposed method.

Blind technique using blocking artifacts and entropy of histograms for image tampering detection

NASA Astrophysics Data System (ADS)

Manu, V. T.; Mehtre, B. M.

2017-06-01

The tremendous technological advancements in recent times has enabled people to create, edit and circulate images easily than ever before. As a result of this, ensuring the integrity and authenticity of the images has become challenging. Malicious editing of images to deceive the viewer is referred to as image tampering. A widely used image tampering technique is image splicing or compositing, in which regions from different images are copied and pasted. In this paper, we propose a tamper detection method utilizing the blocking and blur artifacts which are the footprints of splicing. The classification of images as tampered or not, is done based on the standard deviations of the entropy histograms and block discrete cosine transformations. We can detect the exact boundaries of the tampered area in the image, if the image is classified as tampered. Experimental results on publicly available image tampering datasets show that the proposed method outperforms the existing methods in terms of accuracy.

Current and Potential Pharmacological Treatment Options for Maintenance Therapy in Opioid-Dependent Individuals

PubMed Central

Tetrault, Jeanette M.; Fiellin, David A.

2013-01-01

Opioid dependence, manifesting as addiction to heroin and pharmaceutical opioids is increasing. Internationally, there are an estimated 15.6 million illicit opioid users. The global economic burden of opioid dependence is profound both in terms of HIV and hepatitis C virus transmission, direct healthcare costs, and indirectly through criminal activity, absenteeism and lost productivity. Opioid agonist medications, such as methadone and buprenorphine, that stabilize neuronal systems and provide narcotic blockade are the most effective treatments. Prolonged provision of these medications, defined as maintenance treatment, typically produces improved outcomes when compared with short-duration tapers and withdrawal. The benefits of opioid agonist maintenance include decreased illicit drug use, improved retention in treatment, decreased HIV risk behaviours and decreased criminal behaviour. While regulations vary by country, these medications are becoming increasingly available internationally, especially in regions experiencing rapid transmission of HIV due to injection drug use. In this review, we describe the rationale for maintenance treatment of opioid dependence, discuss emerging uses of opioid antagonists such as naltrexone, and sustained-release formulations of naltrexone and buprenorphine, and provide a description of the experimental therapies. PMID:22235870

Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

PubMed

Pergolizzi, Joseph; Böger, Rainer H; Budd, Keith; Dahan, Albert; Erdine, Serdar; Hans, Guy; Kress, Hans-Georg; Langford, Richard; Likar, Rudolf; Raffa, Robert B; Sacerdote, Paola

2008-01-01

SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities--including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia--and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in neuropathic pain: The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4. The use of opioids in elderly patients with impaired hepatic and renal function: Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that--except for buprenorphine--doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5. Opioids and respiratory depression: Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6. Opioids and immunosuppression: Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7. Safety and tolerability profile of opioids: The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.

Dependence and addiction during chronic opioid therapy.

PubMed

Juurlink, David N; Dhalla, Irfan A

2012-12-01

The use of opioids for chronic noncancer pain has increased dramatically over the past 25 years in North America and has been accompanied by a major increase in opioid addiction and overdose deaths. The increase in opioid prescribing is multifactorial and partly reflects concerns about the effectiveness and safety of alternative medications, particularly the nonsteroidal anti-inflammatory drugs. However, much of the rise in opioid prescribing reflects the assertion, widely communicated to physicians in the 1990s, that the risks of dependence and addiction during chronic opioid therapy were low, predictable, and could be minimized by the use of controlled-release opioid formulations. In this narrative review, we offer a critical appraisal of the publications most frequently cited as evidence that the risk of addiction during chronic opioid therapy is low. We conclude that very few well-designed studies support the notion that opioid addiction is rare during chronic opioid therapy and that none can be readily generalized to present-day practice. Despite serious methodological limitations, these studies have been repeatedly mischaracterized as showing that the risk of addiction during chronic opioid therapy is rare. These studies are countered by a larger, more rigorous and contemporary body of evidence demonstrating that dependence and addiction are relatively common consequences of chronic opioid therapy, occurring in up to one-third of patients in some series.

Opioid Dependence Treatment: Options In Pharmacotherapy

PubMed Central

Stotts, Angela L.; Dodrill, Carrie L.; Kosten, Thomas R.

2010-01-01

The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long term efficacy and patient discomfort remains a significant therapy challenge. Buprenorphine’s effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the US is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence, however, randomized clinical trials are needed. PMID:19538000

Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain

PubMed Central

Chou, Roger; Fanciullo, Gilbert J.; Fine, Perry G.; Adler, Jeremy A.; Ballantyne, Jane C.; Davies, Pamela; Donovan, Marilee I.; Fishbain, David A.; Foley, Kathy M.; Fudin, Jeffrey; Gilson, Aaron M.; Kelter, Alexander; Mauskop, Alexander; O'Connor, Patrick G.; Passik, Steven D.; Pasternak, Gavril W.; Portenoy, Russell K.; Rich, Ben A.; Roberts, Richard G.; Todd, Knox H.; Miaskowski, Christine

2014-01-01

Use of chronic opioid therapy for chronic noncancer pain has increased substantially. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on chronic opioid therapy for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations. Although evidence is limited, the expert panel concluded that chronic opioid therapy can be an effective therapy for carefully selected and monitored patients with chronic noncancer pain. However, opioids are also associated with potentially serious harms, including opioid-related adverse effects and outcomes related to the abuse potential of opioids. The recommendations presented in this document provide guidance on patient selection and risk stratification; informed consent and opioid management plans; initiation and titration of chronic opioid therapy; use of methadone; monitoring of patients on chronic opioid therapy; dose escalations, high-dose opioid therapy, opioid rotation, and indications for discontinuation of therapy; prevention and management of opioid-related adverse effects; driving and work safety; identifying a medical home and when to obtain consultation; management of breakthrough pain; chronic opioid therapy in pregnancy; and opioid-related polices. Perspective: Safe and effective chronic opioid therapy for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion. Although evidence is limited in many areas related to use of opioids for chronic noncancer pain, this guideline provides recommendations developed by a multidisciplinary expert panel following a systematic review of the evidence. PMID:19187889

Extended-release hydrocodone – gift or curse?

PubMed Central

Krashin, Daniel; Murinova, Natalia; Trescot, Andrea M

2013-01-01

Hydrocodone is a semisynthetic opioid, which has been used for decades as a short-acting analgesic combined with acetaminophen (or less commonly ibuprofen). Several long-acting, non-acetaminophen-containing hydrocodone formulations are undergoing trials in the US under the auspices of the US Food and Drug Administration, and may be available shortly. This article reviews some of the advantages (including drug familiarity and lack of acetaminophen toxicity) and potential disadvantages (including altered use patterns and high morphine equivalent dosing) of such a medication formulation. We also discuss the abuse potential of long-acting versus short-acting opioids in general and hydrocodone specifically, as well as the metabolism of hydrocodone. PMID:23358452

New formulations of bupivacaine for the treatment of postoperative pain: liposomal bupivacaine and SABER-Bupivacaine.

PubMed

Skolnik, Aaron; Gan, Tong J

2014-08-01

Although generally considered both safe and effective, local anesthetics are often used in conjunction with opioids postoperatively in part because of the limited duration of drug action of local anesthetics. Much interest exists in extending the duration of local anesthetics' effects, which may reduce the requirement for opioid pain medications that are frequently associated with side effects, including nausea and vomiting, pruritus and respiratory depression. This article introduces liposomal bupivacaine and SABER®-Bupivacaine, two new formulations of bupivacaine that increase the duration of analgesia postoperatively through two novel slow-release technologies. The pharmacodynamics, pharmacokinetics, efficacy and safety of both preparations of bupivacaine are reviewed. An electronic database search conducted using the Cochrane Central Register of Controlled Trials and MEDLINE/PubMed with the following search terms: 'bupivacaine,' 'liposomal bupivacaine', 'liposome bupivacaine', 'Exparel', 'SABER-Bupivacaine', 'SABER Bupivacaine', and 'SABER' yielded 90 articles (no language or date of publication restrictions were imposed). Clinical trials involving liposomal bupivacaine and SABER-Bupivacaine indicate that both safely prolong analgesia, while decreasing opioid requirements when compared with placebo. However, additional clinical studies are necessary to better determine the efficacy and cost-effectiveness of these long-acting local anesthetic formulations.

Interchangeability, Safety and Efficacy of Modified-Release Drug Formulations in the USA: The Case of Opioid and Other Nervous System Drugs.

PubMed

Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Hansen, Richard

2016-04-01

Modified-release drugs may provide clinical advantages compared to immediate-release forms and improve convenience to the patient and health outcomes. Concerns have been raised regarding interchangeability, efficacy, and safety of modified-release formulations. This study analyses all US Food and Drug Administration (FDA)-approved modified-release formulations and market trends, and illustrates how bioequivalence and safety of generic modified-release products compare to their respective brand name drugs and other generic drugs with different formulation design characteristics. This study also examines major concerns related to modified-release formulations: safety of opioids and bioequivalence of generic bupropion and methylphenidate. Study data were derived from the FDA electronic versions of the FDA's Orange Book (OB) and the FDA safety communications web page. Medicare Part D utilization and expenditures data were extracted from the Centers for Medicare and Medicaid. In May 2015, 276 (11.9 %) of the 2325 active ingredients and fixed-dose combinations listed in the FDA's Orange Book had at least one modified-release form approved by the FDA. The number of approvals increased over time; 52.5 % of modified releases were approved in the period 2000-May 2015. The FDA required a risk evaluation and mitigation strategy (REMS) to ensure that the benefits of extended-release opioids outweighed its risks of overdose and abuse. The REMS involved 16 new drug applications and 25 abbreviated new drug applications. The FDA addressed interchangeability problems with generic modified-release alternatives of bupropion and methylphenidate including lack of bioequivalence, reduced efficacy, and increased incidence of adverse events. Systematic post-marketing surveillance studies are needed to assess differences in safety, interchangeability, and efficacy of drugs with modified- and immediate-release formulations.

Prescription opioid abuse, pain and addiction: clinical issues and implications.

PubMed

Ling, Walter; Mooney, Larissa; Hillhouse, Maureen

2011-05-01

Prescription opioid misuse in the USA has increased over threefold since 1990 to epidemic proportions, with substantial increases in prescription opioid use also reported in other countries, such as Australia and New Zealand. The broad availability of prescription pain medications, coupled with public misconceptions about their safety and addictive potential, have contributed to the recent surge in non-medical use of prescription opioids and corresponding increases in treatment admissions for problems related to opioid misuse. Given competing pressures faced by physicians to both diagnose and treat pain syndromes and identify individuals at risk for addictive disorders, the use of opioids in the treatment of pain poses a significant clinical challenge. This paper reviews the interaction between pain and opioid addiction with a focus on clinical management issues, including risk factors for opioid dependence in patients with chronic pain and the use of assessment tools to identify and monitor at-risk individuals. Treatment options for opioid dependence and pain are reviewed, including the use of the partial µ agonist buprenorphine in the management of concurrent pain and opioid addiction. Physicians should strive to find a reasonable balance between minimising potential adverse effects of opioid medications without diminishing legitimate access to opioids for analgesia. The article discusses the need to identify methods for minimising risks and negative consequences associated with opioid analgesics and poses research directions, including the development of abuse-deterrent opioid formulations, genetic risk factors for opioid dependence and opioid-induced hyperalgesia as a potential target for medication therapy. © 2011 Australasian Professional Society on Alcohol and other Drugs.

Prescription opioid abuse, pain and addiction: Clinical issues and implications

PubMed Central

LING, WALTER; MOONEY, LARISSA; HILLHOUSE, MAUREEN

2014-01-01

Issues Prescription opioid misuse in the USA has increased over threefold since 1990 to epidemic proportions, with substantial increases in prescription opioid use also reported in other countries, such as Australia and New Zealand. The broad availability of prescription pain medications, coupled with public misconceptions about their safety and addictive potential, have contributed to the recent surge in non-medical use of prescription opioids and corresponding increases in treatment admissions for problems related to opioid misuse. Given competing pressures faced by physicians to both diagnose and treat pain syndromes and identify individuals at risk for addictive disorders, the use of opioids in the treatment of pain poses a significant clinical challenge. Approach This paper reviews the interaction between pain and opioid addiction with a focus on clinical management issues, including risk factors for opioid dependence in patients with chronic pain and the use of assessment tools to identify and monitor at-risk individuals. Treatment options for opioid dependence and pain are reviewed, including the use of the partial μ agonist buprenorphine in the management of concurrent pain and opioid addiction. Implications Physicians should strive to find a reasonable balance between minimising potential adverse effects of opioid medications without diminishing legitimate access to opioids for analgesia. Conclusions The article discusses the need to identify methods for minimising risks and negative consequences associated with opioid analgesics and poses research directions, including the development of abuse-deterrent opioid formulations, genetic risk factors for opioid dependence and opioid-induced hyperalgesia as a potential target for medication therapy. PMID:21545561

Methadone, commonly used as maintenance medication for outpatient treatment of opioid dependence, kills leukemia cells and overcomes chemoresistance.

PubMed

Friesen, Claudia; Roscher, Mareike; Alt, Andreas; Miltner, Erich

2008-08-01

The therapeutic opioid drug methadone (d,l-methadone hydrochloride) is the most commonly used maintenance medication for outpatient treatment of opioid dependence. In our study, we found that methadone is also a potent inducer of cell death in leukemia cells and we clarified the unknown mechanism of methadone-induced cell killing in leukemia cells. Methadone inhibited proliferation in leukemia cells and induced cell death through apoptosis induction and activated apoptosis pathways through the activation of caspase-9 and caspase-3, down-regulation of Bcl-x(L) and X chromosome-linked inhibitor of apoptosis, and cleavage of poly(ADP-ribose) polymerase. In addition, methadone induced cell death not only in anticancer drug-sensitive and apoptosis-sensitive leukemia cells but also in doxorubicin-resistant, multidrug-resistant, and apoptosis-resistant leukemia cells, which anticancer drugs commonly used in conventional therapies of leukemias failed to kill. Depending on caspase activation, methadone overcomes doxorubicin resistance, multidrug resistance, and apoptosis resistance in leukemia cells through activation of mitochondria. In contrast to leukemia cells, nonleukemic peripheral blood lymphocytes survived after methadone treatment. These findings show that methadone kills leukemia cells and breaks chemoresistance and apoptosis resistance. Our results suggest that methadone is a promising therapeutic approach not only for patients with opioid dependence but also for patients with leukemias and provide the foundation for new strategies using methadone as an additional anticancer drug in leukemia therapy, especially when conventional therapies are less effective.

America's Opioid Epidemic: Supply and Demand Considerations.

PubMed

Clark, David J; Schumacher, Mark A

2017-11-01

America is in the midst of an opioid epidemic characterized by aggressive prescribing practices, highly prevalent opioid misuse, and rising rates of prescription and illicit opioid overdose-related deaths. Medical and lay public sentiment have become more cautious with respect to prescription opioid use in the past few years, but a comprehensive strategy to reduce our reliance on prescription opioids is lacking. Addressing this epidemic through reductions in unnecessary access to these drugs while implementing measures to reduce demand will be important components of any comprehensive solution. Key supply-side measures include avoiding overprescribing, reducing diversion, and discouraging misuse through changes in drug formulations. Important demand-side measures center around educating patients and clinicians regarding the pitfalls of opioid overuse and methods to avoid unnecessary exposure to these drugs. Anesthesiologists, by virtue of their expertise in the use of these drugs and their position in guiding opioid use around the time of surgery, have important roles to play in reducing patient exposure to opioids and providing education about appropriate use. Aside from the many immediate steps that can be taken, clinical and basic research directed at understanding the interaction between pain and opioid misuse is critical to identifying the optimal use of these powerful pain relievers in clinical practice.

Accessibility of opioid analgesics and barriers to optimal chronic pain treatment in Poland in 2000-2015.

PubMed

Dzierżanowski, Tomasz; Ciałkowska-Rysz, Aleksandra

2017-03-01

Based on the international reports, consumption of opioid analgesics in Poland is relatively low. There is limited information on possible impediments to optimal opioid use. This study was aimed to identify possible barriers to access to opioid analgesics and causes of failure to comply with current clinical guidelines. Consumption data per capita in 2000-2015 were analyzed in terms of oral morphine equivalents in total, per prescription type, per reimbursement status, to identify the impact of regulations specific for Poland. The consumption of opioid analgesics has been consistently growing from 36.0 in 2000 to 103.4 mg oral morphine equivalents (OME) per capita in 2015, mainly thanks to strong opioid consumption growth. Tramadol is the most commonly used opioid in Poland. Fentanyl and buprenorphine transdermal formulations are the most frequently used strong opioid analgesics in terms of OME. The vast majority (92.8 %) of opioids were distributed upon for outpatient use in 2015, with a almost fourfold growth of consumption of strong opioids and almost threefold of weak opioids between 2000 and 2015. Strong opioids were 41 % of OME used upon prescription in 2015. Acceleration of consumption growth has been observed since 2013. The prescription pattern does not abide by the current clinical guidelines for pain treatment, and the most often used opioids in Poland are tramadol, buprenorphine, and fentanyl. The use of opioids in Poland grows fast, with acceleration since 2013. The most important legal impediments of optimal opioid analgesics use have been lack of reimbursement, special prescription forms, and complicated prescribing rules.

The Influence of Prescription Opioid Use Duration and Dose on Development of Treatment Resistant Depression

PubMed Central

Scherrer, Jeffrey F.; Salas, Joanne; Sullivan, Mark D.; Schneider, F. David; Bucholz, Kathleen K.; Burroughs, Thomas; Copeland, Laurel; Ahmedani, Brian; Lustman, Patrick J.

2016-01-01

Long-term prescription opioid use is associated both with new-onset and recurrence of depression. Whether chronic opioid use interferes with depression management has not been reported, therefore we determined whether patients’ longer duration of opioid use and higher opioid dose are associated with new-onset treatment resistant depression (TRD) after controlling for confounding from pain and other variables. Data was obtained from Veteran Health Administration (VHA) de-identified patient medical records. We used a retrospective cohort design from 2000–2012. Eligible subjects (n=6,169) were 18–80 years of age, free of cancer and HIV, diagnosed with depression and opioid-free for the 24-month interval prior to the observation period. Duration of a new prescription for opioid analgesic was categorized as 1–30 days, 31–90 days and >90 days. Morphine-equivalent dose (MED) during follow-up categorized as ≤50 mg versus >50 mg per day. Pain and other sources of confounding were controlled by propensity scores and inverse probability of treatment weighting. Cox proportional hazard models were computed to estimate the association between duration and dose of opioid and onset of TRD. After removing confounding by weighting data, opioid use for 31–90 days and for >90 days, compared to 1–30 days, was significantly associated with new onset TRD (HR=1.25; 95%CI: 1.09–1.45 and HR=1.52; 95%CI: 1.32–1.74, respectively). MED was not associated with new onset TRD. The risk of developing TRD increased as time spent on opioid analgesics increased. Long-term opioid treatment of chronic pain may interfere with treatment of depression. PMID:27497660

Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation.

PubMed

Webster, Lynn R

2007-08-01

Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

Polyglycerol-opioid conjugate produces analgesia devoid of side effects.

PubMed

González-Rodríguez, Sara; Quadir, Mohiuddin A; Gupta, Shilpi; Walker, Karolina A; Zhang, Xuejiao; Spahn, Viola; Labuz, Dominika; Rodriguez-Gaztelumendi, Antonio; Schmelz, Martin; Joseph, Jan; Parr, Maria K; Machelska, Halina; Haag, Rainer; Stein, Christoph

2017-07-04

Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.

Pain Therapy Guided by Purpose and Perspective in Light of the Opioid Epidemic

PubMed Central

Severino, Amie L.; Shadfar, Arash; Hakimian, Joshua K.; Crane, Oliver; Singh, Ganeev; Heinzerling, Keith; Walwyn, Wendy M.

2018-01-01

Prescription opioid misuse is an ongoing and escalating epidemic. Although these pharmacological agents are highly effective analgesics prescribed for different types of pain, opioids also induce euphoria, leading to increasing diversion and misuse. Opioid use and related mortalities have developed in spite of initial claims that OxyContin, one of the first opioids prescribed in the USA, was not addictive in the presence of pain. These claims allayed the fears of clinicians and contributed to an increase in the number of prescriptions, quantity of drugs manufactured, and the unforeseen diversion of these drugs for non-medical uses. Understanding the history of opioid drug development, the widespread marketing campaign for opioids, the immense financial incentive behind the treatment of pain, and vulnerable socioeconomic and physical demographics for opioid misuse give perspective on the current epidemic as an American-born problem that has expanded to global significance. In light of the current worldwide opioid epidemic, it is imperative that novel opioids are developed to treat pain without inducing the euphoria that fosters physical dependence and addiction. We describe insights from preclinical findings on the properties of opioid drugs that offer insights into improving abuse-deterrent formulations. One finding is that the ability of some agonists to activate one pathway over another, or agonist bias, can predict whether several novel opioid compounds bear promise in treating pain without causing reward among other off-target effects. In addition, we outline how the pharmacokinetic profile of each opioid contributes to their potential for misuse and discuss the emergence of mixed agonists as a promising pipeline of opioid-based analgesics. These insights from preclinical findings can be used to more effectively identify opioids that treat pain without causing physical dependence and subsequent opioid abuse. PMID:29740351

Safety and efficacy of an oxycodone vaccine: Addressing some of the unique considerations posed by opioid abuse

PubMed Central

Peterson, S. J.; Laudenbach, M.; Baruffaldi, F.; Carroll, F. I.; Comer, S. D.; Navarro, H. A.; Langston, T. L.; Runyon, S. P.; Winston, S.; Pravetoni, M.; Pentel, P. R.

2017-01-01

Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose. PMID:29194445

Opioids Resistance in Chronic Pain Management

PubMed Central

Morrone, Luigi A.; Scuteri, Damiana; Rombolà, Laura; Mizoguchi, Hirokazu; Bagetta, Giacinto

2017-01-01

Abstract: Chronic pain management represents a serious healthcare problem worldwide. Chronic pain affects approximately 20% of the adult European population and is more frequent in women and older people. Unfortunately, its management in the community remains generally unsatisfactory and rarely under the control of currently available analgesics. Opioids have been used as analgesics for a long history and are among the most used drugs; however, while there is no debate over their short term use for pain management, limited evidence supports their efficacy of long-term treatment for chronic non-cancer pain. Therapy with opioids is hampered by inter-individual variability and serious side effects and some opioids often result ineffective in the treatment of chronic pain and their use is controversial. Accordingly, for a better control of chronic pain a deeper knowledge of the molecular mechanisms underlying resistance to opiates is mandatory. PMID:28503117

Trends and changes in prescription opioid analgesic dispensing in Canada 2005–2012: an update with a focus on recent interventions

PubMed Central

2014-01-01

Background Prescription opioid analgesic (POA) utilization has steeply increased globally, yet is far higher in established market economies than elsewhere. Canada features the world’s second-highest POA consumption rates. Following increases in POA-related harm, several POA control interventions have been implemented since 2010. Methods We examined trends and patterns in POA dispensing in Canada by province for 2005–2012, including a focus on the potential effects of interventions. Data on annual dispensing of individual POA formulations – categorized into ‘weak opioids’ and ‘strong opioids’ – from a representative sub-sample of 5,700 retail pharmacies across Canada (from IMS Brogan’s Compuscript) were converted into Defined Daily Doses (DDD), and examined intra- and inter-provincially as well as for Canada (total). Results Total POA dispensing – driven by strong opioids – increased across Canada until 2011; four provinces indicated decreases in strong opioid dispensing; seven provinces indicated decreases specifically in oxycodone dispensing, 2011–2012. The dispensing ratio weak/strong opioids decreased substantively. Major inter-provincial differences in POA dispensing levels and qualitative patterns of POA formulations dispensed persisted. Previous increasing trends in POA dispensing were reversed in select provinces 2011–2012, coinciding with POA-related interventions. Conclusions Further examinations regarding the sustained nature, drivers and consequences of the recent trend changes in POA dispensing – including possible ‘substitution effects’ for oxycodone reductions – are needed. PMID:24572005

System for tamper identification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bobbitt, III, John Thomas; Weeks, George E.

2017-09-05

A system for tamper identification. A fastener has a tamper identification surface with a unique grain structure that is altered if the fastener is removed or otherwise exposed to sufficient torque. After a period of time such as e.g., shipment and/or storage of the sealed container, a determination of whether tampering has occurred can be undertaken by examining the grain structure to determine if it has changed since the fastener was used to seal the container or secure the device.

21 CFR 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... dermatological, dentifrice, insulin, or lozenge product) for retail sale that is not packaged in a tamper..., dentifrice, insulin, or lozenge product) for retail sale shall package the product in a tamper-evident...

21 CFR 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... dermatological, dentifrice, insulin, or lozenge product) for retail sale that is not packaged in a tamper..., dentifrice, insulin, or lozenge product) for retail sale shall package the product in a tamper-evident...

21 CFR 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... dermatological, dentifrice, insulin, or lozenge product) for retail sale that is not packaged in a tamper..., dentifrice, insulin, or lozenge product) for retail sale shall package the product in a tamper-evident...

21 CFR 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... dermatological, dentifrice, insulin, or lozenge product) for retail sale that is not packaged in a tamper..., dentifrice, insulin, or lozenge product) for retail sale shall package the product in a tamper-evident...

21 CFR 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... dermatological, dentifrice, insulin, or lozenge product) for retail sale that is not packaged in a tamper..., dentifrice, insulin, or lozenge product) for retail sale shall package the product in a tamper-evident...

Tamper to delay motion and decrease ionization of a sample during short pulse x-ray imaging

DOEpatents

London, Richard A [Orinda, CA; Szoke,; Abraham, Hau-Riege [Fremont, CA; Stefan P. , Chapman; Henry, N [Livermore, CA

2007-06-26

A system for x-ray imaging of a small sample comprising positioning a tamper so that it is operatively connected to the sample, directing short intense x-ray pulses onto the tamper and the sample, and detecting an image from the sample. The tamper delays the explosive motion of the sample during irradiation by the short intense x-ray pulses, thereby extending the time to obtain an x-ray image of the original structure of the sample.

The prescription opioid epidemic: an overview for anesthesiologists.

PubMed

Alam, Asim; Juurlink, David N

2016-01-01

The objectives for preparing this article were to review the historical context and epidemiology surrounding the North American prescription opioid crisis, to summarize the evidence regarding the benefits and harms of long-term opioid therapy for non-cancer pain, and to outline ways in which anesthesiologists may help ameliorate the problem. We searched PubMed, Google Scholar, and EMBASE™ for relevant articles using various search terms, including pain, opioid epidemic, history of opioid use, perioperative care, and addiction. Related citations were further explored and searched depending on the specific subtopic of interest. In the 1980s and early 1990s, opioids were infrequently used for the treatment of chronic pain. Thereafter, however, physicians were gradually inculcated with the message that long-term opioid therapy was a safe and effective treatment option for patients with chronic non-cancer pain. Pharmaceutical companies supported this growing movement and employed aggressive and sometimes misleading marketing strategies for new opioid formulations. As a result, the practice of prescribing opioids flourished in the late 1990s. The surge in prescribing opioids was accompanied by a marked increase in opioid-related morbidity and mortality. This change in practice transpired despite the absence of randomized trials showing clinically significant benefit from the long-term use of opioids. Subsequently, however, a large and growing body of evidence has emerged quantifying the harms associated with long-term opioid therapy. Anesthesiologists widely prescribe opioids for acute and chronic pain; yet, as a group, they may be largely unaware of the current state of this growing epidemic and what role they can play to rectify this problem. Anesthesiologists are well positioned to take a leadership role in the management of postoperative discharge opioid therapy in an effort to curb the overutilization of opioids. Furthermore, anesthesiologists who regularly prescribe opioids for chronic pain patients should appreciate the limited evidence base for this practice and communicate the risks of opioid therapy to their patients.

National Institute on Drug Abuse International Program: improving opioid use disorder treatment through international research training.

PubMed

Gust, Steven W; McCormally, Judy

2018-07-01

For more than 25 years, the National Institute on Drug Abuse (NIDA) has supported research-training programs, establishing a global research network and expanding the knowledge base on substance use disorders. International research to inform approaches to opioid addiction is particularly important and relevant to the United States, where opioid misuse, addiction, and overdose constitute an emerging public health crisis. This article summarizes the NIDA International Program and illustrates its impact by reviewing recent articles about treatment approaches for opioid use disorders (OUD). Studies in several countries have demonstrated the effectiveness of physician office-based opioid substitution therapies. Other research has demonstrated the effectiveness of different formulations and doses of the opioid antagonist naltrexone, as well as different approaches to providing naloxone to treat opioid overdose. Continuing research into implementation of evidence-based treatment in international settings with limited resources is applicable to US regions that face similar structural, legal, and fiscal constraints. The current review describes international research on OUD treatment and opioid overdose, most coauthored by former NIDA fellows. The findings from outside the United States have important implications for best practices domestically and in other countries that are experiencing increases in OUD prevalence and related overdose deaths.

Trends in Tramadol: Pharmacology, Metabolism, and Misuse.

PubMed

Miotto, Karen; Cho, Arthur K; Khalil, Mohamed A; Blanco, Kirsten; Sasaki, Jun D; Rawson, Richard

2017-01-01

Tramadol is a unique analgesic medication, available in variety of formulations, with both monoaminergic reuptake inhibitory and opioid receptor agonist activity increasingly prescribed worldwide as an alternative for high-affinity opioid medication in the treatment of acute and chronic pain. It is a prodrug that is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 to its more potent opioid analgesic metabolites, particularly the O-demethylation product M1. The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects. The importance of the CYP metabolism has led to the adoption of computer clinical decision support with pharmacogenomics tools guiding tramadol treatment in major medical centers. Tramadol's simultaneous opioid agonist action and serotonin (5-HT) and norepinephrine reuptake inhibitory effects result in a unique side effect profile and important drug interactions that must be considered. Abrupt cessation of tramadol increases the risk for both opioid and serotonin-norepinephrine reuptake inhibitor withdrawal syndromes. This review provides updated important information on the pharmacology, pharmacokinetics, CYP genetic polymorphisms, drug interactions, toxicity, withdrawal, and illicit use of tramadol.

Naloxone for heroin, prescription opioid, and illicitly made fentanyl overdoses: Challenges and innovations responding to a dynamic epidemic.

PubMed

Fairbairn, Nadia; Coffin, Phillip O; Walley, Alexander Y

2017-08-01

Community-based overdose prevention programs first emerged in the 1990's and are now the leading public health intervention for overdose. Key elements of these programs are overdose education and naloxone distribution to people who use opioids and their social networks. We review the evolution of naloxone programming through the heroin overdose era of the 1990's, the prescription opioid era of the 2000's, and the current overdose crisis stemming from the synthetic opioid era of illicitly manufactured fentanyl and its analogues in the 2010's. We present current challenges arising in this new era of synthetic opioids, including variable potency of illicit drugs due to erratic adulteration of the drug supply with synthetic opioids, potentially changing efficacy of standard naloxone formulations for overdose rescue, potentially shorter overdose response time, and reports of fentanyl exposure among people who use drugs but are opioid naïve. Future directions for adapting naloxone programming to the dynamic opioid epidemic are proposed, including scale-up to new venues and social networks, new standards for post-overdose care, expansion of supervised drug consumption services, and integration of novel technologies to detect overdose and deliver naloxone. Copyright © 2017 Elsevier B.V. All rights reserved.

36 CFR 2.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 36 Parks, Forests, and Public Property 1 2014-07-01 2014-07-01 false Trespassing, tampering and... INTERIOR RESOURCE PROTECTION, PUBLIC USE AND RECREATION § 2.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property...

36 CFR 2.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 36 Parks, Forests, and Public Property 1 2013-07-01 2013-07-01 false Trespassing, tampering and... INTERIOR RESOURCE PROTECTION, PUBLIC USE AND RECREATION § 2.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property...

36 CFR 2.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false Trespassing, tampering and... INTERIOR RESOURCE PROTECTION, PUBLIC USE AND RECREATION § 2.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property...

36 CFR 2.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 36 Parks, Forests, and Public Property 1 2012-07-01 2012-07-01 false Trespassing, tampering and... INTERIOR RESOURCE PROTECTION, PUBLIC USE AND RECREATION § 2.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property...

36 CFR 2.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Trespassing, tampering and... INTERIOR RESOURCE PROTECTION, PUBLIC USE AND RECREATION § 2.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property...

40 CFR 205.58-2 - Tampering.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Tampering. 205.58-2 Section 205.58-2 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS TRANSPORTATION EQUIPMENT NOISE EMISSION CONTROLS Medium and Heavy Trucks § 205.58-2 Tampering. (a) For each configuration...

An abuse-deterrent, microsphere-in-capsule formulation of extended-release oxycodone: alternative modes of administration to facilitate pain management in patients with dysphagia.

PubMed

McCarberg, Bill H; Kopecky, Ernest A; O'Connor, Melinda; Marseilles, Ann; Varanasi, Ravi K; Thompson, Christy; Fleming, Alison B

2016-12-01

Patients with chronic pain may experience difficulty swallowing, in part due to worsening disease, comorbid conditions, iatrogenic etiology, or age. Patients or caregivers may manipulate extended-release (ER) opioid formulations to facilitate oral dosing due to a lack of therapeutic options that allow for sprinkle or enteral feeding tube administration. If crushed or broken, current oral ER opioids can be associated with adverse sequelae, including risk of potentially fatal overdose. To review the safety, in vitro dissolution data, and in vivo pharmacokinetic data that support alternative modes of administration of oxycodone DETERx (Xtampza ER) via sprinkling onto soft foods for oral ingestion or via enteral feeding tubes. A review of oxycodone DETERx data from in vitro and in vivo studies was conducted to demonstrate support for alternative routes and modes of administration. There was no difference in the dissolution profile when administered with various soft foods or when mixed with various liquid vehicles and administered via nasogastric (NG) or gastrostomy (G) tubes, based on in vitro studies. When sprinkled onto applesauce and administered orally, the microspheres were bioequivalent to the intact oxycodone capsules. When crushed or chewed, the formulation maintained its pharmacokinetic profile; no bolus dose of opioid was released. The sprinkle-dose study was limited by the single-dose study design, as well as the small sample size. Oxycodone DETERx is the first ER oxycodone formulation that can be administered either intact, sprinkled onto soft foods, or via NG/G tubes, thereby providing options for treating pain in patients who have difficulty swallowing.

36 CFR 1002.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Trespassing, tampering and..., PUBLIC USE AND RECREATION § 1002.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property or real property not open...

36 CFR § 1002.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Trespassing, tampering and... PROTECTION, PUBLIC USE AND RECREATION § 1002.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property or real property not open...

36 CFR 1002.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Trespassing, tampering and..., PUBLIC USE AND RECREATION § 1002.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property or real property not open...

36 CFR 1002.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 false Trespassing, tampering and..., PUBLIC USE AND RECREATION § 1002.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property or real property not open...

36 CFR 1002.31 - Trespassing, tampering and vandalism.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Trespassing, tampering and..., PUBLIC USE AND RECREATION § 1002.31 Trespassing, tampering and vandalism. (a) The following are prohibited: (1) Trespassing. Trespassing, entering or remaining in or upon property or real property not open...

49 CFR Appendix C to Part 218 - Statement of Agency Enforcement Policy on Tampering

Code of Federal Regulations, 2014 CFR

2014-10-01

... Tampering C Appendix C to Part 218 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Pt. 218, App. C Appendix C to Part 218—Statement of Agency Enforcement Policy on Tampering The Rail Safety Improvement Act...

49 CFR Appendix C to Part 218 - Statement of Agency Enforcement Policy on Tampering

Code of Federal Regulations, 2013 CFR

2013-10-01

... Tampering C Appendix C to Part 218 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Pt. 218, App. C Appendix C to Part 218—Statement of Agency Enforcement Policy on Tampering The Rail Safety Improvement Act...

49 CFR Appendix C to Part 218 - Statement of Agency Enforcement Policy on Tampering

Code of Federal Regulations, 2010 CFR

2010-10-01

... Tampering C Appendix C to Part 218 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Pt. 218, App. C Appendix C to Part 218—Statement of Agency Enforcement Policy on Tampering The Rail Safety Improvement Act...

Long-term course of opioid addiction.

PubMed

Hser, Yih-Ing; Evans, Elizabeth; Grella, Christine; Ling, Walter; Anglin, Douglas

2015-01-01

Opioid addiction is associated with excess mortality, morbidities, and other adverse conditions. Guided by a life-course framework, we review the literature on the long-term course of opioid addiction in terms of use trajectories, transitions, and turning points, as well as other factors that facilitate recovery from addiction. Most long-term follow-up studies are based on heroin addicts recruited from treatment settings (mostly methadone maintenance treatment), many of whom are referred by the criminal justice system. Cumulative evidence indicates that opioid addiction is a chronic disorder with frequent relapses. Longer treatment retention is associated with a greater likelihood of abstinence, whereas incarceration is negatively related to subsequent abstinence. Over the long term, the mortality rate of opioid addicts (overdose being the most common cause) is about 6 to 20 times greater than that of the general population; among those who remain alive, the prevalence of stable abstinence from opioid use is low (less than 30% after 10-30 years of observation), and many continue to use alcohol and other drugs after ceasing to use opioids. Histories of sexual or physical abuse and comorbid mental disorders are associated with the persistence of opioid use, whereas family and social support, as well as employment, facilitates recovery. Maintaining opioid abstinence for at least five years substantially increases the likelihood of future stable abstinence. Recent advances in pharmacological treatment options (buprenorphine and naltrexone) include depot formulations offering longer duration of medication; their impact on the long-term course of opioid addiction remains to be assessed.

DEVELOPMENT OF A TAMPER RESISTANT/INDICATING AEROSOL COLLECTION SYSTEM FOR ENVIRONMENTAL SAMPLING AT BULK HANDLING FACILITIES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sexton, L.

2012-06-06

Environmental sampling has become a key component of International Atomic Energy Agency (IAEA) safeguards approaches since its approval for use in 1996. Environmental sampling supports the IAEA's mission of drawing conclusions concerning the absence of undeclared nuclear material or nuclear activities in a Nation State. Swipe sampling is the most commonly used method for the collection of environmental samples from bulk handling facilities. However, augmenting swipe samples with an air monitoring system, which could continuously draw samples from the environment of bulk handling facilities, could improve the possibility of the detection of undeclared activities. Continuous sampling offers the opportunity tomore » collect airborne materials before they settle onto surfaces which can be decontaminated, taken into existing duct work, filtered by plant ventilation, or escape via alternate pathways (i.e. drains, doors). Researchers at the Savannah River National Laboratory and Oak Ridge National Laboratory have been working to further develop an aerosol collection technology that could be installed at IAEA safeguarded bulk handling facilities. The addition of this technology may reduce the number of IAEA inspector visits required to effectively collect samples. The principal sample collection device is a patented Aerosol Contaminant Extractor (ACE) which utilizes electrostatic precipitation principles to deposit particulates onto selected substrates. Recent work has focused on comparing traditional swipe sampling to samples collected via an ACE system, and incorporating tamper resistant and tamper indicating (TRI) technologies into the ACE system. Development of a TRI-ACE system would allow collection of samples at uranium/plutonium bulk handling facilities in a manner that ensures sample integrity and could be an important addition to the international nuclear safeguards inspector's toolkit. This work was supported by the Next Generation Safeguards Initiative (NGSI), Office of Nonproliferation and International Security (NIS), National Nuclear Security Administration (NNSA).« less

25 CFR 11.440 - Tampering with or fabricating physical evidence.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 25 Indians 1 2014-04-01 2014-04-01 false Tampering with or fabricating physical evidence. 11.440 Section 11.440 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAW AND ORDER COURTS OF INDIAN OFFENSES AND LAW AND ORDER CODE Criminal Offenses § 11.440 Tampering with or fabricating physical evidence...

25 CFR 11.440 - Tampering with or fabricating physical evidence.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 25 Indians 1 2011-04-01 2011-04-01 false Tampering with or fabricating physical evidence. 11.440 Section 11.440 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAW AND ORDER COURTS OF INDIAN OFFENSES AND LAW AND ORDER CODE Criminal Offenses § 11.440 Tampering with or fabricating physical evidence...

50 CFR 27.65 - Tampering with vehicles and equipment.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 50 Wildlife and Fisheries 8 2011-10-01 2011-10-01 false Tampering with vehicles and equipment. 27.65 Section 27.65 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM PROHIBITED ACTS Disturbing Violations: Against Nonwildlife Property § 27.65 Tampering with...

50 CFR 27.65 - Tampering with vehicles and equipment.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 50 Wildlife and Fisheries 9 2012-10-01 2012-10-01 false Tampering with vehicles and equipment. 27.65 Section 27.65 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM PROHIBITED ACTS Disturbing Violations: Against Nonwildlife Property § 27.65 Tampering with...

Security of fragile authentication watermarks with localization

NASA Astrophysics Data System (ADS)

Fridrich, Jessica

2002-04-01

In this paper, we study the security of fragile image authentication watermarks that can localize tampered areas. We start by comparing the goals, capabilities, and advantages of image authentication based on watermarking and cryptography. Then we point out some common security problems of current fragile authentication watermarks with localization and classify attacks on authentication watermarks into five categories. By investigating the attacks and vulnerabilities of current schemes, we propose a variation of the Wong scheme18 that is fast, simple, cryptographically secure, and resistant to all known attacks, including the Holliman-Memon attack9. In the new scheme, a special symmetry structure in the logo is used to authenticate the block content, while the logo itself carries information about the block origin (block index, the image index or time stamp, author ID, etc.). Because the authentication of the content and its origin are separated, it is possible to easily identify swapped blocks between images and accurately detect cropped areas, while being able to accurately localize tampered pixels.

Novel Oral Therapies for Opioid-induced Bowel Dysfunction in Patients with Chronic Noncancer Pain.

PubMed

Holder, Renee M; Rhee, Diane

2016-03-01

Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting μ-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting μ-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are needed to further define their role in therapy. © 2016 Pharmacotherapy Publications, Inc.

Integrated optical tamper sensor with planar waveguide

DOEpatents

Carson, Richard F.; Casalnuovo, Stephen A.

1993-01-01

A monolithic optical tamper sensor, comprising an optical emitter and detector, connected by an optical waveguide and placed into the critical entry plane of an enclosed sensitive region, the tamper sensor having a myriad of scraps of a material optically absorbent at the wavelength of interest, such that when the absorbent material is in place on the waveguide, an unique optical signature can be recorded, but when entry is attempted into the enclosed sensitive region, the scraps of absorbent material will be displaced and the optical/electrical signature of the tamper sensor will change and that change can be recorded.

Integrated optical tamper sensor with planar waveguide

DOEpatents

Carson, R.F.; Casalnuovo, S.A.

1993-01-05

A monolithic optical tamper sensor, comprising an optical emitter and detector, connected by an optical waveguide and placed into the critical entry plane of an enclosed sensitive region, the tamper sensor having a myriad of scraps of a material optically absorbent at the wavelength of interest, such that when the absorbent material is in place on the waveguide, an unique optical signature can be recorded, but when entry is attempted into the enclosed sensitive region, the scraps of absorbent material will be displaced and the optical/electrical signature of the tamper sensor will change and that change can be recorded.

A Tamper-Resistant Programming Language System

DTIC Science & Technology

2006-06-02

www.cs.ucsb.edu/~vigna/listpub.html). [15] Gassend, B ., D. Clarke, M. van Dijk, S. Devadas , and E. Suh, “Caches and Merkle Trees for Efficient Memory...CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 23 19a. NAME OF RESPONSIBLE PERSON a. REPORT unclassified b . ABSTRACT...winhec/papers03.mspx). [3] Barak, B ., O. Goldreich, R. Impagliazzo, S. Rudich, A. Sahai, S. Vadhan, and K.Yang, “On the (Im)possibility of Obfuscating

A source-channel coding approach to digital image protection and self-recovery.

PubMed

Sarreshtedari, Saeed; Akhaee, Mohammad Ali

2015-07-01

Watermarking algorithms have been widely applied to the field of image forensics recently. One of these very forensic applications is the protection of images against tampering. For this purpose, we need to design a watermarking algorithm fulfilling two purposes in case of image tampering: 1) detecting the tampered area of the received image and 2) recovering the lost information in the tampered zones. State-of-the-art techniques accomplish these tasks using watermarks consisting of check bits and reference bits. Check bits are used for tampering detection, whereas reference bits carry information about the whole image. The problem of recovering the lost reference bits still stands. This paper is aimed at showing that having the tampering location known, image tampering can be modeled and dealt with as an erasure error. Therefore, an appropriate design of channel code can protect the reference bits against tampering. In the present proposed method, the total watermark bit-budget is dedicated to three groups: 1) source encoder output bits; 2) channel code parity bits; and 3) check bits. In watermark embedding phase, the original image is source coded and the output bit stream is protected using appropriate channel encoder. For image recovery, erasure locations detected by check bits help channel erasure decoder to retrieve the original source encoded image. Experimental results show that our proposed scheme significantly outperforms recent techniques in terms of image quality for both watermarked and recovered image. The watermarked image quality gain is achieved through spending less bit-budget on watermark, while image recovery quality is considerably improved as a consequence of consistent performance of designed source and channel codes.

Development of a video tampering dataset for forensic investigation.

PubMed

Ismael Al-Sanjary, Omar; Ahmed, Ahmed Abdullah; Sulong, Ghazali

2016-09-01

Forgery is an act of modifying a document, product, image or video, among other media. Video tampering detection research requires an inclusive database of video modification. This paper aims to discuss a comprehensive proposal to create a dataset composed of modified videos for forensic investigation, in order to standardize existing techniques for detecting video tampering. The primary purpose of developing and designing this new video library is for usage in video forensics, which can be consciously associated with reliable verification using dynamic and static camera recognition. To the best of the author's knowledge, there exists no similar library among the research community. Videos were sourced from YouTube and by exploring social networking sites extensively by observing posted videos and rating their feedback. The video tampering dataset (VTD) comprises a total of 33 videos, divided among three categories in video tampering: (1) copy-move, (2) splicing, and (3) swapping-frames. Compared to existing datasets, this is a higher number of tampered videos, and with longer durations. The duration of every video is 16s, with a 1280×720 resolution, and a frame rate of 30 frames per second. Moreover, all videos possess the same formatting quality (720p(HD).avi). Both temporal and spatial video features were considered carefully during selection of the videos, and there exists complete information related to the doctored regions in every modified video in the VTD dataset. This database has been made publically available for research on splicing, Swapping frames, and copy-move tampering, and, as such, various video tampering detection issues with ground truth. The database has been utilised by many international researchers and groups of researchers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Secure RFID tag or sensor with self-destruction mechanism upon tampering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nekoogar, Faranak; Dowla, Farid; Twogood, Richard

A circuit board anti-tamper mechanism comprises a circuit board having a frangible portion, a trigger having a trigger spring, a trigger arming mechanism actuated by the trigger wherein the trigger arming mechanism is initially non-actuated, a force producing mechanism, a latch providing mechanical communication between the trigger arming mechanism and the force producing mechanism, wherein the latch initially retains the force producing mechanism in a refracted position. Arming pressure applied to the trigger sufficient to overcome the trigger spring force will actuate the trigger arming mechanism, causing the anti-tamper mechanism to be armed. Subsequent tampering with the anti-tamper mechanism resultsmore » in a decrease of pressure on the trigger below the trigger spring force, thereby causing the trigger arming mechanism to actuate the latch, thereby releasing the force producing mechanism to apply force to the frangible portion of the circuit board, thereby breaking the circuit board.« less

Estimating attractiveness for abuse of a not-yet-marketed "abuse-deterrent" prescription opioid formulation.

PubMed

Butler, Stephen F; Black, Ryan; Grimes Serrano, Jill M; Folensbee, Lesley; Chang, Alan; Katz, Nathaniel

2010-01-01

The present study builds on research to model abusers' perceptions of particular analgesics' attractiveness for abuse and extends these methods to derive an estimate of attractiveness for abuse of a not-yet-marketed abuse-deterrent formulation (ADF) of a prescription opioid (Remoxy), Pain Therapeutics, Inc., San Mateo, CA, and King Pharmaceuticals, Inc., Bristol, TN). In a previous study, the Opioid Attractiveness Technology Scaling (OATS) method identified, from a drug abuser's point of view, the particular features of a prescription opioid relevant to its attractiveness for recreational use. A second online sample rated the extent to which these features applied to particular products they had actually used/abused. These data were used to model the abusers' overall preference for prescription opioids they had used/abused. In the present study, this method was applied to a not-yet-marketed ADF using substance abuse counselors as proxies for prescription opioid abusers. Thirty-eight counselors were given materials describing the new ADF along with four known products. Thirty-two counselors demonstrated sufficient agreement with abusers' ratings of the overall attractiveness of these drugs. The overall model yielded a significant pseudo R(2) of 0.15 (P < 0.001), with increasing model fit based on preferred route of administration, from swallowing whole (pseudo R(2) = 0.06; P < 0.001) and best for those who preferred to inject (pseudo R(2) = 0.40; P < 0.001). Data from a cross-validation group of 16 counselors/proxies were used to calculate the OATS scores for the five rated drugs and revealed significant differences between the ADF and OxyContin (Purdue Pharma LP, Stamford, CT), Percocet (Endo Pharmaceuticals, Chadds Ford, PA), and Vicodin (Abbott Laboratories, Abbott Park, IL), but not Talwin NX (Sanofi-aventis, Bridgewater, NJ), which was identified in the prior study as a highly unattractive drug for recreational purposes. The OATS method shows promise for providing pre-marketing estimates of attractiveness for abuse of not-yet-marketed ADFs.

A Systematic Content Analysis of Policy Barriers Impeding Access to Opioid Medication in Central and Eastern Europe: Results of ATOME.

PubMed

Larjow, Eugenia; Papavasiliou, Evangelia; Payne, Sheila; Scholten, Willem; Radbruch, Lukas

2016-01-01

Reliable access to opioid medication is critical to delivering effective pain management, adequate treatment of opioid dependence, and quality palliative care. However, more than 80% of the world population is estimated to be inadequately treated for pain because of difficulties in accessing opioids. Although barriers to opioid access are primarily associated with restrictive laws, regulations, and licensing requirements, a key problem that significantly limits opioid access relates to policy constraints. To identify and explore policy barriers to opioid access in 12 Eastern and Central European countries involved in the Access to Opioid Medication in Europe project, funded by the European Community's Seventh Framework (FP7/2007-2013, no. 222994) Programme. A systematic content analysis of texts retrieved from documents (e.g., protocols of national problem analyses, strategic planning worksheets, and executive summaries) compiled, reviewed, approved, and submitted by either the Access to Opioid Medication in Europe consortium or the national country teams (comprising experts in pain management, harm reduction, and palliative care) between September 2011 and April 2014 was performed. Twenty-five policy barriers were identified (e.g., economic crisis, bureaucratic issues, lack of training initiatives, stigma, and discrimination), classified under four predetermined categories (financial/economic aspects and governmental support, formularies, education and training, and societal attitudes). Key barriers related to issues of funding allocation, affordability, knowledge, and fears associated with opioids. Reducing barriers and improving access to opioids require policy reform at the governmental level with a set of action plans being formulated and concurrently implemented and aimed at different levels of social, education, and economic policy change. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Impact of abuse-deterrent OxyContin on prescription opioid utilization.

PubMed

Hwang, Catherine S; Chang, Hsien-Yen; Alexander, G Caleb

2015-02-01

We quantified the degree to which the August 2010 reformulation of abuse-deterrent OxyContin affected its use, as well as the use of alternative extended-release and immediate-release opioids. We used the IMS Health National Prescription Audit, a nationally representative source of prescription activity in the USA, to conduct a segmented time-series analysis of the use of OxyContin and other prescription opioids. Our primary time period of interest was 12 months prior to and following August 2010. We performed model checks and sensitivity analyses, such as adjusting for marketing and promotion, using alternative lag periods, and adding extra observation points. OxyContin sales were similar before and after the August 2010 reformulation, with approximately 550 000 monthly prescriptions. After adjusting for declines in the generic extended-release oxycodone market, the formulation change was associated with a reduction of approximately 18 000 OxyContin prescription sales per month (p = 0.02). This decline corresponded to a change in the annual growth rate of OxyContin use, from 4.9% prior to the reformulation to -23.8% during the year after the reformulation. There were no statistically significant changes associated with the sales of alternative extended-release (p = 0.42) or immediate-release (p = 0.70) opioids. Multiple sensitivity analyses supported these findings and their substantive interpretation. The market debut of abuse-deterrent OxyContin was associated with declines in its use after accounting for the simultaneous contraction of the generic extended-release oxycodone market. Further scrutiny into the effect of abuse-deterrent formulations on medication use and health outcomes is vital given their popularity in opioid drug development. Copyright © 2014 John Wiley & Sons, Ltd.

Using Focus Groups to Study Consumer Understanding and Experiences with Tamper-Evident Packaging Devices

ERIC Educational Resources Information Center

Pascall, Melvin A.; Lee, Ken; Fraser, Angela; Halim, Linna

2009-01-01

A focus group with an educational component was used to help initiate a new research hypothesis. Early-stage development of a new tamper-evident invention was improved with input from a consumer focus group. The focus group comprised consumers who were shown several tamper-evident devices, including a new color-changing cap under active…

Development of a Whole Container Seal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuhn, Michael J; Pickett, Chris A; Stinson, Brad J

This paper outlines a technique for utilizing electrically conductive textiles as a whole container seal. This method has the potential to provide more robustness for ensuring that the container has not been breached versus conventional sealing methods that only provide tamper indication at the area used for normal access. The conductive textile is used as a distributed sensor for detecting and localizing container tamper or breach. For sealing purposes, the conductive fabric represents a bounded, near-infinite grid of resistors. The well-known infinite resistance grid problem was used to model and confirm the expected accuracy and validity of this approach. Anmore » experimental setup was built that uses a multiplexed Wheatstone bridge measurement to determine the resistances of a coarse electrode grid across the conductive fabric. Non-uniform resistance values of the grid infer the presence of damage or tears in the fabric. Results suggest accuracy proportional to the electrode spacing in determining the presence and location of disturbances in conductive fabric samples. Current work is focused on constructing experimental prototypes for field and environmental testing to gauge the performance of these whole container seals in real world conditions. We are also developing software and hardware to interface with the whole container seals. The latest prototypes are expected to provide more accuracy in detecting and localizing events, although detection of a penetration should be adequate for most sealing applications. We are also developing smart sensing nodes that integrate digital hardware and additional sensors (e.g., motion, humidity) into the electrode nodes within the whole container seal.« less

Fentanyl Buccal Tablet for the Treatment of Breakthrough Pain: Pharmacokinetics of Buccal Mucosa Delivery and Clinical Efficacy

PubMed Central

Darwish, Mona; Hamed, Ehab; Messina, John

2010-01-01

The treatment of breakthrough pain (BTP), a transitory exacerbation of pain that occurs on a background of otherwise-controlled, persistent pain, requires an opioid formulation and/or method of administration that can provide rapid and extensive systemic exposure. Fentanyl buccal tablet (FBT; FENTORA®, Cephalon, Inc.) employs OraVescent® drug delivery technology, which enhances the rate and extent of fentanyl absorption. OraVescent technology enhances the oral dissolution and buccal absorption of fentanyl, which facilitates rapid uptake of fentanyl into the bloodstream, reducing gastrointestinal absorption and minimizing extensive first-pass metabolism. The resulting pharmacokinetic profile of FBT is characterized by greater bioavailability and a higher early systemic exposure compared with the earlier oral transmucosal fentanyl citrate formulation. In clinical studies of opioid-tolerant patients with cancer-related and noncancer-related BTP, FBT has provided consistent and clinically relevant improvements in pain intensity and pain relief relative to placebo, with a safety and tolerability profile that is generally typical of that observed with other potent opioids. The pharmacokinetic properties of FBT allow for meaningful clinical efficacy, with an onset of action that closely matches the onset of BTP. PMID:20634985

Curcumin Attenuates Opioid Tolerance and Dependence by Inhibiting Ca2+/Calmodulin-Dependent Protein Kinase II α Activity

PubMed Central

Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena

2015-01-01

Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug’s poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose-dependent manner, with ED50 values of 3.9 and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50 = 12.6 mg/kg p.o.) and dependence (ED50 = 3.1 mg/kg p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1–10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity. PMID:25515789

Review of extended-release formulations of Tramadol for the management of chronic non-cancer pain: focus on marketed formulations

PubMed Central

Kizilbash, Arshi; Ngô-Minh, Cường

2014-01-01

Patients with chronic non-malignant pain report impairments of physical, social, and psychological well-being. The goal of pain management should include reducing pain and improving quality of life. Patients with chronic pain require medications that are able to provide adequate pain relief, have minimum dosing intervals to maintain efficacy, and avoid breakthrough pain. Tramadol has proven efficacy and a favourable safety profile. The positive efficacy and safety profile has been demonstrated historically in numerous published clinical studies as well as from post-marketing experience. It is a World Health Organization “Step 2” opioid analgesic that has been shown to be effective, well-tolerated, and valuable, where treatment with strong opioids is not required. A number of extended release formulations of Tramadol are available in Canada and the United States. An optimal extended release Tramadol formulation would be expected to provide consistent pain control with once daily dosing, few sleep interruptions, flexible dosing schedules, and no limitation on taking with meals. Appropriate treatment options should be based on the above proposed attributes. A comparative review of available extended release Tramadol formulations shows that these medications are not equivalent in their pharmacokinetic profile and this may have implications for selecting the optimal therapy for patients with pain syndromes where Tramadol is an appropriate analgesic agent. Differences in pharmacokinetics amongst the formulations may also translate into varied clinical responses in patients. Selection of the appropriate formulation by the health care provider should therefore be based on the patient’s chronic pain condition, needs, and lifestyle. PMID:24711710

Reimbursement of analgesics for chronic pain.

PubMed

Pedersen, Line; Hansen, Anneli Borge; Svendsen, Kristian; Skurtveit, Svetlana; Borchgrevink, Petter C; Fredheim, Olav Magnus S

2012-11-27

The prevalence of chronic non-malignant pain in Norway is between 24% and 30%. The proportion of the population using opioids for non-malignant pain on a long-term basis is around 1%. The purpose of our study was to investigate how many were prescribed analgesics on reimbursable prescription under reimbursement code -71 (chronic non-malignant pain) in 2009 and 2010, which analgesics were prescribed and whether prescribing practices were in accordance with national guidelines. We retrieved pseudonymised data from the National Prescription Database on all those who received drugs with reimbursement code -71 in 2009 and 2010. The data contain information on drug, dosage, formulation, reimbursement code and date of issue. 90,731 patients received reimbursement for drugs indicated for chronic non-malignant pain in 2010. Of these, 6,875 were given opioids, 33,242 received paracetamol, 25,865 non-steroid inflammatory drugs (NSAIDs), 20,654 amitryptiline and 16,507 gabapentin. Oxycodone was the most frequently prescribed opioid, followed by buprenorphine, tramadol and codeine/paracetamol. Of those who were prescribed opioids, 4,047 (59%) received mainly slow-release opioids, 2,631 (38%) also received benzodiazepines and 2,418 (35%) received benzodiazepine-like sleep medications. The number of patients who received analgesics and opioids on reimbursable prescriptions was low compared to the proportion of the population with chronic pain and the proportion using opioids long-term. 38% of those reimbursed for opioids also used benzodiazepines, which is contrary to official Norwegian guidelines.

High-dose buprenorphine: perioperative precautions and management strategies.

PubMed

Roberts, D M; Meyer-Witting, M

2005-02-01

Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.

Primary Care Physicians' Knowledge and Attitudes Regarding Prescription Opioid Abuse and Diversion.

PubMed

Hwang, Catherine S; Turner, Lydia W; Kruszewski, Stefan P; Kolodny, Andrew; Alexander, G Caleb

2016-04-01

Physicians are a key stakeholder in the epidemic of prescription opioid abuse. Therefore, we assessed their knowledge of opioid abuse and diversion, as well as their support for clinical and regulatory interventions to reduce opioid-related morbidity and mortality. We conducted a nationally representative postal mail survey of 1000 practicing internists, family physicians, and general practitioners in the United States between February and May 2014. The adjusted response rate was 58%, and all physicians (100%) believed that prescription drug abuse was a problem in their communities. However, only two-thirds (66%) correctly reported that the most common route of abuse was swallowing pills whole, and nearly one-half (46%) erroneously reported that abuse-deterrent formulations were less addictive than their counterparts. In addition, a notable minority of physicians (25%) reported being "not at all" or "only slightly concerned" about the potential for opioid diversion from the licit to the illicit market when this practice is common at all levels of the pharmaceutical supply chain. Most physicians supported clinical and regulatory interventions to reduce prescription opioid abuse, including the use of patient contracts (98%), urine drug testing (90%), requiring prescribers to check a centralized database before prescribing opioids (88%), and instituting greater restrictions on the marketing and promotion of opioids (77% to 82%). Despite this, only one-third of physicians (33%) believed that interventions to reduce prescription opioid abuse had a moderate or large effect on preventing patients' clinically appropriate access to pain treatment. Although physicians are unaware of some facets of prescription opioid-related morbidity, most support a variety of clinical and regulatory interventions to improve the risk-benefit balance of these therapies.

Opioid Challenge Evaluation of Blockade by Extended-Release Naltrexone in Opioid-Abusing Adults: Dose-Effects and Time-Course

PubMed Central

Bigelow, George E.; Preston, Kenzie L.; Schmittner, John; Dong, Qunming; Gastfriend, David R.

2013-01-01

Background Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans. Methods Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-hr intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) Visual Analog Scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade. Results Blockade of the VAS “any drug effect” response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150 and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing. Conclusions These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment. PMID:22079773

Strategies to Prevent Opioid Misuse, Abuse, and Diversion That May Also Reduce the Associated Costs

PubMed Central

Hahn, Kathryn L.

2011-01-01

Background The use of prescription opioid drugs has the potential to lead to patient abuse of these medications, addiction, and diversion. Such an abuse is associated with increased costs because of excessive healthcare utilization. Finding ways to minimize the risk for abuse and addiction can enhance patient outcomes and reduce costs to patients and to payers. Objective To review current strategies that may reduce the risk for misuse and abuse of opioid medications, which in turn can enhance patient outcomes and lower costs to health insurers and patients. Discussion Implementing approaches that will encourage the use of safe practices (universal precautions) in pain management by providers can reduce the risk for abuse and misuse associated with chronic pain medications, especially opioids. These approaches include, but are not limited to, extensive physician and patient education regarding these medications and their associated risks for abuse; the development of prescription monitoring programs to detect physician or pharmacy shopping; the detection of inappropriate prescribing and medical errors; the use of physician-patient contracts concerning opioid treatment; the requirement of presenting a photo identification to pick up an opioid prescription at the pharmacy; urine drug toxicology screening; provisions for safe disposal of unused opioids; referrals to pain and addiction specialists; and potentially encouraging the use of opioid formulations aimed at reducing abuse. Conclusion Supporting such approaches by health insurers and educating providers and patients on the risks associated with chronic pain medications can help minimize the risk of prescription opioid abuse, addiction, and diversion; reduce health services utilization associated with opioid abuse; improve patient outcomes; and reduce overall costs. PMID:25126342

Non-contact tamper sensing by electronic means

DOEpatents

Gritton, Dale G.

1993-01-01

A tamper-sensing system for an electronic tag 10 which is to be fixed to a surface 11 of an article 12, the tamper-sensing system comprising a capacitor having two non-contacting, capacitively-coupled elements 16, 19. Fixing of the body to the article will establish a precise location of the capacitor elements 16 and 19 relative to each other. When interrogated, the tag will generate a tamper-sensing signal having a value which is a function of the amount of capacity of the capacitor elements. The precise relative location of the capacitor elements cannot be duplicated if the tag is removed and affixed to a surrogate article having a fiducial capacitor element 19 fixed thereto. A very small displacement, in the order of 2-10 microns, of the capacitor elements relative to each other if the tag body is removed and fixed to a surrogate article will result in the tamper-sensing signal having a different, and detectable, value when the tag is interrogated.

A graphite oxide (GO)-based remote readable tamper evident seal

DOE PAGES

Cattaneo, Alessandro; Bossert, Jason Andrew; Guzman, Christian; ...

2016-09-08

Here, this paper presents a prototype of a remotely readable graphite oxide (GO) paper-based tamper evident seal. The proposed device combines the tunable electrical properties offered by reduced graphite oxide (RGO) with a compressive sampling scheme. The benefit of using RGO as a tamper evident seal material is the sensitivity of its electrical properties to the common mechanisms adopted to defeat tamper-evident seals. RGO’s electrical properties vary upon local stress or cracks induced by mechanical action (e.g., produced by shimming or lifting attacks). Further, modification of the seal’s electrical properties can result from the incidence of other defeat mechanisms, suchmore » as temperature changes, solvent treatment and steam application. The electrical tunability of RGO enables the engraving of a circuit on the area of the tamper evident seal intended to be exposed to malicious attacks. The operation of the tamper evident seal, as well as its remote communication functionality, is supervised by a microcontroller unit (MCU). The MCU uses the RGO-engraved circuitry to physically implement a compressive sampling acquisition procedure. The compressive sampling scheme provides the seal with self-authentication and self-state-of-health awareness capabilities. Finally, the prototype shows potential for use in low-power, embedded, remote-operation nonproliferation security related applications.« less

Sociodemographic profile and pattern of opioid abuse among patients presenting to a de-addiction centre in tertiary care Hospital of Kashmir

PubMed Central

Farhat, Samina; Hussain, Syed Sajad; Rather, Yasir Hassan; Hussain, Syed Karrar

2015-01-01

Background: The substances abuse has become one of the major public health problems of present society. Recently there has been an increase in the incidence of substance abuse including that of opioids throughout the world. The proper assessment of the current trends and pattern of opioid abuse can be helpful in more effective intervention of this menace. Materials and Methods: To find out various socio-demographic variables and pattern of opioid abuse, a predevised questionnaire was administered to 200 opioid patients who presented to de-addiction center for treatment. Results: Majority of the participants (75%) were of young age group (20–30 years) and the mean age of subjects was 27.6 years. More than half of participants (55%) were abusing the opioid substances for < 3 years followed by 30% of the abusers who were using the opioids for 4–6 years. Oral route was the most common route(35%)of substance administration followed by chasing(13%) and intravenous(11%) routes. Diverted pharmaceuticals emerged as one of the common substances of abuse, and peer pressure was found to be the main reason to start substance abuse. Conclusion: A comprehensive preventive program targeting young adults needs to be formulated and strict laws against sales of diverted pharmaceuticals to be implemented. PMID:26229346

The opioid crisis: past, present and future policy climate in Ontario, Canada.

PubMed

Morin, Kristen A; Eibl, Joseph K; Franklyn, Alexandra M; Marsh, David C

2017-11-02

Addressing opioid use disorder has become a priority in Ontario, Canada, because of its high economic, social and health burden. There continues to be stigma and criticism relating to opioid use disorder and treatment options. The result has been unsystematic, partial, reactive policies and programs developed based on divergent points of view. The aim of this manuscript is to describe how past and present understandings, narratives, ideologies and discourse of opioid use, have impacted policies over the course of the growing opioid crisis. Assessing the impact of policy is complex. It involves consideration of conceptual issues of what impacts policy change. In this manuscript we argue that the development of polices and initiatives regarding opioids, opioid use disorder and opioid agonist treatment in the last decade, have been more strongly associated with the evolution of ideas, narratives and discourses rather than research relating to opioids. We formulate our argument using a framework by Sumner, Crichton, Theobald, Zulu, and Parkhurs. We use examples from the Canadian context to outline our argument such as: the anti- drug legislation from the Canadian Federal Conservative government in 2007; the removal of OxyContin™ from the drug formulary in 2012; the rapid expansion of opioid agonist treatment beginning in the early 2000s, the unilateral decision made regarding fee cuts for physicians providing opioid agonist treatment in 2015; and the most recent implementation of a narcotics monitoring system, which are all closely linked with the shifts in public opinion and discourse at the time of which these policies and programs are implemented. We conclude with recommendations to consider a multifactorial response using evidence and stakeholder engagement to address the opioid crisis, rather than a reactive policy approach. We suggest that researchers have an important role in shaping future policy by reframing ideas through knowledge translation, formation of values, creation of new knowledge and adding to the quality of public discourse and debate.

Use of Pharmacotherapies in the Treatment of Alcohol Use Disorders and Opioid Dependence in Primary Care

PubMed Central

Lee, Jinhee; Kresina, Thomas F.; Campopiano, Melinda; Lubran, Robert; Clark, H. Westley

2015-01-01

Substance-related and addictive disorders are chronic relapsing conditions that substantially impact public health. Effective treatments for these disorders require addressing substance use/dependence comprehensively as well as other associated comorbidities. Comprehensive addressing of substance use in a medical setting involves screening for substance use, addressing substance use directly with the patient, and formulating an appropriate intervention. For alcohol dependence and opioid dependence, pharmacotherapies are available that are safe and effective when utilized in a comprehensive treatment paradigm, such as medication assisted treatment. In primary care, substance use disorders involving alcohol, illicit opioids, and prescription opioid abuse are common among patients who seek primary care services. Primary care providers report low levels of preparedness and confidence in identifying substance-related and addictive disorders and providing appropriate care and treatment. However, new models of service delivery in primary care for individuals with substance-related and addictive disorders are being developed to promote screening, care and treatment, and relapse prevention. The education and training of primary care providers utilizing approved medications for the treatment of alcohol use disorders and opioid dependence in a primary care setting would have important public health impact and reduce the burden of alcohol abuse and opioid dependence. PMID:25629034

Open-label dose-finding trial of buprenorphine implants (Probuphine) for treatment of heroin dependence.

PubMed

White, Jason; Bell, James; Saunders, John B; Williamson, Paul; Makowska, Maria; Farquharson, Aaron; Beebe, Katherine L

2009-07-01

Buprenorphine, a mu-opioid receptor partial agonist, has been shown to be safe and effective for treatment of opioid dependence. A novel implantable formulation of buprenorphine (Probuphine), using a polymer matrix sustained-release technology, has been developed to offer treatment for opioid dependence while minimizing risks of patient noncompliance and illicit diversion. The goal of the current study was to conduct an initial, open-label, evaluation of the safety, pharmacokinetics, and efficacy of two doses of Probuphine in subjects with opioid dependence maintained on sublingual buprenorphine. Two doses of Probuphine were evaluated in 12 heroin-dependent volunteers switched from daily sublingual buprenorphine dosing to either two or four Probuphine implants based upon their buprenorphine daily maintenance dose of 8 mg or 16 mg respectively, and were monitored for 6 months. Probuphine implants provided continuous steady state delivery of buprenorphine until their removal at 6 months. Withdrawal symptoms and craving remained low throughout the 6 months. For the 12 subjects, an average of 59% of urines were opioid-negative across the 6 month treatment period. Injection site reactions were present in half of patients, but none were serious. No safety concerns were evident. These results suggest that Probuphine implants offer significant promise for enhancing delivery of effective opioid substitution treatment while minimizing risk for abuse of medication.

Towards the development of tamper-resistant, ground-based mobile sensor nodes

NASA Astrophysics Data System (ADS)

Mascarenas, David; Stull, Christopher; Farrar, Charles

2011-11-01

Mobile sensor nodes hold great potential for collecting field data using fewer resources than human operators would require and potentially requiring fewer sensors than a fixed-position sensor array. It would be very beneficial to allow these mobile sensor nodes to operate unattended with a minimum of human intervention. In order to allow mobile sensor nodes to operate unattended in a field environment, it is imperative that they be capable of identifying and responding to external agents that may attempt to tamper with, damage or steal the mobile sensor nodes, while still performing their data collection mission. Potentially hostile external agents could include animals, other mobile sensor nodes, or humans. This work will focus on developing control policies to help enable a mobile sensor node to identify and avoid capture by a hostile un-mounted human. The work is developed in a simulation environment, and demonstrated using a non-holonomic, ground-based mobile sensor node. This work will be a preliminary step toward ensuring the cyber-physical security of ground-based mobile sensor nodes that operate unattended in potentially unfriendly environments.

Functional neuroimaging of emotional processing in women with polycystic ovary syndrome: a case-control pilot study

PubMed Central

Marsh, Courtney A.; Berent-Spillson, Alison; Love, Tiffany; Persad, Carol C.; Pop-Busui, Rodica; Zubieta, Jon-Kar; Smith, Yolanda R.

2013-01-01

Objective To evaluate emotional processing in women with insulin-resistant polycystic ovary syndrome (IR-PCOS) and its relationship to glucose regulation and the mu-opioid system. Design Case-control pilot. Setting Tertiary referring medical center. Patient(s) Seven women with IR-PCOS and five non-insulin-resistant controls, aged 21–40 years, recruited from the general population. Intervention(s) Sixteen weeks of metformin (1,500 mg/day) in women with IR-PCOS. Main Outcome Measure(s) Assessment of mood, metabolic function, and neuronal activation during an emotional task using functional magnetic resonance imaging (fMRI), and mu-opioid receptor availability using positive emission tomography (PET). Result(s) We found that insulin-resistant PCOS patients [1] had greater limbic activation during an emotion task than controls (n = 5); [2] trended toward decreased positive affect and increased trait anxiety; [3] after metformin treatment, had limbic activation that no longer differed from controls; and [4] had positive correlations between fMRI limbic activation during emotional processing and mu-opioid binding potential. Conclusion(s) Patients with IR-PCOS had greater regional activation during an emotion task than the controls, although this resolved with metformin therapy. Alterations in mu-opioid neurotransmission may underlie limbic system activity and mood disorders in IR-PCOS. Clinical Trial Registration Number NCT00670800. PMID:23557757

Buprenorphine in the treatment of opioid addiction: opportunities, challenges and strategies.

PubMed

Li, Xiaofan; Shorter, Daryl; Kosten, Thomas R

2014-10-01

Buprenorphine follows the success of methadone as another milestone in the history of treatment for opioid addiction. Buprenorphine can be used in an office-based setting where it is clearly effective, highly accepted by patients and has a favorable safety profile and less abuse potential. However, the adoption of buprenorphine treatment has been slow in the USA. This article first reviews the history of medication-assisted opioid addiction treatment and the current epidemic opioid addiction, followed by a review of the efficacy, pharmacology and clinical prescription of buprenorphine in office-based care. We then explore the possible barriers in using buprenorphine and the ways to overcome these barriers, including new formulations, educational programs and policy regulations that strike a balance between accessibility and reducing diversion. Buprenorphine can align addiction treatment with treatments for other chronic medical illnesses. However, preventing diversion will require graduate and continuing medical education and integrated care models for delivery of buprenorphine to those in need.

Tamper-indicating seals : practices, problems, and standards

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnston, R. G.

2003-01-01

Tamper-indicating seals have been used by customs officials for over 7,000 years. Today, seals are widely used to help counter theft, smuggling, sabotage, vandalism, terrorism, and espionage. Despite their antiquity and modern widespread use, however, there remains considerable confusion about seals, as well as a lot of misconceptions, wishful thinking, sloppy terminology, and poor practice. The absence of meaningful norms and standards, together with the surprisingly limited amount of research and development (R&D) in the field of tamper detection, has also hindered the effective use of seals. The Vulnerability Assessment Team (VAT) at Los Alamos National Laboratory has intensively studiedmore » tamper-indicating seals for the last 12 years. We have engaged in vulnerability assessments, R&D, consulting, and training for over two dozen United States government agencies and private companies, as well as for the International Atomic Energy Agency (IAEA) and Euratom. The VAT has also analyzed over 200 different types of seals in detail. This paper summarizes some of our conclusions, recommendations, and warnings regarding seals and tamper detection.« less

Resistance exercise decreases heroin self-administration and alters gene expression in the nucleus accumbens of heroin-exposed rats.

PubMed

Smith, Mark A; Fronk, Gaylen E; Abel, Jean M; Lacy, Ryan T; Bills, Sarah E; Lynch, Wendy J

2018-04-01

Preclinical studies consistently report that aerobic exercise decreases drug self-administration and other forms of drug-seeking behavior; however, relatively few studies have examined other types of physical activity. The purpose of the present study was to examine the effects of resistance exercise (i.e., strength training) on heroin self-administration and mRNA expression of genes known to mediate opioid reinforcement and addictive behavior in the nucleus accumbens (NAc) of heroin-exposed rats. Female rats were obtained during late adolescence and divided into two groups. Resistance exercise rats were trained to climb a vertical ladder wearing a weighted vest; sedentary control rats were placed repeatedly on the ladder oriented horizontally on its side. All rats were implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. mRNA expression in the NAc core and shell was examined following behavioral testing. Resistance exercise significantly decreased heroin self-administration, resulting in a downward shift in the dose-effect curve. Resistance exercise also reduced mRNA expression for mu opioid receptors and dopamine D1, D2, and D3 receptors in the NAc core. Resistance exercise increased mRNA expression of dopamine D5 receptors in the NAc shell and increased mRNA expression of brain-derived neurotrophic factor (exons I, IIB, IIC, IV, VI, IX) in the NAc core. These data indicate that resistance exercise decreases the positive reinforcing effects of heroin and produces changes in opioid and dopamine systems in the NAc of heroin-exposed rats.

Variants of opioid system genes are associated with non-dependent opioid use and heroin dependence.

PubMed

Randesi, Matthew; van den Brink, Wim; Levran, Orna; Blanken, Peter; Butelman, Eduardo R; Yuferov, Vadim; da Rosa, Joel Correa; Ott, Jurg; van Ree, Jan M; Kreek, Mary Jeanne

2016-11-01

Heroin addiction is a chronic, relapsing brain disease. Genetic factors are involved in the development of drug addiction. The aim of this study was to determine whether specific variants in genes of the opioid system are associated with non-dependent opioid use and heroin dependence. Genetic information from four subject groups was collected: non-dependent opioid users (NOD) [n=163]; opioid-dependent (OD) patients in methadone maintenance treatment (MMT) [n=143]; opioid-dependent MMT-resistant patients in heroin-assisted treatment (HAT) [n=138]; and healthy controls with no history of opioid use (HC) [n=153]. Eighty-two variants in eight opioid system genes were studied. To establish the role of these genes in (a) non-dependent opioid use, and (b) heroin dependence, the following groups were compared: HC vs. NOD; HC vs. OD (MMT+HAT); and NOD vs. OD (MMT+HAT). Five unique SNPs in four genes showed nominally significant associations with non-dependent opioid use and heroin dependence. The association of the delta opioid receptor (OPRD1) intronic SNP rs2236861 with non-dependent opioid use (HC vs. NOD) remained significant after correction for multiple testing (OR=0.032; p corrected =0.015). This SNP exhibited a significant gene-gene interaction with prepronociceptin (PNOC) SNP rs2722897 (OR=5.24; p corrected =0.041) (HC vs. NOD). This study identifies several new and some previously reported associations of variants with heroin dependence and with non-dependent opioid use, an important and difficult to obtain group not extensively studied previously. Further studies are warranted to confirm and elucidate the potential roles of these variants in the vulnerability to illicit drug use and drug addiction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Tamper indicating bolt

DOEpatents

Blagin, Sergei V.; Barkanov, Boris P.

2004-09-14

A tamper-indicating fastener has a cylindrical body with threads extending from one end along a portion of the body, and a tamper indicating having a transducer for converting physical properties of the body into electronic data; electronics for recording the electronic data; and means for communicating the recorded information to a remote location from said fastener. The electronics includes a capacitor that varies as a function of force applied by the fastener, and non-volatile memory for recording instances when the capacitance varies, providing an indication of unauthorized access.

International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database.

PubMed

McDonald, Rebecca; Danielsson Glende, Øyvind; Dale, Ola; Strang, John

2018-02-01

Non-injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer-reviewed domain. Through examination of a hitherto-unsearched database, we expand public knowledge of non-injectable formulations, tracing their development and novelty, with the aim to describe and compare their pharmacokinetic properties. (i) The PatentScope database of the World Intellectual Property Organization was searched for relevant English-language patent applications; (ii) Pharmacokinetic data were extracted, collated and analysed; (iii) PubMed was searched using Boolean search query '(nasal OR intranasal OR nose OR buccal OR sublingual) AND naloxone AND pharmacokinetics'. Five hundred and twenty-two PatentScope and 56 PubMed records were identified: three published international patent applications and five peer-reviewed papers were eligible. Pharmacokinetic data were available for intranasal, sublingual, and reference routes. Highly concentrated formulations (10-40 mg mL -1 ) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non-concentrated intranasal spray (1 mg mL -1 ; 1 mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (≥10 mg mL -1 ) had bioavailability of 21-42% (relative to intravenous) and 26-57% (relative to intramuscular), with peak concentrations (dose-adjusted C max  = 0.8-1.7 ng mL -1 ) reached in 19-30 min (t max ). Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume. We find consistent direction of development of intranasal sprays to high-concentration, low-volume formulations with bioavailability in the 20-60% range. These have potential to deliver a therapeutic dose in 0.1 mL volume. [McDonald R, Danielsson Glende Ø, Dale O, Strang J. International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev 2017;00:000-000]. © 2017 Australasian Professional Society on Alcohol and other Drugs.

Magnesium enhances opioid-induced analgesia - What we have learnt in the past decades?

PubMed

Bujalska-Zadrożny, Magdalena; Tatarkiewicz, Jan; Kulik, Kamila; Filip, Małgorzata; Naruszewicz, Marek

2017-03-01

Opioids are increasingly used in alleviating pain, including cancer-related pain and postoperative pain. Unfortunately, the development of tolerance, the resistance of neuropathic pain on opioid analgesia or other undesirable effects may limit their utility. In order to reduce opioid doses, and thereby to avoid the risk of side effects and sudden deaths due to overdosing, attempts have been made to introduce co-analgesics. Due to an increasing amount of data concerning a potential enhance of opioid analgesia by the physiological antagonist of N-methyl-d-aspartate receptors, magnesium ions (Mg 2+ ), a concomitant use of such a combination seems to be interesting from a clinical point of view. Therefore, the aim of this review is to provide an analysis of existing preclinical and clinical studies in the context of the benefits of using this combination in clinical practice. A potential mechanism of magnesium - opioid interaction is also suggested. The potential influence of Mg on opioid adverse/side effects as well as conclusions on the safety of combined administration of magnesium and opioid drugs were also summarized. Data from animal studies indicate that magnesium increases opioid analgesia in chronic (e.g., neuropathic, inflammatory) as well as acute pain. In clinical trials, most authors confirmed that magnesium reduces opioid consumption and alleviates postoperative pain scores while not increasing the risk of side effects after opioids. However, more clinical studies are needed concerning an influence of Mg on opioid activity in other difficult to treat types of pain, especially neuropathic and inflammatory. Copyright © 2016 Elsevier B.V. All rights reserved.

Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma

PubMed Central

Friesen, Claudia; Hormann, Inis; Roscher, Mareike; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf; Debatin, Klaus-Michael; Miltner, Erich

2014-01-01

Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The µ-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin-induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas’ resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3-isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells. PMID:24626197

Three Newly Approved Analgesics: An Update

PubMed Central

Saraghi, Mana; Hersh, Elliot V.

2013-01-01

Since 2008, three new analgesic entities, tapentadol immediate release (Nucynta) diclofenac potassium soft gelatin capsules (Zipsor), and bupivacaine liposome injectable suspension (EXPAREL) were granted US Food and Drug Administration (FDA) approval to treat acute pain. Tapentadol immediate-release is a both a mu-opioid agonist and a norepinephrine reuptake inhibitor, and is indicated for the treatment of moderate to severe pain. Diclofenac potassium soft gelatin capsules are a novel formulation of diclofenac potassium, which is a nonsteroidal anti-inflammatory drug (NSAID), and its putative mechanism of action is through inhibition of cyclooxygenase enzymes. This novel formulation of diclofenac allows for improved absorption at lower doses. Liposomal bupivacaine is a new formulation of bupivacaine intended for single-dose infiltration at the surgical site for postoperative analgesia. Bupivacaine is slowly released from this liposomal vehicle and can provide prolonged analgesia at the surgical site. By utilizing NSAIDs and local anesthetics to decrease the transmission of afferent pain signals, less opioid analgesics are needed to achieve analgesia. Since drug-related adverse events are frequently dose related, lower doses from different drug classes may be employed to reduce the incidence of adverse effects, while producing synergistic analgesia as part of a multimodal analgesic approach to acute pain. PMID:24423420

Impact of a new palliative care consultation team on opioid prescription in a University Hospital.

PubMed

Centeno, Carlos; Portela, María Angustias; Noguera, Antonio; Idoate, Antonio; Rubiales, Alvaro Sanz

2009-01-16

There are no validated measuring tools to gauge the effectiveness of a Hospital Palliative Care Consultation Team (PCCT). One way would be to consider its effect on the consumption of opioids expressed in total amounts and different formulations administered. We perform this study to evaluate the impact of a hospital PCCT on the trends of opioid prescription in a University Hospital. A seven year retrospective study on opioid prescription was carried out in the Clínica Universidad de Navarra. The period includes three years before and three years after the PCCT was implemented. Prescription was analysed calculating yearly the Defined Daily Dose (DDD) adjusted to 1000 hospital stays (DDD/1000HS). Indicators considered were the proportion of patients treated using opioids compared to the total estimated in need of treatment (rate of effectiveness) and the proportion of patients potentially requiring opioids but not treated who were incorporated into the treatment group (rate of improvement). From 2001 to 2007, total opioid prescription was low in non-oncology Departments (range: 69-110 DDD/1000HS) while parenteral morphine and fentanyl did not register any changes. In the same period of time, total opioid prescription increased in the Oncology Department from 240 to 558 DDD/1000HS. The rate of effectiveness in the three years prior to the implantation of the consultation team was 64% and in the three following years rose to 87%. The rate of improvement prior to the palliative care consultation team was 43% and in the three following years was 64%. A change in opioid prescription was registered after the implementation of the PCCT resulting in an increase in the prescription of parenteral morphine and methadone and a decrease in transdermal fentanyl. Implementation of a PCCT in a University Hospital is associated with a higher and more adequate use of opioids.

Impact of a new palliative care consultation team on opioid prescription in a University Hospital

PubMed Central

Centeno, Carlos; Portela, María Angustias; Noguera, Antonio; Idoate, Antonio; Rubiales, Álvaro Sanz

2009-01-01

Background There are no validated measuring tools to gauge the effectiveness of a Hospital Palliative Care Consultation Team (PCCT). One way would be to consider its effect on the consumption of opioids expressed in total amounts and different formulations administered. We perform this study to evaluate the impact of a hospital PCCT on the trends of opioid prescription in a University Hospital. Methods A seven year retrospective study on opioid prescription was carried out in the Clínica Universidad de Navarra. The period includes three years before and three years after the PCCT was implemented. Prescription was analysed calculating yearly the Defined Daily Dose (DDD) adjusted to 1000 hospital stays (DDD/1000HS). Indicators considered were the proportion of patients treated using opioids compared to the total estimated in need of treatment (rate of effectiveness) and the proportion of patients potentially requiring opioids but not treated who were incorporated into the treatment group (rate of improvement). Results From 2001 to 2007, total opioid prescription was low in non-oncology Departments (range: 69–110 DDD/1000HS) while parenteral morphine and fentanyl did not register any changes. In the same period of time, total opioid prescription increased in the Oncology Department from 240 to 558 DDD/1000HS. The rate of effectiveness in the three years prior to the implantation of the consultation team was 64% and in the three following years rose to 87%. The rate of improvement prior to the palliative care consultation team was 43% and in the three following years was 64%. A change in opioid prescription was registered after the implementation of the PCCT resulting in an increase in the prescription of parenteral morphine and methadone and a decrease in transdermal fentanyl. Conclusion Implementation of a PCCT in a University Hospital is associated with a higher and more adequate use of opioids. PMID:19149875

Using a Morphine Equivalence Metric to Quantify Opioid Consumption: Examining the Capacity to Provide Effective Treatment of Debilitating Pain at the Global, Regional, and Country Levels

PubMed Central

Gilson, Aaron M.; Maurer, Martha A.; Ryan, Karen M.; Cleary, James F.; Rathouz, Paul J.

2014-01-01

Context Morphine has been considered the gold standard for treating moderate to severe pain, although many new opioid products and formulations have been marketed in the last two decades and should be considered when examining opioid consumption. Understanding opioid consumption is improved by using an equianalgesic measure that controls for the strengths of all examined opioids. Objectives The research objective was to utilize a morphine equivalence metric to determine the extent that morphine consumption relates to the total consumption of all other study opioids. Methods A Morphine Equivalence (ME) metric was created for morphine and for the aggregate consumption of each study opioid (Total ME), adjusted for country population to allow for uniform equianalgesic comparisons. Graphical and statistical evaluations of morphine use and Total ME consumption trends (between 1980 and 2009) were made for the global and geographic regional levels, and for selected developed and developing countries. Results Global morphine consumption rose dramatically in the early 1980s but has been significantly outpaced by Total ME since 1996. As expected, the extent of morphine and Total ME consumption varied notably among regions, with the Americas, Europe, and Oceania regions accounting for the highest morphine use and Total ME in 2009. Developing and least developed countries, compared to developed countries, demonstrated lower overall Total ME consumption. Conclusion Generally, worldwide morphine use has not increased at the rate of Total ME, especially in recent years. Examining a country's ability to effectively manage moderate to severe pain should extend beyond morphine to account for all available potent opioids. PMID:23017614

Tamper-indicating seal

DOEpatents

Fiarman, S.; Degen, M.F.; Peters, H.F.

1982-08-13

There is disclosed a tamper-indicating seal that permits in the field inspection and detection of tampering. Said seal comprises a shrinkable tube having a visible pattern of markings which is shrunk over th item to be sealed, and a second transparent tube, having a second visible marking pattern, which is shrunk over the item and the first tube. The relationship between the first and second set of markings produces a pattern so that the seal may not be removed without detection. The seal is particularly applicable to UF/sub 6/ cylinder valves.

Active Time Domain Reflectometry for Tamper Indication in Unattended Safeguards Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheen, David M.; Smith, Leon E.; Tedeschi, Jonathan R.

2015-07-14

The International Atomic Energy Agency (IAEA) continues to expand its use of unattended measurement systems. An increasing number of systems and an expanding family of instruments create challenges in terms of deployment efficiency and the implementation of data authentication measures. In collaboration with the IAEA, tamper-indicating measures to address data-transmission authentication challenges with unattended safeguards systems are under investigation. Pacific Northwest National Laboratory is studying the viability of active time-domain reflectometry (TDR) along two parallel but interconnected paths: (1) swept-frequency TDR as the highly flexible, laboratory gold standard to which field-deployable options can be compared, and (2) a low-cost commerciallymore » available spread-spectrum TDR technology as one option for field implementation. This paper describes the TDR methods under investigation and the associated benchtop test-bed, tampering scenarios of interest,, and viability measurement results to date (e.g., comparison of relative sensitivity to tamper scenarios).« less

Determinants of Fentanyl and other Potent μ Opioid Agonist Misuse in Opioid-Dependent Individuals

PubMed Central

Cicero, Theodore J.; Ellis, Matthew S.; Paradis, Alethea; Ortbal, Zachary

2010-01-01

Purpose Based on preclinical and clinical abuse liability assessments, fentanyl and other potent μ opioid agonists (e.g. hydromorphone and morphine) should be the most misused opioids if accessibility in the real world were not an issue. Since the latter is seldom true, we postulated that there would be a significant mismatch between actual and predicted rates of misuse. Methods We recruited 1,818 prescription-opioid dependent patients entering drug treatment programs to complete an anonymous survey, covering drug use and health related issues. Results Hydrocodone and oxycodone products were the drugs of choice in 75% of patients, whereas potent μ opioid agonists (fentanyl, hydromorphone and morphine), with the greatest predicted abuse potential, were very rarely chosen (<5% each). Most unexpectedly, the rank order of the actual drug of choice and the preferred drug in an ideal world were highly correlated. The reason most commonly given for the failure to endorse fentanyl, for example, as an actual or preferred drug, was fear of toxicity and overdose. We found few differences in drug use patterns between a subset of high-risk, impaired health care professionals (N=196) and all other patients other than source of drug, (forged prescriptions and doctors more common and dealers much less common in the HC sample). Conclusions These results indicate that it should not be assumed- particularly for new drug formulations- that a high potential for abuse will result in actual abuse; and, most importantly, that the hesitancy to use potent opioids because of fears of abuse may be misguided. PMID:20597128

THE ROLE OF MULTIDRUG RESISTANCE ASSOCIATED PROTEIN (MRP) IN THE BLOOD-BRAIN BARRIER AND OPIOID ANALGESIA

PubMed Central

Su, Wendy; Pasternak, Gavril W.

2013-01-01

The blood brain barrier protects the brain from circulating compounds and drugs. The ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) is involved with the barrier, both preventing the influx of agent from the blood into the brain and facilitating the efflux of compounds from the brain into the blood, raising the possibility of a similar role for other transporters. Multidrug resistance associated protein (MRP), a 190 kDa protein similar to Pgp is also ABC transport that has been implicated in the blood brain barrier. The current study explores its role in opioid action. Immunohistochemically, it is localized in the choroid plexus in ratsand can be selectively downregulated by antisense treatment at both the level of mRNA, as shown by RT-PCR, and protein, as demonstrated immunohistochemically. Behaviorally, downregulation of MRP significantly enhances the analgesic potency of systemic morphine in MRP knockout mice and in antisense-treated rats by lowering the blood brain barrier. Following intracerebroventricular administration, a number of compounds, including some opioids, are rapidly secreted from the brain into the blood where they contribute to the overall analgesic effects by activating peripheral systems. MRP plays a role in this efflux. Downregulating MRP expression leads to a corresponding decrease in the transport and a diminished analgesic response from opioids administered intracerebroventricularly. Thus, the transporter protein MRP plays a role in maintaining the blood-brain barrier and modulates the activity of opioids. PMID:23508590

Adherence Monitoring with Chronic Opioid Therapy for Persistent Pain: A Biopsychosocial-spiritual Approach to Mitigate Risk

PubMed Central

Matteliano, Deborah; St. Marie, Barbara J.; Oliver, June

2013-01-01

Opioids represent a mainstay in the pharmacological management of persistent pain. While these drugs are intended to support improved comfort and function, the inherent risk of abuse or addiction must be considered in the delivery of care. The experience of living with persistent pain often includes depression, fear, loss, and anxiety, leading to feelings of hopelessness, helplessness, and spiritual crisis. Collectively, these factors represent an increased risk for all patients, particularly those with a past history of substance abuse or addiction. This companion article to the American Society for Pain Management Nursing (ASPMN) Position Statement on Pain Management in Patients with Substance Use Disorders (2012) focuses on the intersection of persistent pain, SUD, and chronic opioid therapy and the clinical implications of monitoring adherence with safe use of opioids for those with persistent pain. This paper presents an approach to the comprehensive assessment of persons with persistent pain when receiving opioid therapy by presenting an expansion of the biopsychosocial model to now include spiritual factors associated with pain and SUD, thus formulating a biopsychosocial-spiritual approach to mitigate risk. Key principles are provided for adherence monitoring using the biopsychosocial-spiritual assessment model developed by the authors as a means of promoting sensitive and respectful care. PMID:24602442

DOE Office of Scientific and Technical Information (OSTI.GOV)

Band, L.; Xu, Heng; Bykov, V.

The present study demonstrates that pretreatment of rat brain membranes with (+)-cis-3-methylfentanyl ((+)-cis-MF), followed by extensive washing of the membranes, produces a wash-resistant decreasing in the binding of ({sup 3}H)-(D-ala{sup 2}, D-leu{sup 5})enkephalin to the d binding site of the opioid receptor complex ({delta}{sub cx} binding site). Intravenous administration of (+)-cis-MF (50 {mu}g/kg) to rats produced a pronounced catalepsy and also produced a wash-resistant masking of {delta}{sub cx} and {mu} binding sites in membranes prepared 120 min post-injection. Administration of 1 mg/kg i.v. of the opioid antagonist, 6-desoxy-6{beta}-fluoronaltrexone (cycloFOXY), 100 min after the injection of (+)-cis-MF (20 min prior tomore » the preparation of membranes) completely reversed the catatonia and restored masked {delta}{sub cx} binding sites to control levels. This was not observed with (+)-cycloFOXY. The implications of these and other findings for the mechanism of action of (+)-cis-MF and models of the opioid receptors are discussed.« less

Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial

PubMed Central

Comer, Sandra D.; Sullivan, Maria A.; Yu, Elmer; Rothenberg, Jami L.; Kleber, Herbert D.; Kampman, Kyle; Dackis, Charles; O'Brien, Charles P.; Chiang, C. Nora; Hawks, Richard L.

2013-01-01

Context Naltrexone is a medication available in oral form that can completely block the effects produced by opioid agonists, such as heroin. However, poor medication compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence. Objective To evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence. Design, Setting, and Participants Randomized, double-blind, placebo-controlled, 8-week multi-center trial of male and female heroin-dependent patients who participated in the study between September 2000 and November 2003. Participants were stratified by years of heroin use (≥5, <4.9) and gender, and then randomized to receive one of three doses: placebo, 192 mg, or 384 mg depot naltrexone. Doses were administered at the beginning of Week 1 and then again four weeks later at the beginning of Week 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit. Main Outcome Measures Primary outcome measures were retention in treatment and percentage of opioid-negative urine samples. Results A total of 60 patients were randomized at two centers. Retention in treatment was dose related with 39%, 60%, and 68% of the patients in the placebo, naltrexone 192 mg, and naltrexone 384 mg groups, respectively, remaining in treatment at the end of the two-month treatment period. Analysis of the time to dropout revealed a significant main effect of dose with mean time to dropout of 27, 36, and 48 days, respectively, for the placebo, naltrexone 192 mg, and naltrexone 384 mg groups. The percentage of urine samples negative for opioids varied significantly as a function of dose, as did the percentage of urine samples negative for methadone, cocaine, benzodiazepines, and amphetamine. The percentage of urine samples negative for cannabinoids was not significantly different across groups. When the data were recalculated without the assumption that missing urine samples were positive, however, a main effect of group was not found for any of the drugs tested with the exception of cocaine, where the percentage of cocaine-negative urines was lower in the placebo group. Adverse events were minimal and generally mild in severity. This sustained-release formulation of naltrexone was well tolerated and produced a robust and dose-related increase in treatment retention. Conclusion The present data provide exciting new evidence for the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence. PMID:16461865

Tamper-indicating device having a glass body

DOEpatents

Johnston, Roger G.; Garcia, Anthony R. E.

2003-04-29

A tamper-indicating device is described. The device has a first glass body member and a second glass body member that are attached to each other through a hasp. The glass body members of the device can be tempered. The body members can be configured with hollow volumes into which powders, microparticles, liquids, gels, or combinations thereof are sealed. The choice, the amount, and the location of these materials can produce a visible, band pattern to provide each body member with a unique fingerprint identifier, which makes it extremely difficult to repair or replace once it is damaged in order to avoid tamper detection.

Detection of Tampering Inconsistencies on Mobile Photos

NASA Astrophysics Data System (ADS)

Cao, Hong; Kot, Alex C.

Fast proliferation of mobile cameras and the deteriorating trust on digital images have created needs in determining the integrity of photos captured by mobile devices. As tampering often creates some inconsistencies, we propose in this paper a novel framework to statistically detect the image tampering inconsistency using accurately detected demosaicing weights features. By first cropping four non-overlapping blocks, each from one of the four quadrants in the mobile photo, we extract a set of demosaicing weights features from each block based on a partial derivative correlation model. Through regularizing the eigenspectrum of the within-photo covariance matrix and performing eigenfeature transformation, we further derive a compact set of eigen demosaicing weights features, which are sensitive to image signal mixing from different photo sources. A metric is then proposed to quantify the inconsistency based on the eigen weights features among the blocks cropped from different regions of the mobile photo. Through comparison, we show our eigen weights features perform better than the eigen features extracted from several other conventional sets of statistical forensics features in detecting the presence of tampering. Experimentally, our method shows a good confidence in tampering detection especially when one of the four cropped blocks is from a different camera model or brand with different demosaicing process.

Prospects of Using of κ-Opioid Receptor Agonists U-50,488 and ICI 199,441 for Improving Heart Resistance to Ischemia/Reperfusion.

PubMed

Tsibulnikov, S Yu; Maslov, L N; Mukhomedzyanov, A V; Krylatov, A V; Tsibulnikova, M R; Lishmanov, Yu B

2015-10-01

We studied the ability of the agonist of κ1-opioid receptors U-50,488 in doses of 0.1 and 1 mg/kg to simulate ischemic pre- and postconditioning of the heart and κ-opioid receptors ICI 199,441 in a dose of 0.1 mg/kg to simulate the antiarrhythmic effect of heart preconditioning. The duration of ischemia was 10 or 45 min and the duration of reperfusion was 10 min or 2 h. Administration of 1 mg/kg U-50,488 both before ischemia and 5 min before reperfusion produced a pronounced antiarrhythmic effect. U-50,488 injected 5 min before reperfusion 2-fold reduced the ratio of infarction to risk area. Administration of ICI 199,441 in a dose of 0.1 mg/kg 15 min before ischemia produced a potent antiarrhythmic effect. Antiarrhythmic effect of κ-opioid receptor agonists depended on activation of κ-opioid receptors.

Risk Evaluation and Mitigation Strategies (REMS) for extended-release and long-acting opioid analgesics: considerations for palliative care practice.

PubMed

Gudin, Jeffrey

2012-06-01

Prescription opioid analgesics are an essential treatment option for patients with moderate to severe pain. Over the last decade the increased medical use of these agents has contributed to a public health epidemic of abuse, addiction, and overdose-related deaths. These medications remain mainstays in both primary care and pain management practices. As palliative services are incorporated at earlier stages of the disease process and the number of individuals with chronic illness increases, palliative care specialists may encounter an increasing number of patients with opioid abuse and addiction problems. Extended-release (ER) and long-acting (LA) opioid formulations are administered to patients with moderate to severe chronic pain requiring around-the-clock analgesia. Given the large quantity of active ingredient contained within some dosage strengths, this medication class is associated with serious risks when taken improperly. In response to growing reports of abuse and overdose deaths, the US Food and Drug Administration (FDA) announced the need for a risk mitigation strategy for the entire class of medication. The class-wide Risk Evaluation and Mitigation Strategy (REMS) for ER/LA opioids will emphasize prescriber training and patient education to ensure that the therapeutic benefits outweigh the risks of addiction, unintentional overdose, and death. As primary care, pain management, and palliative care clinicians often encounter patients who require ER/LA opioids, an understanding of the suggested requirements and potential impact of this regulation is essential.

An analysis of errors, discrepancies, and variation in opioid prescriptions for adult outpatients at a teaching hospital

PubMed Central

Bicket, Mark C.; Kattail, Deepa; Yaster, Myron; Wu, Christopher L.; Pronovost, Peter

2017-01-01

Objective To determine opioid prescribing patterns and rate of three types of errors, discrepancies, and variation from ideal practice. Design Retrospective review of opioid prescriptions processed at an outpatient pharmacy Setting Tertiary institutional medical center Patients We examined 510 consecutive opioid medication prescriptions for adult patients processed at an institutional outpatient pharmacy in June 2016 for patient, provider, and prescription characteristics. Main Outcome Measure(s) We analyzed prescriptions for deviation from best practice guidelines, lack of two patient identifiers, and noncompliance with Drug Enforcement Agency (DEA) rules. Results Mean patient age (SD) was 47.5 years (17.4). The most commonly prescribed opioid was oxycodone (71%), usually not combined with acetaminophen. Practitioners prescribed tablet formulation to 92% of the sample, averaging 57 (47) pills. We identified at least one error on 42% of prescriptions. Among all prescriptions, 9% deviated from best practice guidelines, 21% failed to include two patient identifiers, and 41% were noncompliant with DEA rules. Errors occurred in 89% of handwritten prescriptions, 0% of electronic health record (EHR) computer-generated prescriptions, and 12% of non-EHR computer-generated prescriptions. Inter-rater reliability by kappa was 0.993. Conclusions Inconsistencies in opioid prescribing remain common. Handwritten prescriptions continue to demonstrate higher associations of errors, discrepancies, and variation from ideal practice and government regulations. All computer-generated prescriptions adhered to best practice guidelines and contained two patient identifiers, and all EHR prescriptions were fully compliant with DEA rules. PMID:28345746

50 CFR 27.65 - Tampering with vehicles and equipment.

Code of Federal Regulations, 2010 CFR

2010-10-01

... INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM PROHIBITED ACTS Disturbing Violations: Against... motor vehicle, boat, equipment or machinery or attempting to tamper with, enter, or start any motor vehicle, boat, equipment or machinery on any national wildlife refuge without proper authorization is...

75 FR 79049 - Final Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-17

... (RG) 5.80, ``Pressure-Sensitive and Tamper-Indicating Device Seals for Material Control and Accounting... and licenses. Regulatory Guide 5.80, ``Pressure-Sensitive and Tamper-Indicating Device Seals for... and Use of Pressure-Sensitive Seals on Containers for Onsite Storage of Special Nuclear Material...

40 CFR 205.173-2 - Tampering.

Code of Federal Regulations, 2010 CFR

2010-07-01

... removal or puncturing the muffler, baffles, header pipes, or any other component which conducts exhaust... EQUIPMENT NOISE EMISSION CONTROLS Motorcycle Exhaust Systems § 205.173-2 Tampering. The manufacturer must... exhaust system which causes the motorcycle to exceed the Federal noise standard. Use of the motorcycle...

Critical Dimensions of Water-tamped Slabs and Spheres of Active Material

DOE R&D Accomplishments Database

Greuling, E.; Argo, H.: Chew, G.; Frankel, M. E.; Konopinski, E.J.; Marvin, C.; Teller, E.

1946-08-06

The magnitude and distribution of the fission rate per unit area produced by three energy groups of moderated neutrons reflected from a water tamper into one side of an infinite slab of active material is calculated approximately in section II. This rate is directly proportional to the current density of fast neutrons from the active material incident on the water tamper. The critical slab thickness is obtained in section III by solving an inhomogeneous transport integral equation for the fast-neutron current density into the tamper. Extensive use is made of the formulae derived in "The Mathematical Development of the End-Point Method" by Frankel and Goldberg. In section IV slight alterations in the theory outlined in sections II and III were made so that one could approximately compute the critical radius of a water-tamper sphere of active material. The derived formulae were applied to calculate the critical dimensions of water-tamped slabs and spheres of solid UF{sub 6} leaving various (25) isotope enrichment fractions. Decl. Dec. 16, 1955.

Prescription opioid analgesics for pain management in Australia: 20 years of dispensing.

PubMed

Islam, M M; McRae, I S; Mazumdar, S; Taplin, S; McKetin, R

2016-08-01

Opioid prescribing/dispensing data can inform policy surrounding regulation by informing trends and types of opioid prescribed and geographic variations. In Australia so far only partial data on dispensing have been published, and data for states/territories remain unknown. Using a range of measures, this study examines 20-year (1992-2011) trends in prescription opioid analgesics in Australia - both nationally and for individual jurisdictions. Dispensing data were obtained from the Drug Utilisation Sub-Committee and the Pharmaceutical Benefits Scheme (PBS) websites. Trends in numbers of prescriptions and daily defined dose (DDD)/1000 people/day were examined over time and across states/territories. Seasonal variations in PBS/Repatriation Pharmaceutical Benefits Scheme (RPBS) items for nationwide dispensing were adjusted using a centred moving smoothing technique. In two decades, 165.32 million prescriptions for opioids were dispensed, with codeine and its derivatives the most prescribed formulation (50.1%) followed by tramadol (13.5%) and oxycodone derivatives (12.7%). In terms of DDD/1000 people/day, dispensing increased from 5.38 in 1992 to 14.46 in 2011. There are significant increasing trends for total, PBS/RPBS and under co-payment prescriptions (priced below patient co-payment). The DDD/1000 people/day for items dispensed through PBS/RPBS was highest in Tasmania. Prescription opioid dispensing increased substantially over the study period. With an ageing population, this trend is likely to continue in future. A growing concern about harms associated with opioid use warrants balanced control measures so that harms could be minimised without reducing effective pain treatment. Research examining utilisation in small geographic areas may help design spatially tailored interventions. A real-time drug-monitoring programme may reduce undue prescribing and dispensing. © 2016 Royal Australasian College of Physicians.

Translational approach to the pathophysiology of panic disorder: Focus on serotonin and endogenous opioids.

PubMed

Graeff, Frederico G

2017-05-01

Panic patients experience recurrent panic attacks. Two main neurochemical hypotheses have been proposed to explain this vulnerability. The first suggests that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organizes defensive reactions to cope with proximal threats as well as of sympathomotor control areas of the rostral ventrolateral medulla that generate neurovegetative symptoms of the panic attack. The second proposes that endogenous opioids buffer panic attacks in normal subjects, and their deficit results in heightened sensitivity to suffocation and separation anxiety in panic patients. Experimental results obtained in rat models of panic indicate that serotonin interacts synergistically with endogenous opioids in the dorsal periaqueductal gray through 5-HT1A and μ-opioid receptors to inhibit proximal defense and, supposedly, panic attacks. These findings allow reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology. They also indicate that endogenous opioids are likely to participate in the panicolytic action of antidepressants and suggest that exogenous opioids may be useful for treating panic patients resistant to conventional pharmacotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evidence of tampering in watermark identification

NASA Astrophysics Data System (ADS)

McLauchlan, Lifford; Mehrübeoglu, Mehrübe

2009-08-01

In this work, watermarks are embedded in digital images in the discrete wavelet transform (DWT) domain. Principal component analysis (PCA) is performed on the DWT coefficients. Next higher order statistics based on the principal components and the eigenvalues are determined for different sets of images. Feature sets are analyzed for different types of attacks in m dimensional space. The results demonstrate the separability of the features for the tampered digital copies. Different feature sets are studied to determine more effective tamper evident feature sets. The digital forensics, the probable manipulation(s) or modification(s) performed on the digital information can be identified using the described technique.

An Analysis of 34,218 Pediatric Outpatient Controlled Substance Prescriptions.

PubMed

George, Jessica A; Park, Paul S; Hunsberger, Joanne; Shay, Joanne E; Lehmann, Christoph U; White, Elizabeth D; Lee, Benjamin H; Yaster, Myron

2016-03-01

Prescription errors are among the most common types of iatrogenic errors. Because of a previously reported 82% error rate in handwritten discharge narcotic prescriptions, we developed a computerized, web-based, controlled substance prescription writer that includes weight-based dosing logic and alerts to reduce the error rate to (virtually) zero. Over the past 7 years, >34,000 prescriptions have been created by hospital providers using this platform. We sought to determine the ongoing efficacy of the program in prescription error reduction and the patterns with which providers prescribe controlled substances for children and young adults (ages 0-21 years) at hospital discharge. We examined a database of 34,218 controlled substance discharge prescriptions written by our institutional providers from January 1, 2007 to February 14, 2014, for demographic information, including age and weight, type of medication prescribed based on patient age, formulation of dispensed medication, and amount of drug to be dispensed at hospital discharge. In addition, we randomly regenerated 2% (700) of prescriptions based on stored data and analyzed them for errors using previously established error criteria. Weights that were manually entered into the prescription writer by the prescriber were compared with the patient's weight in the hospital's electronic medical record. Patients in the database averaged 9 ± 6.1 (range, 0-21) years of age and 36.7 ± 24.9 (1-195) kg. Regardless of age, the most commonly prescribed opioid was oxycodone (73%), which was prescribed as a single agent uncombined with acetaminophen. Codeine was prescribed to 7% of patients and always in a formulation containing acetaminophen. Liquid formulations were prescribed to 98% of children <6 years of age and to 16% of children >12 years of age (the remaining 84% received tablet formulations). Regardless of opioid prescribed, the amount of liquid dispensed averaged 106 ± 125 (range, 2-3240) mL, and the number of tablets dispensed averaged 51 ± 51 (range, 1-1080). Of the subset of 700 regenerated prescriptions, all were legible (drug, amount dispensed, dose, patient demographics, and provider name) and used best prescribing practice (e.g., no trailing zero after a decimal point, leading zero for doses <1). Twenty-five of the 700 (3.6%) had incorrectly entered weights compared with the most recent weight in the chart. Of these, 14 varied by 10% or less and only 2 varied by >15%. Of these, 1 resulted in underdosing (true weight 80 kg prescribed for a weight of 50 kg) and the other in overdosing (true weight 10 kg prescribed for a weight of 30 kg). A computerized prescription writer eliminated most but not all the errors common to handwritten prescriptions. Oxycodone has supplanted codeine as the most commonly prescribed oral opioid in current pediatric pain practice and, independent of formulation, is dispensed in large quantities. This study underscores the need for liquid opioid formulations in the pediatric population and, because of their abuse potential, the urgent need to determine how much of the prescribed medication is actually used by patients.

Persistence and healthcare utilization associated with the use of buprenorphine/naloxone film and tablet formulation therapy in adults with opioid dependence.

PubMed

Clay, Emilie; Khemiri, Amine; Zah, Vladimir; Aballéa, Samuel; Ruby, Jane; Asche, Carl V

2014-09-01

Buprenorphine/naloxone film was developed to improve retention in treatment and reduce public health risks over the tablet formulation for opioid dependence. To compare patient persistence and resource utilization between formulations for the treatment of opioid dependence. A longitudinal, retrospective cohort analysis was conducted to compare persistence and healthcare costs in a private US insurance claims database. Previously untreated patients, who initiated treatment with buprenorphine/naloxone following the introduction of the film, were classified in two groups according to the initial prescription. Persistence was defined as the proportion of patients continuing treatment for at least 6 months. Resource utilization and related costs were calculated over the 6- and 12-month periods after treatment initiation. Film and tablet groups included 2796 and 1510 patients enrolled over 9.76 and 13.76 months on average, respectively, from initiation of treatment. Patient characteristics were similar between groups. Mean prescribed doses were 14.62 and 14.26 mg/day in film and tablet groups. Among patients enrolled for at least 6 months from the initial treatment, persistence rates were 63.78% with film vs 58.13% with tablet. Time to treatment discontinuation was longer in the film group, with a hazard ratio of 0.818 (p = 0.0005, 95% CI = [0.730;0.916]) adjusted for baseline characteristics. Patients treated with film had significantly more outpatient visits (+4%, p = 0.0185) and lower probability to be hospitalized (-17%, p = 0.0158), resulting in lower total healthcare costs over the 12-month period after initiation (-27%, p < 0.0001). Patients treated with the film formulation of buprenorphine/naloxone appeared to stay longer on treatment, have a lower probability of hospital admission, and lower health care costs compared to patients treated with the tablet. This study, based on insurance claims data, has the advantage of reflecting real-world practice, but one cannot rule out the existence of bias due to differences in patient or prescriber profiles, despite adjustments made for observed characteristics at treatment initiation.

Digital image modification detection using color information and its histograms.

PubMed

Zhou, Haoyu; Shen, Yue; Zhu, Xinghui; Liu, Bo; Fu, Zigang; Fan, Na

2016-09-01

The rapid development of many open source and commercial image editing software makes the authenticity of the digital images questionable. Copy-move forgery is one of the most widely used tampering techniques to create desirable objects or conceal undesirable objects in a scene. Existing techniques reported in the literature to detect such tampering aim to improve the robustness of these methods against the use of JPEG compression, blurring, noise, or other types of post processing operations. These post processing operations are frequently used with the intention to conceal tampering and reduce tampering clues. A robust method based on the color moments and other five image descriptors is proposed in this paper. The method divides the image into fixed size overlapping blocks. Clustering operation divides entire search space into smaller pieces with similar color distribution. Blocks from the tampered regions will reside within the same cluster since both copied and moved regions have similar color distributions. Five image descriptors are used to extract block features, which makes the method more robust to post processing operations. An ensemble of deep compositional pattern-producing neural networks are trained with these extracted features. Similarity among feature vectors in clusters indicates possible forged regions. Experimental results show that the proposed method can detect copy-move forgery even if an image was distorted by gamma correction, addictive white Gaussian noise, JPEG compression, or blurring. Copyright © 2016. Published by Elsevier Ireland Ltd.

Medical Image Tamper Detection Based on Passive Image Authentication.

PubMed

Ulutas, Guzin; Ustubioglu, Arda; Ustubioglu, Beste; V Nabiyev, Vasif; Ulutas, Mustafa

2017-12-01

Telemedicine has gained popularity in recent years. Medical images can be transferred over the Internet to enable the telediagnosis between medical staffs and to make the patient's history accessible to medical staff from anywhere. Therefore, integrity protection of the medical image is a serious concern due to the broadcast nature of the Internet. Some watermarking techniques are proposed to control the integrity of medical images. However, they require embedding of extra information (watermark) into image before transmission. It decreases visual quality of the medical image and can cause false diagnosis. The proposed method uses passive image authentication mechanism to detect the tampered regions on medical images. Structural texture information is obtained from the medical image by using local binary pattern rotation invariant (LBPROT) to make the keypoint extraction techniques more successful. Keypoints on the texture image are obtained with scale invariant feature transform (SIFT). Tampered regions are detected by the method by matching the keypoints. The method improves the keypoint-based passive image authentication mechanism (they do not detect tampering when the smooth region is used for covering an object) by using LBPROT before keypoint extraction because smooth regions also have texture information. Experimental results show that the method detects tampered regions on the medical images even if the forged image has undergone some attacks (Gaussian blurring/additive white Gaussian noise) or the forged regions are scaled/rotated before pasting.

Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

PubMed Central

Headrick, John P; See Hoe, Louise E; Du Toit, Eugene F; Peart, Jason N

2015-01-01

Ischaemic heart disease (IHD) remains a major cause of morbidity/mortality globally, firmly established in Westernized or ‘developed’ countries and rising in prevalence in developing nations. Thus, cardioprotective therapies to limit myocardial damage with associated ischaemia–reperfusion (I–R), during infarction or surgical ischaemia, is a very important, although still elusive, clinical goal. The opioid receptor system, encompassing the δ (vas deferens), κ (ketocyclazocine) and μ (morphine) opioid receptors and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears as a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central opioid receptor signalling may also enhance the ability of the heart to withstand I–R injury. The δ- and κ-opioid receptors are strongly implicated in cardioprotection across models and species (including anti-infarct and anti-arrhythmic actions), with mixed evidence for μ opioid receptor-dependent protection in animal and human tissues. A small number of clinical trials have provided evidence of cardiac benefit from morphine or remifentanil in cardiopulmonary bypass or coronary angioplasty patients, although further trials of subtype-specific opioid receptor agonists are needed. The precise roles and utility of this GPCR family in healthy and diseased human myocardium, and in mediating central and peripheral survival responses, warrant further investigation, as do the putative negative influences of ageing, IHD co-morbidities, and relevant drugs on opioid receptor signalling and protective responses. PMID:25521834

Inhibitory effects of opioids on compound action potentials in frog sciatic nerves and their chemical structures.

PubMed

Mizuta, Kotaro; Fujita, Tsugumi; Nakatsuka, Terumasa; Kumamoto, Eiichi

2008-08-01

An opioid tramadol more effectively inhibits compound action potentials (CAPs) than its metabolite mono-O-demethyl-tramadol (M1). To address further this issue, we examined the effects of opioids (morphine, codeine, ethylmorphine and dihydrocodeine) and cocaine on CAPs by applying the air-gap method to the frog sciatic nerve. All of the opioids at concentrations less than 10 mM reduced the peak amplitude of the CAP in a reversible and dose-dependent manner. The sequence of the CAP peak amplitude reductions was ethylmorphine>codeine>dihydrocodeine> or = morphine; the effective concentration for half-maximal inhibition (IC(50)) of ethylmorphine was 4.6 mM. All of the CAP inhibitions by opioids were resistant to a non-specific opioid-receptor antagonist naloxone. The CAP peak amplitude reductions produced by morphine, codeine and ethylmorphine were related to their chemical structures in such that this extent enhanced with an increase in the number of -CH(2) in a benzene ring, as seen in the inhibitory actions of tramadol and M1. Cocaine reduced CAP peak amplitudes with an IC(50) value of 0.80 mM. It is concluded that opioids reduce CAP peak amplitudes in a manner being independent of opioid-receptor activation and with an efficacy being much less than that of cocaine. It is suggested that the substituted groups of -OH bound to the benzene ring of morphine, codeine and ethylmorphine as well as of tramadol and M1, the structures of which are quite different from those of the opioids, may play an important role in producing nerve conduction block.

Adherence monitoring with chronic opioid therapy for persistent pain: a biopsychosocial-spiritual approach to mitigate risk.

PubMed

Matteliano, Deborah; St Marie, Barbara J; Oliver, June; Coggins, Candace

2014-03-01

Opioids represent a mainstay in the pharmacologic management of persistent pain. Although these drugs are intended to support improved comfort and function, the inherent risk of abuse or addiction must be considered in the delivery of care. The experience of living with persistent pain often includes depression, fear, loss, and anxiety, leading to feelings of hopelessness, helplessness, and spiritual crisis. Collectively, these factors represent an increased risk for all patients, particularly those with a history of substance abuse or addiction. This companion article to the American Society for Pain Management Nursing "Position Statement on Pain Management in Patients with Substance Use Disorders" (2012) focuses on the intersection of persistent pain, substance use disorder (SUD), and chronic opioid therapy and the clinical implications of monitoring adherence with safe use of opioids for those with persistent pain. This paper presents an approach to the comprehensive assessment of persons with persistent pain when receiving opioid therapy by presenting an expansion of the biopsychosocial model to include spiritual factors associated with pain and SUD, thus formulating a biopsychosocial-spiritual approach to mitigate risk. Key principles are provided for adherence monitoring using the biopsychosocial-spiritual assessment model developed by the authors as a means of promoting sensitive and respectful care. Copyright © 2014 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Reality and responsibility revisited: Stakeholder accountability in the effort to develop safer opioids.

PubMed

Passik, Steven D; Heit, Howard A; DeGeorge, Michael

This supplement is dedicated to an exploration of the science, potential utility, and the current state of abuse-deterrent formulations (ADF) of opioid analgesics. There are many stakeholders in the search for safer pain treatments in general, and safer opioid therapy in particular. Healthcare providers, patients, third-party payors, law enforcement and government regulators, the pharmaceutical industry, and the media all have a stake in seeing pain treated and addiction and overdose avoided. As it applies to ADFs, obviously not everyone has a stake in seeing that ADFs succeed commercially; but all stakeholders certainly have a responsibility to see that any potential advance, including ADFs, in protecting the public health is fairly and thoroughly evaluated. Particularly at a time of crisis. In this article, we revisit the framework used by Passik, Heit, and Kirsh (2006) to evaluate stakeholders' responsibilities with regard to both the opioid abuse and chronic pain epidemics. After evaluating the present status of aspirations delineated over a decade ago, we discuss the updated roles and responsibilities of each stakeholder, with emphasis on the role of ADFs as this technology was unavailable when the original manuscript was written.

In-vitro and in-vivo characterization of a buprenorphine delivery system.

PubMed

Kleppner, Sofie R; Patel, Raj; McDonough, Joseph; Costantini, Lauren C

2006-03-01

Buprenorphine is a mu-opioid receptor partial agonist with enhanced safety and comparable efficacy to methadone for treatment of opioid dependence. The sublingual formulation of buprenorphine, approved for treatment of opioid dependence, produces variable buprenorphine blood levels and requires frequent dosing that limits patient compliance. To achieve stable buprenorphine levels that may improve patient outcome, an implantable sustained buprenorphine delivery system was developed. Each implant consists of ethylene vinyl acetate copolymer and 90 mg buprenorphine HCl, and measures 26 mm in length and 2.4 mm in diameter. Steady-state release in-vitro was 0.5 mg/implant/day. In-vivo pharmacokinetics and safety were examined for up to 52 weeks in beagle dogs receiving 8, 16 or 24 subcutaneous implants. Plasma buprenorphine concentrations correlated with the number of implants administered. Peak buprenorphine concentrations were generally reached within 24 h after implantation. Steady-state plasma levels were attained between 3 and 8 weeks, and were maintained for study duration, with a calculated mean release rate of 0.14+/-0.04 mg/implant/day. There were no test-article-related adverse effects. This delivery system can provide long-term stable systemic buprenorphine levels, and may increase patient compliance, thereby improving outcome for opioid-dependent patients.

Assessment of the trends in medical use and misuse of opioid analgesics from 2004 to 2011.

PubMed

Atluri, Sairam; Sudarshan, Gururau; Manchikanti, Laxmaiah

2014-01-01

The epidemic of medical use and abuse of opioid analgesics is linked to the economic burden of opioid-related abuse and fatalities in the United States. Multiple studies have estimated the extent to which prescription opioid analgesics contribute to the national drug abuse problem; studies also assessing the trends in medical use and abuse of opioid analgesics have confirmed the relationship between increasing medical use of opioids and increasing fatalities.The available data is limited until 2002. Retrospective analysis of data from 2004 to 2011 from 2 databases: Automation of Reports and Consolidated Orders System (ARCOS) for opioid use data and Drug Abuse Warning Network (DAWN) for drug misuse data. To determine the proportion of drug abuse related to opioid analgesics and the various trends in the medical use and abuse of 8 opioid analgesics commonly used to treat pain: buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone. The data obtained from DAWN is a nationally representative sample of hospital emergency department admissions resulting from drug abuse. Main outcome measure was the identification of trends in the medical use and misuse of opioid analgesics from 2004 to 2011. From 2004 to 2011, there was an increase in the medical use of all opioids except for a 20% decrease in codeine. The abuse of all opioids including codeine increased during this period. Increases in medical use ranged from 2,318% for buprenorphine to 35% for fentanyl, including 140% for hydromorphone, 117% for oxycodone, 73% for hydrocodone, 64% for morphine, and 37% for methadone. The misuse increased 384% for buprenorphine with available data from 2006 to 2011, whereas from 2004 to 2011, it increased 438% for hydromorphone, 263% for oxycodone, 146% for morphine, 107% for hydrocodone, 104% for fentanyl, 82% for methadone, and 39% for codeine. Comparison of opioid use showed an overall increase of 1,448% from 1996 to 2011, with increases of 690% from 1996 to 2004 and 100% from 2004 to 2011. In contrast, misuse increased more dramatically: 4,680% from 1996 to 2011, with increases of 1,372% from 1996 through 2004 and 245% from 2004 to 2011. The number of patients seeking rehabilitation for substance abuse also increased 187% for opioids, whereas it increased 87% for heroin, 40% for marijuana, and decreased 7% for cocaine. Limitations of this assessment include the lack of data from 2003, lack of data available on meperidine, and that the aggregate data systems used in the study did not identify specific formulations or commercial products. The present trend of continued increase in the medical use of opioid analgesics appears to contribute to increases in misuse, resulting in multiple health consequences.

Tamper resistant magnetic stripes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naylor, R.B.; Sharp, D.J.

1999-11-09

This invention relates to a magnetic stripe comprising a medium in which magnetized particles are suspended and in which the encoded information is recorded by actual physical rotation or alignment of the previously magnetized particles within the flux reversals of the stripe which are 180{degree} opposed in their magnetic polarity. The magnetized particles are suspended in a medium which is solid, or physically rigid, at ambient temperatures but which at moderately elevated temperatures, such as 40 C, is thinable to a viscosity permissive of rotation of the particles therein under applications of moderate external magnetic field strengths within acceptable timemore » limits.« less

Tamper resistant magnetic stripes

DOEpatents

Naylor, Richard Brian; Sharp, Donald J.

1999-01-01

This invention relates to a magnetic stripe comprising a medium in which magnetized particles are suspended and in which the encoded information is recorded by actual physical rotation or alignment of the previously magnetized particles within the flux reversals of the stripe which are 180.degree. opposed in their magnetic polarity. The magnetized particles are suspended in a medium which is solid, or physically rigid, at ambient temperatures but which at moderately elevated temperatures, such as 40.degree. C., is thinable to a viscosity permissive of rotation of the particles therein under applications of moderate external magnetic field strengths within acceptable time limits.

Detecting Test Tampering Using Item Response Theory

ERIC Educational Resources Information Center

Wollack, James A.; Cohen, Allan S.; Eckerly, Carol A.

2015-01-01

Test tampering, especially on tests for educational accountability, is an unfortunate reality, necessitating that the state (or its testing vendor) perform data forensic analyses, such as erasure analyses, to look for signs of possible malfeasance. Few statistical approaches exist for detecting fraudulent erasures, and those that do largely do not…

Single-dose evaluation of safety, tolerability and pharmacokinetics of newly formulated hydromorphone immediate-release and hydrophilic matrix extended-release tablets in healthy Japanese subjects without co-administration of an opioid antagonist.

PubMed

Toyama, Kaoru; Uchida, Naoki; Ishizuka, Hitoshi; Sambe, Takehiko; Kobayashi, Shinichi

2015-09-01

This single dose, open-label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate-release (IR) and hydrophilic matrix extended-release (ER) hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquid-chromatography tandem mass-spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0-inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0-inf and Cmax increased with food for both IR and ER tablets. The AUC0-inf of hydromorphone-3-glucoside was one-tenth of that of hydromorphone-3-glucuronide. A single oral administration of the hydromorphone tablets would be well-tolerated in healthy Japanese subjects despite a lack of co-administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once-daily dosing. © 2015, The American College of Clinical Pharmacology.

A statewide effort to reduce high-dose opioid prescribing through coordinated care organizations.

PubMed

Hartung, Daniel M; Alley, Lindsey; Leichtling, Gillian; Korthuis, P Todd; Hildebran, Christi

2018-05-01

Oregon's Medicaid program is delivered through 16 Coordinated Care Organizations (CCOs) participating in a statewide performance improvement program to reduce high-dose opioid prescribing. CCOs were allowed flexibility to develop their own dose targets and any policies, trainings, guidelines, and/or materials to meet these targets. In this study, we characterize CCO strategies to reduce high-dose opioid prescribing across the 16 CCOs. We reviewed relevant CCO documents and conducted semi-structured interviews with CCO administrators to acquire opioid-related policies, practices, timelines and contextual factors. We applied a systematic coding procedure to develop a comprehensive description of each CCO's strategy. We used administrative data from the state to summarize contextual utilization data for each CCO. Most CCOs selected a target daily morphine milligram equivalent (MME) dose of 90 mg. Sixteen issued quantity limits related to dose, eight restricted specific drug formulations (short-acting or long-acting), and 11 allowed for time-limited taper plan periods for patients over threshold. Many CCOs also employed provider trainings, feedback reports, and/or onsite technical assistance. Other innovations included incentive measures, electronic health record alerts, and toolkits with materials on local alternative therapy resources and strategies for patient communication. CCOs leveraging collaborations with regional partners appeared to mount a greater intensity of interventions than independently operating CCOs. CCOs developed a diversity of interventions to confront high-risk opioid prescribing within their organization. As healthcare systems mount interventions to reduce risky opioid prescribing, it is critical to carefully describe these activities and examine their impact on process and health outcomes. Copyright © 2018 Elsevier Ltd. All rights reserved.

Probuphine® (buprenorphine implant): a promising candidate in opioid dependence

PubMed Central

Barnwal, Preeti; Das, Saibal; Mondal, Somnath; Ramasamy, Anand; Maiti, Tanay; Saha, Arunava

2016-01-01

Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine®, a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine®, and relevant clinical trials addressing the efficacy and safety of Probuphine®. This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits. PMID:28348732

Probuphine® (buprenorphine implant): a promising candidate in opioid dependence.

PubMed

Barnwal, Preeti; Das, Saibal; Mondal, Somnath; Ramasamy, Anand; Maiti, Tanay; Saha, Arunava

2017-03-01

Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine®, a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine®, and relevant clinical trials addressing the efficacy and safety of Probuphine®. This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits.

Pain: Systematic Review of Pharmacy Compounding of Pain Medication.

PubMed

Shawaqfeh, Mohammad S; Harrington, Catherine

2018-01-01

There are limited resources available for pharmacists and doctors to reference proper compounded formulas for pain medications. The systematic review discussed within this article provides the foundation for a searchable database, allowing users to find various compounded formulations. It also provides data about the safety and efficacy of the preparations. Compounding information about several drug classes was reviewed. Those drug classes included, but were not limited to, opioids, non-steroidal anti-inflammatory drugs, central nervous system agents, and anesthetics, with evidence that of the various drugs that could be compounded for pain, anesthetics, non-steroidal anti-inflammatory drugs, and opioids ranked highest within the articles researched. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Single-molecular diodes based on opioid derivatives.

PubMed

Siqueira, M R S; Corrêa, S M; Gester, R M; Del Nero, J; Neto, A M J C

2015-12-01

We propose an efficient single-molecule rectifier based on a derivative of opioid. Electron transport properties are investigated within the non-equilibrium Green's function formalism combined with density functional theory. The analysis of the current-voltage characteristics indicates obvious diode-like behavior. While heroin presents rectification coefficient R>1, indicating preferential electronic current from electron-donating to electron-withdrawing, 3 and 6-acetylmorphine and morphine exhibit contrary behavior, R<1. Our calculations indicate that the simple inclusion of acetyl groups modulate a range of devices, which varies from simple rectifying to resonant-tunneling diodes. In particular, the rectification rations for heroin diodes show microampere electron current with a maximum of rectification (R=9.1) at very low bias voltage of ∼0.6 V and (R=14.3)∼1.8 V with resistance varying between 0.4 and 1.5 M Ω. Once most of the current single-molecule diodes usually rectifies in nanoampere, are not stable over 1.0 V and present electrical resistance around 10 M. Molecular devices based on opioid derivatives are promising in molecular electronics.

Desensitization and Tolerance of Mu Opioid Receptors on Pontine Kölliker-Fuse Neurons.

PubMed

Levitt, Erica S; Williams, John T

2018-01-01

Acute desensitization of mu opioid receptors is thought to be an initial step in the development of tolerance to opioids. Given the resistance of the respiratory system to develop tolerance, desensitization of neurons in the Kölliker-Fuse (KF), a key area in the respiratory circuit, was examined. The activation of G protein-coupled inwardly rectifying potassium current was measured using whole-cell voltage-clamp recordings from KF and locus coeruleus (LC) neurons contained in acute rat brain slices. A saturating concentration of the opioid agonist [Met 5 ]-enkephalin (ME) caused significantly less desensitization in KF neurons compared with LC neurons. In contrast to LC, desensitization in KF neurons was not enhanced by activation of protein kinase C or in slices from morphine-treated rats. Cellular tolerance to ME and morphine was also lacking in KF neurons from morphine-treated rats. The lack of cellular tolerance in KF neurons correlates with the relative lack of tolerance to the respiratory depressant effect of opioids. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

First Dutch national guidelines--pharmacological care for detained opioid addicts.

PubMed

Arends, M T; De Haan, H A; Van 't Hoff, G I C M

2009-01-01

Heterogenic care of addicted detainees in the various prisons in The Netherlands triggered the National Agency of Correctional Institutions of the Ministry of Justice, to order the Dutch Institute for Health Care Improvement (CBO) to formulate the first national guideline titled 'Pharmacological care for detained addicts'. This article presents the content of this guideline, which mainly focuses on opioid-dependent addicts. In The Netherlands, approximately 50% of the detainees are problematic substance abusers, while again half of this group suffers from psychiatric co-morbidity. In addition, somatic co-morbidity, especially infectious diseases, is also common. Due to the moderate outcome seen with voluntary drug counselling regimes in prison, there is a policy shift to extent utilization of legally enforced approaches. Continuity of care is of great importance. In case of opioid addicts this, in general, means continuation of methadone maintenance treatment. Aftercare immediately after detention and optimalization of medical information transfer is crucial. This guideline aims to realize optimal and uniform management of addiction disorders in the Dutch prison system.

Three New Methods for Analysis of Answer Changes

ERIC Educational Resources Information Center

Sinharay, Sandip; Johnson, Matthew S.

2017-01-01

In a pioneering research article, Wollack and colleagues suggested the "erasure detection index" (EDI) to detect test tampering. The EDI can be used with or without a continuity correction and is assumed to follow the standard normal distribution under the null hypothesis of no test tampering. When used without a continuity correction,…

Test-Tampering Found Rampant in Atlanta System

ERIC Educational Resources Information Center

Samuels, Christina A.

2011-01-01

The author reports on a state investigation into Atlanta's impressive gains on state tests which finds that test-tampering was rampant in the much-praised school system. The report unveiled by the Georgia governor's office states that Atlanta teachers and principals for years methodically altered answer sheets for students taking state tests,…

DEVELOPMENT OF A CERAMIC TAMPER INDICATING SEAL: SRNL CONTRIBUTIONS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krementz, D.; Brinkman, K.; Martinez-Rodriguez, M.

2013-06-03

Savannah River National Laboratory (SRNL) and Sandia National Laboratories (SNL) are collaborating on development of a Ceramic Seal, also sometimes designated the Intrinsically Tamper Indicating Ceramic Seal (ITICS), which is a tamper indicating seal for international safeguards applications. The Ceramic Seal is designed to be a replacement for metal loop seals that are currently used by the IAEA and other safeguards organizations. The Ceramic Seal has numerous features that enhance the security of the seal, including a frangible ceramic body, protective and tamper indicating coatings, an intrinsic unique identifier using Laser Surface Authentication, electronics incorporated into the seal that providemore » cryptographic seal authentication, and user-friendly seal wire capture. A second generation prototype of the seal is currently under development whose seal body is of Low Temperature Co-fired Ceramic (LTCC) construction. SRNL has developed the mechanical design of the seal in an iterative process incorporating comments from the SNL vulnerability review team. SRNL is developing fluorescent tamper indicating coatings, with recent development focusing on optimizing the durability of the coatings and working with a vendor to develop a method to apply coatings on a 3-D surface. SRNL performed a study on the effects of radiation on the electronics of the seal and possible radiation shielding techniques to minimize the effects. SRNL is also investigating implementation of Laser Surface Authentication (LSA) as a means of unique identification of each seal and the effects of the surface coatings on the LSA signature.« less

Opiate Antagonists Do Not Interfere With the Clinical Benefits of Stimulants in ADHD: A Double-Blind, Placebo-Controlled Trial of the Mixed Opioid Receptor Antagonist Naltrexone.

PubMed

Spencer, Thomas J; Bhide, Pradeep; Zhu, Jinmin; Faraone, Stephen V; Fitzgerald, Maura; Yule, Amy M; Uchida, Mai; Spencer, Andrea E; Hall, Anna M; Koster, Ariana J; Biederman, Joseph

Methylphenidate activates μ-opioid receptors, which are linked to euphoria. μ-Opioid antagonists, such as naltrexone, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential. This study assessed whether the combination of naltrexone with methylphenidate is well-tolerated while preserving the clinical benefits of stimulants in subjects with attention-deficit/hyperactivity disorder (ADHD). We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate from January 2013 to July 2015. Spheroidal Oral Drug Absorption System (SODAS) methylphenidate was administered twice daily, was titrated to approximately 1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with a test dose of immediate-release methylphenidate. The primary outcome measure was the Adult ADHD Investigator Symptom Report Scale (AISRS). Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS methylphenidate and randomly assigned to naltrexone 50 mg or placebo. Thirty-one subjects completed the study through week 3, and 25 completed through week 6. Throughout 6 weeks of blinded naltrexone and open methylphenidate treatment, the coadministration of naltrexone with methylphenidate did not interfere with the clinical effectiveness of methylphenidate for ADHD symptoms. Additionally, the combination of naltrexone and methylphenidate did not produce an increase in adverse events compared with methylphenidate alone. Our findings provide support for the concept of combining opioid receptor antagonists with stimulants to provide an effective stimulant formulation with less abuse potential. ClinicalTrials.gov identifier: NCT01673594​. © Copyright 2017 Physicians Postgraduate Press, Inc.

The Social Construction of the Urban Use of Information Technology: The Case of Tampere, Finland

ERIC Educational Resources Information Center

Inkinen, Tommi

2006-01-01

This paper explores the social use of information and communication technologies (ICTs) in the city of Tampere, Finland. It focuses on two essential elements: the city (as the location with national context) and citizens (as members of the "local" information society). The paper also examines the question of building social networks via…

A multicenter, primary-care-based, open-label study to assess the success of converting opioid-experienced patients with chronic moderate-to-severe pain to morphine sulfate and naltrexone hydrochloride extended-release capsules using a standardized conversion guide.

PubMed

Setnik, Beatrice; Roland, Carl L; Sommerville, Kenneth W; Pixton, Glenn C; Berke, Robert; Calkins, Anne; Goli, Veeraindar

2015-01-01

To evaluate the conversion of opioid-experienced patients with chronic moderate-to-severe pain to extended-release morphine sulfate with sequestered naltrexone hydrochloride (MSN) using a standardized conversion guide. This open-label, single-arm study was conducted in 157 primary care centers in the United States. A total of 684 opioid-experienced adults with chronic moderate-to-severe pain were converted to oral administration of MSN from transdermal fentanyl and oral formulations of hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and other morphine products using a standardized conversion guide. The primary endpoint was the percentage of patients achieving a stable MSN dose within a 6-week titration phase. Secondary endpoints included duration of time to stable dose, number of titration steps, safety and efficacy measures, and investigator assessment of conversion guide utility. Of the 684 patients, 51.3% were converted to a stable dose of MSN (95% confidence interval: 47.5%, 55.1%). The mean (standard deviation) number of days to stable dose was 20 (8.94), and number of titration steps to stable dose was 2.4 (1.37). The majority of adverse events were mild/moderate and consistent with opioid therapy. Mean pain scores at stable dose decreased from baseline. Investigators were generally satisfied with the conversion guide and, in 94% of cases, reported they would use it again. Conversion to MSN treatment using the standardized MSN conversion guide was an attainable goal in approximately half of the population of opioid-experienced patients with chronic moderate-to-severe pain. Investigators found the guide to be a useful tool to assist conversion of opioid-experienced patients to MSN.

Understanding long-term opioid prescribing for non-cancer pain in primary care: a qualitative study.

PubMed

McCrorie, Carolyn; Closs, S José; House, Allan; Petty, Duncan; Ziegler, Lucy; Glidewell, Liz; West, Robert; Foy, Robbie

2015-09-11

The place of opioids in the management of chronic, non-cancer pain is limited. Even so their use is escalating, leading to concerns that patients are prescribed strong opioids inappropriately and alternatives to medication are under-used. We aimed to understand the processes which bring about and perpetuate long-term prescribing of opioids for chronic, non-cancer pain. We held semi-structured interviews with patients and focus groups with general practitioners (GPs). Participants included 23 patients currently prescribed long-term opioids and 15 GPs from Leeds and Bradford, United Kingdom (UK). We used a grounded approach to the analysis of transcripts. Patients are driven by the needs for pain relief, explanation, and improvement or maintenance of quality of life. GPs' responses are shaped by how UK general practice is organised, available therapeutic choices and their expertise in managing chronic pain, especially when facing diagnostic uncertainty or when their own approach is at odds with the patient's wishes. Four features of the resulting transaction between patients and doctors influence prescribing: lack of clarity of strategy, including the risk of any plans being subverted by urgent demands; lack of certainty about locus of control in decision-making, especially in relation to prescribing; continuity in the doctor-patient relationship; and mutuality and trust. Problematic prescribing occurs when patients experience repeated consultations that do not meet their needs and GPs feel unable to negotiate alternative approaches to treatment. Therapeutic short-termism is perpetuated by inconsistent clinical encounters and the absence of mutually-agreed formulations of underlying problems and plans of action. Apart from commissioning improved access to appropriate specialist services, general practices should also consider how they manage problematic opioid prescribing and be prepared to set boundaries with patients.

Rates of opioid dispensing and overdose after introduction of abuse-deterrent extended-release oxycodone and withdrawal of propoxyphene.

PubMed

Larochelle, Marc R; Zhang, Fang; Ross-Degnan, Dennis; Wharam, J Frank

2015-06-01

In the second half of 2010, abuse-deterrent extended-release oxycodone hydrochloride (OxyContin; Purdue Pharma) was introduced and propoxyphene was withdrawn from the US market. The effect of these pharmaceutical market changes on opioid dispensing and overdose rates is unknown. To evaluate the association between 2 temporally proximate changes in the opioid market and opioid dispensing and overdose rates. Claims from a large national US health insurer were analyzed, using an interrupted time series study design. Participants included an open cohort of 31.3 million commercially insured members aged 18 to 64 years between January 1, 2003, and December 31, 2012, with median follow-up of 20 months (last follow-up, December 31, 2012). Introduction of abuse-deterrent OxyContin (resistant to crushing or dissolving) on August 9, 2010, and market withdrawal of propoxyphene on November 19, 2010. Standardized opioid dispensing rates and prescription opioid and heroin overdose rates were the primary outcomes. We used segmented regression to analyze changes in outcomes from 30 quarters before to 8 quarters after the 2 interventions. Two years after the opioid market changes, total opioid dispensing decreased by 19% from the expected rate (absolute change, -32.2 mg morphine-equivalent dose per member per quarter [95% CI, -38.1 to -26.3]). By opioid subtype, the absolute change in dispensing by milligrams of morphine-equivalent dose per member per quarter at 2 years was -11.3 (95% CI, -12.4 to -10.1) for extended-release oxycodone, 3.26 (95% CI, 1.40 to 5.12) for other long-acting opioids, -8.19 (95% CI, -9.30 to -7.08) for propoxyphene, and -16.2 (95% CI, -18.8 to -13.5) for other immediate-release opioids. Two years after the market changes, the estimated overdose rate attributed to prescription opioids decreased by 20% (absolute change, -1.10 per 100,000 members per quarter [95% CI, -1.47 to -0.74]), but heroin overdose increased by 23% (absolute change, 0.26 per 100,000 members per quarter [95% CI, -0.01 to 0.53]). Opioid dispensing and prescription opioid overdoses decreased substantially after 2 major changes in the pharmaceutical market in late 2010. Pharmaceutical market interventions may have value in combatting the prescription opioid overdose epidemic, but heroin overdose rates continue to increase. Complementary strategies to identify and treat opioid abuse and addiction are urgently needed.

Selective reward deficit in mice lacking beta-endorphin and enkephalin.

PubMed

Hayward, Michael D; Pintar, John E; Low, Malcolm J

2002-09-15

It has been impossible to unequivocally identify which endogenous opioids modulate the incentive value of rewarding stimuli because these peptides are not highly selective for any single opioid receptor subtype. Here, we present evidence based on the measurement of instrumental behavior of beta-endorphin and enkephalin knock-out mice that both opioid peptides play a positive role. A progressive ratio schedule was used to measure how hard an animal would work for food reinforcers. The loss of either opioid reduced responding under this schedule, regardless of the palatability of the three different formulas of reinforcers used. The phenotype of mice lacking both endogenous opioids was nearly identical to the phenotype of mice mutant for either individual opioid. Responses were tested in nondeprived and deprived feeding states but were reduced in beta-endorphin- and enkephalin-deficient mice only when they were maintained under nondeprived conditions. Other operant manipulations ruled out variables that might contribute nonspecifically to this result such as differences in acquisition, early satiation, motor performance deficit, and reduced resistance to extinction. In contrast to the effects on instrumental performance, the loss of either or both endogenous opioids did not influence preference for water flavored with sucrose or saccharin in a two-bottle free-choice drinking paradigm. We conclude that both beta-endorphin and enkephalin positively contribute to the incentive-motivation to acquire food reinforcers. Because the attenuation of operant responding was observed only during a nondeprived motivational state, the hedonics of feeding are likely altered rather than energy homeostasis.

Opioid Addiction: Social Problems Associated and Implications of Both Current and Possible Future Treatments, including Polymeric Therapeutics for Giving Up the Habit of Opioid Consumption.

PubMed

Benéitez, M Cristina; Gil-Alegre, M Esther

2017-01-01

Detoxification programmes seek to implement the most secure and compassionate ways of withdrawing from opiates so that the inevitable withdrawal symptoms and other complications are minimized. Once detoxification has been achieved, the next stage is to enable the patient to overcome his or her drug addiction by ensuring consumption is permanently and completely abandoned, only after which can the subject be regarded as fully recovered. A systematic search on the common databases of relevant papers published until 2016 inclusive. Our study of the available oral treatments for opioid dependence has revealed that no current treatment can actually claim to be fully effective. These treatments require daily oral administration and, consequently, regular visits to dispensaries, which in most cases results in a lack of patient compliance, which causes fluctuations in drug plasma levels. We then reviewed alternative treatments in the available scientific literature on polymeric sustained release formulations. Research has been done not only on release systems for detoxification but also on release systems for giving up the habit of taking opioids. These efforts have obtained the recent authorization of polymeric systems for use in patients that could help them to reduce their craving for drugs.

Treatment of pruritus with topically applied opiate receptor antagonist.

PubMed

Bigliardi, Paul L; Stammer, Holger; Jost, Gerhard; Rufli, Theo; Büchner, Stanislaw; Bigliardi-Qi, Mei

2007-06-01

Pruritus is the most common and distressing skin symptom, and treatment of itch is a problem for thousands of people. The currently available therapies are not very effective. Therefore there is an urgent need to find new effective topical drugs against itching. We conducted two separate studies to evaluate the efficacy of topically applied naltrexone, an opioid receptor antagonist, in the treatment of severe pruritus. The objective of the first open study was to correlate the clinical efficacy of topically applied naltrexone in different pruritic skin disorders to a change of epidermal mu-opiate receptor (MOR) expression. The second study was a double-blind, placebo-controlled, crossover study on pruritus in atopic dermatitis. Initially we performed an open pilot study on 18 patients with different chronic pruritic disorders using a topical formulation of 1% naltrexone for 2 weeks. A punch biopsy was performed in 11 patients before and after the application of the naltrexone cream and the staining of epidermal MOR was measured. Subsequently, a randomized, placebo-controlled, crossover trial was performed with the same formulation. We included in this trial 40 patients with localized and generalized atopic dermatitis with severe pruritus. In the open study more than 70% of the patients using the 1% naltrexone cream experienced a significant reduction of pruritus. More interestingly, the topical treatment with naltrexone caused an increase of epidermal MOR staining. The regulation of the epidermal opioid receptor correlated with the clinical assessment. The placebo-controlled, crossover trial demonstrated clearly that the cream containing naltrexone had an overall 29.4% better effect compared with placebo. The formulation containing naltrexone required a median of 46 minutes to reduce the itch symptoms to 50%; the placebo, 74 minutes. We could only take biopsy specimens in 11 patients, which means that a satisfactory statistical analysis of the changes of epidermal MOR staining was not possible. In addition, there was an insufficient number of patients with nephrogenic pruritus and pruritic psoriasis to draw definitive conclusions. The placebo-controlled study showed a significant advantage of topically applied naltrexone over the placebo formulation. This finding is supported by the biopsy results from the open studies, showing a regulation of MOR expression in epidermis after treatment with topical naltrexone, especially in atopic dermatitis. These results clearly show potential for topically applied opioid receptor antagonist in the treatment of pruritus. The placebo formulation also had some antipruritic effects. This underlines the importance of rehydration therapy for dry skin in the treatment of pruritus.

Authentication via wavefront-shaped optical responses

NASA Astrophysics Data System (ADS)

Eilers, Hergen; Anderson, Benjamin R.; Gunawidjaja, Ray

2018-02-01

Authentication/tamper-indication is required in a wide range of applications, including nuclear materials management and product counterfeit detection. State-of-the-art techniques include reflective particle tags, laser speckle authentication, and birefringent seals. Each of these passive techniques has its own advantages and disadvantages, including the need for complex image comparisons, limited flexibility, sensitivity to environmental conditions, limited functionality, etc. We have developed a new active approach to address some of these short-comings. The use of an active characterization technique adds more flexibility and additional layers of security over current techniques. Our approach uses randomly-distributed nanoparticles embedded in a polymer matrix (tag/seal) which is attached to the item to be secured. A spatial light modulator is used to adjust the wavefront of a laser which interacts with the tag/seal, and a detector is used to monitor this interaction. The interaction can occur in various ways, including transmittance, reflectance, fluorescence, random lasing, etc. For example, at the time of origination, the wavefront-shaped reflectance from a tag/seal can be adjusted to result in a specific pattern (symbol, words, etc.) Any tampering with the tag/seal would results in a disturbance of the random orientation of the nanoparticles and thus distort the reflectance pattern. A holographic waveplate could be inserted into the laser beam for verification. The absence/distortion of the original pattern would then indicate that tampering has occurred. We have tested the tag/seal's and authentication method's tamper-indicating ability using various attack methods, including mechanical, thermal, and chemical attacks, and have verified our material/method's robust tamper-indicating ability.

Optically resonant subwavelength films for tamper-indicating tags and seals

NASA Astrophysics Data System (ADS)

Alvine, Kyle J.; Suter, Jonathan D.; Bernacki, Bruce E.; Bennett, Wendy D.

2015-05-01

We present the design, modeling and performance of a proof-of-concept tamper indicating approach that exploits newlydeveloped subwavelength-patterned films. These films have a nanostructure-dependent resonant optical reflection that is wavelength, angle, and polarization dependent. As such, they can be tailored to fabricate overlay transparent films for tamper indication and authentication of sensitive or controlled materials not possible with currently-known technologies. An additional advantage is that the unique optical signature is dictated by the geometry and fabrication process of the nanostructures in the film, rather than on the material used. The essential structure unit in the subwavelength resonant coating is a nanoscale Open-Ring Resonator (ORR). This building block is fabricated by coating a dielectric nanoscale template with metal to form a hemispherical shell-like structure. This curved metallic shell structure has a cross-section with an intrinsic capacitance and inductance and is thus the optical equivalent to the well-known "LC" circuit where the capacitance and inductance are determined by the nanoshell dimensions. For structures with sub 100 nm scale, this resonance occurs in the visible electromagnetic spectrum, and in the IR for larger shells. Tampering of the film would be visible though misalignment of the angle-sensitive features in the film. It is additionally possible to add in intrinsic oxidation and strain sensitive matrix materials to further complicate tamper repair and counterfeiting. Cursory standoff readout would be relatively simple using a combination of a near-infrared (or visible) LED flashlight and polarizer or passively using room lighting illumination and a dispersive detector.

Ketamine for cancer pain: what is the evidence?

PubMed

Jonkman, Kelly; van de Donk, Tine; Dahan, Albert

2017-06-01

In this review, we assess the benefit of ketamine in the treatment of terminal cancer pain that is refractory to opioid treatment and/or complicated by neuropathy. While randomized controlled trials consistently show lack of clinical efficacy of ketamine in treating cancer pain, a large number of open-label studies and case series show benefit. Ketamine is an N-methyl-D-aspartate receptor antagonist that at low-dose has effective analgesic properties. In cancer pain, ketamine is usually prescribed as adjuvant to opioid therapy when pain becomes opioid resistant or when neuropathic pain symptoms dominate the clinical picture. A literature search revealed four randomized controlled trials that examined the benefit of oral, subcutaneous or intravenous ketamine in opioid refractory cancer pain. None showed clinically relevant benefit in relieving pain or reducing opioid consumption. This suggests absence of evidence of benefit for ketamine as adjuvant analgesic in cancer pain. These findings contrast the benefit from ketamine observed in a large number of open-label studies and (retrospective) case series. We relate the opposite outcomes to methodological issues. The complete picture is such that there is still insufficient evidence to state with certainty that ketamine is not effective in cancer pain.

A Mechanism for Anonymous Credit Card Systems

NASA Astrophysics Data System (ADS)

Tamura, Shinsuke; Yanase, Tatsuro

This paper proposes a mechanism for anonymous credit card systems, in which each credit card holder can conceal individual transactions from the credit card company, while enabling the credit card company to calculate the total expenditures of transactions of individual card holders during specified periods, and to identify card holders who executed dishonest transactions. Based on three existing mechanisms, i.e. anonymous authentication, blind signature and secure statistical data gathering, together with implicit transaction links proposed here, the proposed mechanism enables development of anonymous credit card systems without assuming any absolutely trustworthy entity like tamper resistant devices or organizations faithful both to the credit card company and card holders.

Benefit from NASA

NASA Image and Video Library

1995-01-01

Digital data matrix, used to identify the millions of Space Shuttle parts, is being commercialized to make barcoding tamper resistant and invisible to the naked eye. These codes are applied directly to the product regardless of shape, size or color. The markings can range from as small as four microns to as large as two square feet. Using the Vericode Symbol which include such details as the manufacturer, serial numbers, the lot number of the parent material, design changes, special processing to which the part was subjected-everything needed to determine accurately and automatically, the extent of the recall needed, which might be a couple of hundred cars instead of tens of thousands.

"Old Age and Loneliness: Cross-Sectional and Longitudinal Analyses in the Tampere Longitudinal Study on Aging"

ERIC Educational Resources Information Center

Jylha, Marja

2004-01-01

The purpose of this study was to examine whether older age is associated with increasing loneliness in people aged 60 and over. Data came from TamELSA, a population-based prospective longitudinal study in Tampere, Finland. The followup time was 20 years. Loneliness was measured by a single question--"Do you feel lonely?"--with the…

2007 Beyond SBIR Phase II: Bringing Technology Edge to the Warfighter

DTIC Science & Technology

2007-08-23

Systems Trade-Off Analysis and Optimization Verification and Validation On-Board Diagnostics and Self - healing Security and Anti-Tampering Rapid...verification; Safety and reliability analysis of flight and mission critical systems On-Board Diagnostics and Self - Healing Model-based monitoring and... self - healing On-board diagnostics and self - healing ; Autonomic computing; Network intrusion detection and prevention Anti-Tampering and Trust

Naval Arms Control: A Post-Cold War Reappraisal

DTIC Science & Technology

1991-06-01

94 A . BACKGRO UN D ......................................................................................... 94 B. WHY ...control, but that an appropriate time may come to exist in the future. For reasons why naval arms control may make more sense in the future, but not...34. Current Research on Peace And Violence. Tampere Peace Research Institute, Tampere Finland, Vol XIII, No. 2, 1990, pp. 65-86. For reasons why naval

Ion beam inertial confinement target

DOEpatents

Bangerter, Roger O.; Meeker, Donald J.

1985-01-01

A target for implosion by ion beams composed of a spherical shell of frozen DT surrounded by a low-density, low-Z pusher shell seeded with high-Z material, and a high-density tamper shell. The target has various applications in the inertial confinement technology. For certain applications, if desired, a low-density absorber shell may be positioned intermediate the pusher and tamper shells.

A Theorem and its Application to Finite Tampers

DOE R&D Accomplishments Database

Feynman, R. P.

1946-08-15

A theorem is derived which is useful in the analysis of neutron problems in which all neutrons have the same velocity. It is applied to determine extrapolated end-points, the asymptotic amplitude from a point source, and the neutron density at the surface of a medium. Formulas fro the effect of finite tampers are derived by its aid, and their accuracy discussed.

A tamper-indicating quantum seal

DOE PAGES

Williams, Brian P.; Britt, Keith A.; Humble, Travis S.

2016-01-04

Technical means for identifying when tampering occurs is a critical part of many containment and surveillance technologies. Conventional fiber optic seals provide methods for monitoring enclosed inventories, but they are vulnerable to spoofing attacks based on classical physics. We address these vulnerabilities with the development of a quantum seal that offers the ability to detect the intercept-resend attack using quantum integrity verification. Our approach represents an application of entanglement to provide guarantees in the authenticity of the seal state by verifying it was transmitted coherently. We implement these ideas using polarization-entangled photon pairs that are verified after passing through amore » fiber-optic channel testbed. Using binary detection theory, we find the probability of detecting inauthentic signals is greater than 0.9999 with a false alarm chance of 10 –9 for a 10 second sampling interval. In addition, we show how the Hong-Ou-Mandel effect concurrently provides a tight bound on redirection attack, in which tampering modifies the shape of the seal. Our measurements limit the tolerable path length change to sub-millimeter disturbances. As a result, these tamper-indicating features of the quantum seal offer unprecedented security for unattended monitoring systems.« less

An Efficient Semi-fragile Watermarking Scheme for Tamper Localization and Recovery

NASA Astrophysics Data System (ADS)

Hou, Xiang; Yang, Hui; Min, Lianquan

2018-03-01

To solve the problem that remote sensing images are vulnerable to be tampered, a semi-fragile watermarking scheme was proposed. Binary random matrix was used as the authentication watermark, which was embedded by quantizing the maximum absolute value of directional sub-bands coefficients. The average gray level of every non-overlapping 4×4 block was adopted as the recovery watermark, which was embedded in the least significant bit. Watermarking detection could be done directly without resorting to the original images. Experimental results showed our method was robust against rational distortions to a certain extent. At the same time, it was fragile to malicious manipulation, and realized accurate localization and approximate recovery of the tampered regions. Therefore, this scheme can protect the security of remote sensing image effectively.

[Use of opioids in palliative care of children with advanced cancer].

PubMed

Fernández Urtubia, Belem; Trevigno Bravo, Antonella; Rodríguez Zamora, Natalie; Palma Torres, Chery; Cid Barria, Luis

2016-01-01

Despite advances in the treatment of cancer in paediatric patients, 15% of children die from the illness progression in Chile, and pain is the most significant symptom in advanced stages. Although the World Health Organization guidelines demonstrate that opioids are fundamental in pain management, there is still resistance to their use. The main objective of this article was to describe the experience in the use of opioids for pain management in paediatric patients with advanced cancer in palliative care (PC). Retrospective study of patients admitted into the PC Program at the Hospital Roberto del Río between 2002 and 2013. Analysis was carried out on demographic data; oncological diagnosis; pain intensity on admission and discharge, according to validated scales; use of non-steroidal anti-inflammatory drugs; weak opioids; strong opioids; adjuvants drugs; the presence of secondary effects resulting from the use of morphine, and the need for palliative sedation. Of the 99 medical records analysed, the median age was 8 years, 64.6% were male, and there was a similar distribution in three oncological diagnosis groups. Upon admission, 43.4% presented intense to severe pain, and upon discharge there were four patients, but with a maximum VAS score of 7 in only one case. Of the 66 patients taking strong opioids, 89% required less than 0.5mg/kg/hr. Constipation was the most frequently observed secondary effect. Two thirds of the patients studied required strong opioids, with which adequate pain management was achieved, with no serious complications observed. The use of opioids in this group of patients, following a protocol, is considered effective and safe. Copyright © 2015 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

A Trustworthy Key Generation Prototype Based on DDR3 PUF for Wireless Sensor Networks

PubMed Central

Liu, Wenchao; Zhang, Zhenhua; Li, Miaoxin; Liu, Zhenglin

2014-01-01

Secret key leakage in wireless sensor networks (WSNs) is a high security risk especially when sensor nodes are deployed in hostile environment and physically accessible to attackers. With nowadays semi/fully-invasive attack techniques attackers can directly derive the cryptographic key from non-volatile memory (NVM) storage. Physically Unclonable Function (PUF) is a promising technology to resist node capture attacks, and it also provides a low cost and tamper-resistant key provisioning solution. In this paper, we designed a PUF based on double-data-rate SDRAM Type 3 (DDR3) memory by exploring its memory decay characteristics. We also described a prototype of 128-bit key generation based on DDR3 PUF with integrated fuzzy extractor. Due to the wide adoption of DDR3 memory in WSN, our proposed DDR3 PUF technology with high security levels and no required hardware changes is suitable for a wide range of WSN applications. PMID:24984058

The role of optics in secure credentials

NASA Astrophysics Data System (ADS)

Lichtenstein, Terri L.

2006-02-01

The global need for secure ID credentials has grown rapidly over the last few years. This is evident both in government and commercial sectors. Governmental programs include national ID card programs, permanent resident cards for noncitizens, biometric visas or border crossing cards, foreign worker ID programs and secure vehicle registration programs. The commercial need for secure credentials includes secure banking and financial services, security and access control systems and digital healthcare record cards. All of these programs necessitate the use of multiple tamper and counterfeit resistant features for credential authentication and cardholder verification. It is generally accepted that a secure credential should include a combination of overt, covert and forensic security features. The LaserCard optical memory card is a proven example of a secure credential that uses a variety of optical features to enhance its counterfeit resistance and reliability. This paper will review those features and how they interact to create a better credential.

New drugs for pain management in advanced cancer patients.

PubMed

Mercadante, Sebastiano

2017-04-01

Advanced cancer patients represent a frail population, often requiring aggressive pain management, particularly in the late stage of disease, when untreated pain is one the most important causes of suffering. Areas covered: In the last decade, a series of new analgesics have been introduced in the market to offer additional options amongst existent drugs. The characteristics of these drugs, their efficacy and tolerability are examined on the basis of existent studies. Expert opinion: Although new analgesic preparations have been developed in recent years, no specific drug has provided a better analgesic performance in comparison with others. Some technologies have been developed to increase the safety or decrease the opioid-related adverse effects, with some molecules providing extra-opioid analgesia. However, existing studies did not present relevant advantages over traditional opioids. The new formulations developed to provide a rapid and non-invasive analgesia for breakthrough pain have really changed the approach to this phenomenon, characterized by a specific temporal pattern requiring a short onset, and duration of the analgesic effect. The availability of new drugs, indeed, may enlarge the possibilities of individualizing treatment, according to specific clinical needs and individual response.

Evaluation of an Extended-Release, Abuse-Deterrent, Microsphere-in-Capsule Analgesic for the Management of Patients with Chronic Pain With Dysphagia (CPD).

PubMed

Fleming, Alison B; Carlson, Douglas R; Varanasi, Ravi K; Grima, Michael; Mayock, Stephen P; Saim, Said; Kopecky, Ernest A

2016-03-01

Patients who have chronic pain with dysphagia (difficulty swallowing) (CPD) often have difficulty taking oral medication and, as such, alter their medications by crushing or chewing in an attempt to make it easier to swallow. Such manipulation of currently marketed, extended-release (ER) opioid analgesics can significantly alter the pharmacokinetic (PK) properties of the formulations, resulting in poor treatment outcome or serious adverse events. There is an unmet medical need for oral ER opioid formulations suitable for patients with CPD. The primary objectives of this study were to conduct in vitro studies to evaluate alternate means of administration of a new, extended-release (ER), abuse-deterrent, microsphere-in-capsule formulation of oxycodone for patients with CPD. Specifically, these studies investigated the in vitro equivalence of drug release rates from Oxycodone DETERx® ER intact capsules (control condition) and administration via alternate modes-opening the capsule and sprinkling the microspheres onto soft foods or administration through enteral tubes. Secondary objectives were to compare alternate modes of administration of Oxycodone DETERx® to a commercially available ER-morphine product. Soft food study: Oxycodone DETERx® microspheres were sprinkled onto and mixed with several soft foods (ie, applesauce, vanilla pudding, strawberry jam, yogurt, and vanilla ice cream); the effect of drug contact time (0, 30, and 60 minutes) on drug release was studied. Enteral tube study: Oxycodone DETERx® microspheres were administered through varying sizes of nasogastric (10 and 12 Fr.) tubes and a 16 Fr. gastrostomy tube using 5 different delivery vehicles (ie, water, liquid nutritional feeds [Jevity®, Ensure®], and milk [whole milk and 2% milk]). Drug release rate was characterized using a standard in vitro dissolution methodology; dissolution of intact Oxycodone DETERx® capsules served as the control for both the soft food and enteral tube studies. Oxycodone concentration was measured using a standardized high-performance liquid chromatography (HPLC) assay. Similarity factor (f2) analysis was used to compare similarity of the dissolution profiles of test and control conditions. The mean dissolution profile of Oxycodone DETERx® microspheres sprinkled onto and mixed with each of the soft foods were similar (f2 > 50) to that of the control. Study drug-food contact time did not impact dissolution profiles. The dissolution data obtained from Oxycodone DETERx® microspheres passed through enteral feeding tubes of varying sizes were similar (f2 > 50) to that of the control. Unlike a marketed morphine sulfate ER pellet formulation, Oxycodone DETERx® did not clog any of the studied enteral tubes. A new ER, abuse-deterrent, microsphere-in-capsule formulation of oxycodone can be administered by sprinkling onto soft food without affecting the drug release profile of the formulation. The formulation can also be administered directly via enteral tubes without affecting drug release and without clogging enteral tubes. Oxycodone DETERx® may offer physicians and patients with CPD an alternate treatment option, especially in those patients who have dysphagia or an aversion to swallowing monolithic tablet/capsule formulations and for whom analgesic patches or other opioid formulations are not a viable therapeutic option. © 2015 World Institute of Pain.

Triboluminescent tamper-indicating device

DOEpatents

Johnston, Roger G.; Garcia, Anthony R. E.

2002-01-01

A tamper-indicating device is described. The device has a transparent or translucent cylindrical body that includes triboluminescent material, and an outer opaque layer that prevents ambient light from entering. A chamber in the body holds an undeveloped piece of photographic film bearing an image. The device is assembled from two body members. One of the body members includes a recess for storing film and an optical assembly that can be adjusted to prevent light from passing through the assembly and exposing the film. To use the device with a hasp, the body members are positioned on opposite sides of a hasp, inserted through the hasp, and attached. The optical assembly is then manipulated to allow any light generated from the triboluminescent materials during a tampering activity that damages the device to reach the film and destroy the image on the film.

Security protection of DICOM medical images using dual-layer reversible watermarking with tamper detection capability.

PubMed

Tan, Chun Kiat; Ng, Jason Changwei; Xu, Xiaotian; Poh, Chueh Loo; Guan, Yong Liang; Sheah, Kenneth

2011-06-01

Teleradiology applications and universal availability of patient records using web-based technology are rapidly gaining importance. Consequently, digital medical image security has become an important issue when images and their pertinent patient information are transmitted across public networks, such as the Internet. Health mandates such as the Health Insurance Portability and Accountability Act require healthcare providers to adhere to security measures in order to protect sensitive patient information. This paper presents a fully reversible, dual-layer watermarking scheme with tamper detection capability for medical images. The scheme utilizes concepts of public-key cryptography and reversible data-hiding technique. The scheme was tested using medical images in DICOM format. The results show that the scheme is able to ensure image authenticity and integrity, and to locate tampered regions in the images.

Characterizing and Implementing Efficient Primitives for Privacy-Preserving Computation

DTIC Science & Technology

2015-07-01

the mobile device. From this, the mobile will detect any tampering from the malicious party by a discrepancy in these returned values, eliminating...the need for an output MAC. If no tampering is detected , the mobile device then decrypts the output of computation. APPROVED FOR PUBLIC RELEASE...useful error messages when the compiler detects a problem with an application, making debugging the application significantly easier than with other

Adolescent pedometer protocols: examining reactivity, tampering and participants' perceptions.

PubMed

Scott, Joseph John; Morgan, Philip James; Plotnikoff, Ronald Cyril; Trost, Stewart Graeme; Lubans, David Revalds

2014-01-01

The aim of this study was to investigate adolescents' potential reactivity and tampering while wearing pedometers by comparing different monitoring protocols to accelerometer output. The sample included adolescents (N = 123, age range = 14-15 years) from three secondary schools in New South Wales, Australia. Schools were randomised to one of the three pedometer monitoring protocols: (i) daily sealed (DS) pedometer group, (ii) unsealed (US) pedometer group or (iii) weekly sealed (WS) pedometer group. Participants wore pedometers (Yamax Digi-Walker CW700, Yamax Corporation, Kumamoto City, Japan) and accelerometers (Actigraph GT3X+, Pensacola, USA) simultaneously for seven days. Repeated measures analysis of variance was used to examine potential reactivity. Bivariate correlations between step counts and accelerometer output were calculated to explore potential tampering. The correlation between accelerometer output and pedometer steps/day was strongest among participants in the WS group (r = 0.82, P ≤ 0.001), compared to the US (r = 0.63, P ≤ 0.001) and DS (r = 0.16, P = 0.324) groups. The DS (P ≤ 0.001) and US (P = 0.003), but not the WS (P = 0.891), groups showed evidence of reactivity. The results suggest that reactivity and tampering does occur in adolescents and contrary to existing research, pedometer monitoring protocols may influence participant behaviour.

Detection of inter-frame forgeries in digital videos.

PubMed

K, Sitara; Mehtre, B M

2018-05-26

Videos are acceptable as evidence in the court of law, provided its authenticity and integrity are scientifically validated. Videos recorded by surveillance systems are susceptible to malicious alterations of visual content by perpetrators locally or remotely. Such malicious alterations of video contents (called video forgeries) are categorized into inter-frame and intra-frame forgeries. In this paper, we propose inter-frame forgery detection techniques using tamper traces from spatio-temporal and compressed domains. Pristine videos containing frames that are recorded during sudden camera zooming event, may get wrongly classified as tampered videos leading to an increase in false positives. To address this issue, we propose a method for zooming detection and it is incorporated in video tampering detection. Frame shuffling detection, which was not explored so far is also addressed in our work. Our method is capable of differentiating various inter-frame tamper events and its localization in the temporal domain. The proposed system is tested on 23,586 videos of which 2346 are pristine and rest of them are candidates of inter-frame forged videos. Experimental results show that we have successfully detected frame shuffling with encouraging accuracy rates. We have achieved improved accuracy on forgery detection in frame insertion, frame deletion and frame duplication. Copyright © 2018. Published by Elsevier B.V.

The introduction of buprenorphine-naloxone film in opioid substitution therapy in Australia: Uptake and issues arising from changing buprenorphine formulations.

PubMed

Larance, Briony; Dietze, Paul; Ali, Robert; Lintzeris, Nicholas; White, Nancy; Jenkinson, Rebecca; Degenhardt, Louisa

2015-11-01

Buprenorphine-naloxone (BNX) film for opioid dependence treatment was introduced in Australia in 2011. A key difference in State policy approaches saw transfer from BNX tablets to BNX film mandated in South Australia (SA) with New South Wales (NSW) and Victoria (VIC) having less stringent policies. This study examined (i) how initiations and transfers were implemented, (ii) the profile and predictors of adverse effects as self-reported by BNX film clients, and (iii) dosing issues. Survey of 334 buprenorphine (BPN), BNX tablet and BNX film clients and semi-structured interviews with 39 key experts (KEs) in 2012. Comparisons are made between clients interviewed in SA versus NSW and VIC combined. Among the 180 current BNX film clients, 23% started treatment on BNX film, 18% requested a transfer to BNX film and 59% (n = 106) reported their clinic/prescriber recommended transfer to BNX film. Among clients who were offered but refused a transfer to BNX film (n = 66), the most common reason was 'I am happy with my current treatment and do not see a reason to change' (53%). Some opioid substitution therapy clients and KE viewed transfers as 'forced' (i.e. no choice of buprenorphine formulation). Multivariable regression showed residing in SA (vs. NSW/VIC) and a shorter length of current treatment episode were associated with more BNX film-attributed adverse effects but clinic/prescriber-recommended transfer was not. The introduction of BNX film in Australia varied across States. A perception of restricted choice in medication may have undermined initial acceptance in SA. © 2015 Australasian Professional Society on Alcohol and other Drugs.

Complex mixtures, complex responses: Assessing pharmaceutical mixtures using field and laboratory approaches

USGS Publications Warehouse

Schoenfuss, Heiko L.; Furlong, Edward T.; Phillips, Patrick J.; Scott, Tia-Marie; Kolpin, Dana W.; Cetkovic-Cvrlje, Marina; Lesteberg, Kelsey E.; Rearick, Daniel C.

2016-01-01

Pharmaceuticals are present in low concentrations (<100 ng/L) in most municipal wastewater effluents but may be elevated locally because of factors such as input from pharmaceutical formulation facilities. Using existing concentration data, the authors assessed pharmaceuticals in laboratory exposures of fathead minnows (Pimephales promelas) and added environmental complexity through effluent exposures. In the laboratory, larval and mature minnows were exposed to a simple opioid mixture (hydrocodone, methadone, and oxycodone), an opioid agonist (tramadol), a muscle relaxant (methocarbamol), a simple antidepressant mixture (fluoxetine, paroxetine, venlafaxine), a sleep aid (temazepam), or a complex mixture of all compounds. Larval minnow response to effluent exposure was not consistent. The 2010 exposures resulted in shorter exposed minnow larvae, whereas the larvae exposed in 2012 exhibited altered escape behavior. Mature minnows exhibited altered hepatosomatic indices, with the strongest effects in females and in mixture exposures. In addition, laboratory-exposed, mature male minnows exposed to all pharmaceuticals (except the selective serotonin reuptake inhibitor mixture) defended nest sites less rigorously than fish in the control group. Tramadol or antidepressant mixture exposure resulted in increased splenic T lymphocytes. Only male minnows exposed to whole effluent responded with increased plasma vitellogenin concentrations. Female minnows exposed to pharmaceuticals (except the opioid mixture) had larger livers, likely as a compensatory result of greater prominence of vacuoles in liver hepatocytes. The observed alteration of apical endpoints central to sustaining fish populations confirms that effluents containing waste streams from pharmaceutical formulation facilities can adversely impact fish populations but that the effects may not be temporally consistent. The present study highlights the importance of including diverse biological endpoints spanning levels of biological organization and life stages when assessing contaminant interactions.

New trends in the development of opioid peptide analogues as advanced remedies for pain relief.

PubMed

Gentilucci, Luca

2004-01-01

The search for new peptides to be used as analgesics in place of morphine has been mainly directed to develop peptide analogues or peptidomimetics having higher biological stability and receptor selectivity. Indeed, most of the alkaloid opioid counterindications are due to the scarce stability and the contemporary activation of different receptor types. However, the development of several extremely stable and selective peptide ligands for the different opioid receptors, and the recent discovery of the micro-receptor selective endomorphins, rendered this search less fundamental. In recent years, other opioid peptide properties have been investigated in the search for new pharmacological tools. The utility of a drug depends on its ability to reach appropriate receptors at the target tissue and to remain metabolically stable in order to produce the desired effect. This review deals with the recent investigations on peptide bioavailability, in particular barrier penetration and resistance against enzymatic degradation; with the development of peptides having activity at different receptors; with chimeric peptides, with propeptides, and with non-conventional peptides, lacking basic pharmacophoric features.

Budgetary impact of the utilization of buprenorphine/naloxone sublingual film and tablet for Medicaid in the United States.

PubMed

Asche, Carl V; Clay, Emilie; Kharitonova, Elizaveta; Zah, Vladimir; Ruby, Jane; Aballéa, Samuel

2015-01-01

The buprenorphine/naloxone combination for the treatment of opioid dependence is available in a film or tablet formulation. Recent retrospective studies demonstrated that treatment with the sublingual film formulation is associated with improved treatment retention and lower healthcare costs. In March 2013, generic buprenorphine/naloxone tablets were approved in the US. A budget impact model was built to compare healthcare expenditures for different market shares of sublingual film and tablet. A Markov model was developed to track a cohort of opioid dependent patients treated with sublingual film or tablet through the following treatment phases: initiation, maintenance, discontinuation, off-treatment and reinitiation. Transition probabilities and costs for each phase were estimated from the MarketScan Medicaid database for the period between 1 March 2010 and 30 June 2012. The total expenditure for the plan and expenditure per plan member per month were predicted over 5 years. Two market share scenarios were considered: 1) sublingual film is progressively replaced by generic tablet (current situation) and 2) the sublingual film holds a market share of 100%. Predicted total costs over 5 years were $6400 million when the sublingual film holds a market share of 100% (as per Scenario 2) which is lower than when sublingual film is progressively replaced by generic tablet (current situation as per Scenario 1) by $64 million. These savings were mostly driven by inpatient care ($56 million saved over 5 years), followed by emergency room care ($27 million) and pharmaceutical costs ($24 million). Costs of outpatient care attenuated the difference as they were predicted to be higher by $44 million in Scenario 2. The reduction in total cost per member per month reached $0.027 in the fifth year. Results were most sensitive to price rebates and to the probability of non-psychiatric hospitalization. While using the sublingual film formulation for more patients treated with buprenorphine/naloxone is predicted to increase outpatient care costs, it would generate savings in emergency care and hospitalizations. In the treatment of opioid dependence, total direct medical costs for Medicaid would be lower for sublingual film treated patients, at current drug prices.

Opioid and amphetamine dependence is associated with methicillin-resistant Staphylococcus aureus (MRSA): An epidemiological register study with 73,201 Swedish in- and outpatients 1997-2013.

PubMed

Dahlman, Disa; Berge, Jonas; Nilsson, Anna C; Kral, Alex H; Bjorkman, Per; Hakansson, Anders C

2017-02-01

While methicillin-resistant Staphylococcus aureus (MRSA) is increasing in prevalence globally, Sweden is still a low-prevalence country enabling studies on the natural MRSA spread in subpopulations unaffected by a surrounding highly infected population. Substance dependence and injection drug use have been risk factors for MRSA carriage and infection in other countries. In this retrospective, longitudinal register study, we investigated MRSA epidemiology 1997-2013 in opioid and amphetamine-dependent individuals, in comparison with alcohol-dependent subjects. Data from the national Swedish in- and outpatients registers included 73,201 individuals from 1997, 1999, 2004, 2009 and 2013. We analyzed substance use disorder and demographic predictors for MRSA using generalized estimating equations. The main finding was that both opioid (adjusted odds ratio [AOR] = 2.82; 95% confidence interval [CI] = 2.16, 3.67) and amphetamine dependence (AOR = 2.71; 95% CI = 1.70, 4.16) were significantly associated with MRSA diagnosis compared with alcohol dependence, when adjusting for age, sex and year. These findings are of value to understand the dynamics of MRSA epidemiology among substance dependent persons with presumably low socioeconomic status and potential injection drug use, and implicate repeated surveillance of MRSA among these patients.

Ranking of sabotage/tampering avoidance technology alternatives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrews, W.B.; Tabatabai, A.S.; Powers, T.B.

1986-01-01

Pacific Northwest Laboratory conducted a study to evaluate alternatives to the design and operation of nuclear power plants, emphasizing a reduction of their vulnerability to sabotage. Estimates of core melt accident frequency during normal operations and from sabotage/tampering events were used to rank the alternatives. Core melt frequency for normal operations was estimated using sensitivity analysis of results of probabilistic risk assessments. Core melt frequency for sabotage/tampering was estimated by developing a model based on probabilistic risk analyses, historic data, engineering judgment, and safeguards analyses of plant locations where core melt events could be initiated. Results indicate the most effectivemore » alternatives focus on large areas of the plant, increase safety system redundancy, and reduce reliance on single locations for mitigation of transients. Less effective options focus on specific areas of the plant, reduce reliance on some plant areas for safe shutdown, and focus on less vulnerable targets.« less

Detection of shifted double JPEG compression by an adaptive DCT coefficient model

NASA Astrophysics Data System (ADS)

Wang, Shi-Lin; Liew, Alan Wee-Chung; Li, Sheng-Hong; Zhang, Yu-Jin; Li, Jian-Hua

2014-12-01

In many JPEG image splicing forgeries, the tampered image patch has been JPEG-compressed twice with different block alignments. Such phenomenon in JPEG image forgeries is called the shifted double JPEG (SDJPEG) compression effect. Detection of SDJPEG-compressed patches could help in detecting and locating the tampered region. However, the current SDJPEG detection methods do not provide satisfactory results especially when the tampered region is small. In this paper, we propose a new SDJPEG detection method based on an adaptive discrete cosine transform (DCT) coefficient model. DCT coefficient distributions for SDJPEG and non-SDJPEG patches have been analyzed and a discriminative feature has been proposed to perform the two-class classification. An adaptive approach is employed to select the most discriminative DCT modes for SDJPEG detection. The experimental results show that the proposed approach can achieve much better results compared with some existing approaches in SDJPEG patch detection especially when the patch size is small.

Effect size comparison of ketorolac nasal spray and commonly prescribed oral combination opioids for pain relief after third molar extraction surgery.

PubMed

Niebler, Gwendolyn; Dayno, Jeffrey

2016-01-01

Opioids are frequently used for treatment of moderate to severe short-term pain, but concerns exist about this treatment approach. Ketorolac tromethamine nasal spray, a nonsteroidal anti-inflammatory, is indicated for the short-term management of moderate to moderately severe pain requiring analgesia at the opioid level. However, there are no direct comparison studies between ketorolac nasal spray and opioids. The objective of this study was to use an effect size analysis to compare the effectiveness of ketorolac nasal spray with oral combination opioid formulations in treating moderate to severe short-term pain. An effect size analysis of three randomized, double-blind, placebo-controlled studies of third molar extraction surgery compared pain relief with ketorolac nasal spray and commonly prescribed combination opioids including hydrocodone/acetaminophen (APAP), oxycodone/APAP, oxycodone/ibuprofen and tramadol HCl/APAP. Effect size comparisons were made using total pain relief scores (TOTPAR6 or TOTPAR8; the weighted sum of pain relief scores through 6 or 8 h). Pain relief was measured using a five-point categorical rating scale (0 = none; 4 = complete). The effect size equivalent correlation, r, was determined using an online effect size calculator. The treatment effect size r compared with placebo was classified using established criteria (small = 0.20-0.49, moderate = 0.50-0.79 and large = ≥ 0.80). TOTPAR6 data indicated a moderate effect size for ketorolac nasal spray 31.5 mg (0.51) and oxycodone/ibuprofen 5/400 mg (0.64) and a small effect size for hydrocodone/APAP 7.5/500 mg (0.24) and oxycodone/APAP 5/325 mg (0.32). TOTPAR8 data indicated small effect sizes for ketorolac nasal spray (0.48), hydrocodone/APAP 10/650 mg (0.43), tramadol HCl/APAP 75/650 mg (0.35) and tramadol HCl/APAP 37.5/325 mg (0.17). The treatment effect sizes of ketorolac nasal spray were similar to or higher than the opioid comparators after third molar surgery, a well-accepted pain model. These results support ketorolac nasal spray as an effective treatment for moderate to moderately severe short-term pain.

Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial.

PubMed

DeFulio, Anthony; Everly, Jeffrey J; Leoutsakos, Jeannie-Marie S; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E; Silverman, Kenneth

2012-01-01

Naltrexone provides excellent opioid blockade, but its clinical utility is limited because opioid-dependent patients typically refuse it. An injectable suspension of naltrexone for extended release (XR-NTX) was recently approved by the FDA for treatment of opioid dependence. XR-NTX treatment may require concurrent behavioral intervention to maximize adherence and effectiveness, thus we sought to evaluate employment-based reinforcement as a method of improving adherence to XR-NTX in opiate dependent adults. Opioid-dependent adults (n=38) were detoxified and inducted onto oral naltrexone, then randomly assigned to contingency or prescription conditions. Participants received up to six doses of XR-NTX at four-week intervals. All participants could earn vouchers for attendance and performance at a therapeutic workplace. Contingency participants were required to accept XR-NTX injections to access the workplace and earn vouchers. Prescription participants could earn vouchers independent of their acceptance of XR-NTX injections. Contingency participants accepted significantly more naltrexone injections than prescription participants (87% versus 52%, p=.002), and were more likely to accept all injections (74% versus 26%, p=.004). Participants in the two conditions provided similar percentages of samples negative for opiates (72% versus 65%) and for cocaine (58% versus 54%). Opiate positivity was significantly more likely when samples were also cocaine positive, independent of naltrexone blockade (p=.002). Long-term adherence to XR-NTX in unemployed opiate dependent adults is low under usual care conditions. Employment-based reinforcement can maintain adherence to XR-NTX. Ongoing cocaine use appears to interfere with the clinical effectiveness of XR-NTX on opiate use. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Forensic detection of noise addition in digital images

NASA Astrophysics Data System (ADS)

Cao, Gang; Zhao, Yao; Ni, Rongrong; Ou, Bo; Wang, Yongbin

2014-03-01

We proposed a technique to detect the global addition of noise to a digital image. As an anti-forensics tool, noise addition is typically used to disguise the visual traces of image tampering or to remove the statistical artifacts left behind by other operations. As such, the blind detection of noise addition has become imperative as well as beneficial to authenticate the image content and recover the image processing history, which is the goal of general forensics techniques. Specifically, the special image blocks, including constant and strip ones, are used to construct the features for identifying noise addition manipulation. The influence of noising on blockwise pixel value distribution is formulated and analyzed formally. The methodology of detectability recognition followed by binary decision is proposed to ensure the applicability and reliability of noising detection. Extensive experimental results demonstrate the efficacy of our proposed noising detector.

The US Opioid Crisis: Current Federal and State Legal Issues.

PubMed

Soelberg, Cobin D; Brown, Raeford E; Du Vivier, Derick; Meyer, John E; Ramachandran, Banu K

2017-11-01

The United States is in the midst of a devastating opioid misuse epidemic leading to over 33,000 deaths per year from both prescription and illegal opioids. Roughly half of these deaths are attributable to prescription opioids. Federal and state governments have only recently begun to grasp the magnitude of this public health crisis. In 2016, the Centers for Disease Control and Prevention released their Guidelines for Prescribing Opioids for Chronic Pain. While not comprehensive in scope, these guidelines attempt to control and regulate opioid prescribing. Other federal agencies involved with the federal regulatory effort include the Food and Drug Administration (FDA), the Drug Enforcement Agency (DEA), and the Department of Justice. Each federal agency has a unique role in helping to stem the burgeoning opioid misuse epidemic. The DEA, working with the Department of Justice, has enforcement power to prosecute pill mills and physicians for illegal prescribing. The DEA could also implement use of prescription drug monitoring programs (PDMPs), currently administered at the state level, and use of electronic prescribing for schedule II and III medications. The FDA has authority to approve new and safer formulations of immediate- and long-acting opioid medications. More importantly, the FDA can also ask pharmaceutical companies to cease manufacturing a drug. Additionally, state agencies play a critical role in reducing overdose deaths, protecting the public safety, and promoting the medically appropriate treatment of pain. One of the states' primary roles is the regulation of practice of medicine and the insurance industry within their borders. Utilizing this authority, states can both educate physicians about the dangers of opioids and make physician licensure dependent on registering and using PDMPs when prescribing controlled substances. Almost every state has implemented a PDMP to some degree; however, in addition to mandating their use, increased interstate sharing of prescription information would greatly improve PDMPs' effectiveness. Further, states have the flexibility to promote innovative interventions to reduce harm such as legislation allowing naloxone access without a prescription. While relatively new, these types of laws have allowed first responders, patients, and families access to a lifesaving drug. Finally, states are at the forefront of litigation against pharmaceutical manufacturers. This approach is described as analogous to the initial steps in fighting tobacco companies. In addition to fighting for dollars to support drug treatment programs and education efforts, states are pursuing these lawsuits as a means of holding pharmaceutical companies accountable for misleading marketing of a dangerous product.

Self-recovery reversible image watermarking algorithm

PubMed Central

Sun, He; Gao, Shangbing; Jin, Shenghua

2018-01-01

The integrity of image content is essential, although most watermarking algorithms can achieve image authentication but not automatically repair damaged areas or restore the original image. In this paper, a self-recovery reversible image watermarking algorithm is proposed to recover the tampered areas effectively. First of all, the original image is divided into homogeneous blocks and non-homogeneous blocks through multi-scale decomposition, and the feature information of each block is calculated as the recovery watermark. Then, the original image is divided into 4×4 non-overlapping blocks classified into smooth blocks and texture blocks according to image textures. Finally, the recovery watermark generated by homogeneous blocks and error-correcting codes is embedded into the corresponding smooth block by mapping; watermark information generated by non-homogeneous blocks and error-correcting codes is embedded into the corresponding non-embedded smooth block and the texture block via mapping. The correlation attack is detected by invariant moments when the watermarked image is attacked. To determine whether a sub-block has been tampered with, its feature is calculated and the recovery watermark is extracted from the corresponding block. If the image has been tampered with, it can be recovered. The experimental results show that the proposed algorithm can effectively recover the tampered areas with high accuracy and high quality. The algorithm is characterized by sound visual quality and excellent image restoration. PMID:29920528

Synthetic Geopolymers for Controlled Delivery of Oxycodone: Adjustable and Nanostructured Porosity Enables Tunable and Sustained Drug Release

PubMed Central

Forsgren, Johan; Pedersen, Christian; Strømme, Maria; Engqvist, Håkan

2011-01-01

In this article we for the first time present a fully synthetic mesoporous geopolymer drug carrier for controlled release of opioids. Nanoparticulate precursor powders with different Al/Si-ratios were synthesized by a sol-gel route and used in the preparation of different geopolymers, which could be structurally tailored by adjusting the Al/Si-ratio and the curing temperatures. In particular, it was shown that the pore sizes of the geopolymers decreased with increasing Al/Si ratio and that completely mesoporous geopolymers could be produced from precursor particles with the Al/Si ratio 2∶1. The mesoporosity was shown to be associated with a sustained and linear in vitro release profile of the opioid oxycodone. A clinically relevant release period of about 12 h was obtained by adjusting the size of the pellets. The easily fabricated and tunable geopolymers presented in this study constitute a novel approach in the development of controlled release formulations, not only for opioids, but whenever the clinical indication is best treated with a constant supply of drugs and when the mechanical stability of the delivery vehicle is crucial. PMID:21423616

Endomorphin derivatives with improved pharmacological properties.

PubMed

Varamini, Pegah; Blanchfield, Joanne T; Toth, Istvan

2013-01-01

Centrally acting opioids, such as morphine, are the most frequently used analgesic agents for the treatment of severe pain. However, their usefulness is limited by the production of a range of adverse effects such as constipation, respiratory depression, tolerance and physical dependence. In addition, opioids generally exhibit poor efficacy against neuropathic pain. Endomorphin-1 and -2, two endogenous opioid peptides, have been shown to produce potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, native endomorphins are poorly suited to clinical applications without modifications. Like all small peptides, endomorphins suffer from poor metabolic stability and a relative inability to penetrate the gastro-intestinal mucosa and blood-brain-barrier. Since the discovery of endomorphins in 1997, a huge number of endomorphin analogs have been designed and synthesized with the aim of developing compounds with improved barrier penetration and resistance to enzymatic degradation. In this review we describe various strategies that have been adopted so far to conquer the major drawbacks associated with endomorphins. They include chemical modifications to produce locally or globally-restricted peptide analogs in addition to application of peptidase inhibitors, which is of minor importance compared to the former strategy. Diverse approaches that resulted in the design and synthesis of pharmacologically active endomorphin analogs with less adverse effects are also discussed giving an insight into the development of opioid peptides with an improved side effect profile.

Role of opioid tone in the pathophysiology of hyperinsulinemia and insulin resistance in polycystic ovarian disease.

PubMed

Fulghesu, A M; Ciampelli, M; Guido, M; Murgia, F; Caruso, A; Mancuso, S; Lanzone, A

1998-02-01

Hyperinsulinemia secondary to a poorly characterized disorder of insulin action is a feature of polycystic ovarian disease (PCOD). On the other hand, being generally admitted that opioids may play a role in glycoregulation and that opioid tone is altered in PCOD, an involvement of the opioids in determining the hyperinsulinemia of PCOD patients could be suggested. The aim of this study was to evaluate the effect of a chronic opioid blockade on insulin metabolism and peripheral insulin sensitivity in PCOD hyperinsulinemic patients. Twenty-three women with PCOD were studied. An oral glucose tolerance test (OGTT) and a clamp study were performed at baseline (during the follicular phase) and after 6 weeks of naltrexone administration (50 mg/d orally). Based on the insulinemic response to the OGTT, 16 women were classified as hyperinsulinemic and seven as normoinsulinemic. Naltrexone treatment significantly reduced fasting (P < .05) and area under the curve (AUC) (P < .02) plasma insulin levels only in the hyperinsulinemic group. Moreover, hyperinsulinemic patients showed similar C-peptide incremental areas after naltrexone treatment, whereas in the same patients the fractional hepatic insulin extraction calculated from the incremental areas of insulin and C-peptide was found to be increased after chronic opioid blockade by naltrexone. For peripheral insulin sensitivity, the hyperinsulinemic group showed significantly lower (P < .01) total-body glucose utilization (M) compared with the normoinsulinemic group. No change in the M value was found after treatment in both groups. These data suggest that the insulin sensitivity and hyperinsulinemia after an OGTT are two distinct deranged features of the insulin disorder of PCOD patients.

Barriers to Using Nonpharmacologic Approaches and Reducing Opioid Use in Primary Care.

PubMed

Giannitrapani, Karleen F; Ahluwalia, Sangeeta C; McCaa, Matthew; Pisciotta, Maura; Dobscha, Steven; Lorenz, Karl A

2017-10-20

Opioid prescribing for chronic pain, including the potential for over-reliance and misuse, is a public health concern. In the context of Veterans Administration (VA) primary care team-based pain management, we aimed to understand providers' perceptions of barriers to reducing opioid use and improving the use of nonpharmacologic pain management therapies (NPTs) for chronic pain. A semistructured interview elucidated provider experiences with assessing and managing pain. Emergent themes were mapped to known dimensions of VA primary care access. Informants included 60 primary care providers, registered nurses, licensed practical nurses, clerks, psychologists, and social workers at two VA Medical Centers. Nine multidisciplinary focus groups. Provider perceptions of barriers to reducing opioids and improving use of NPTs for patients with chronic pain clustered around availability and access. Barriers to NPT access included the following subthemes: geographical (patient distance from service), financial (out-of-pocket cost to patient), temporal (treatment time delays), cultural (belief that NPTs increased provider workload, perception of insufficient training on NPTs, perceptions of patient resistance to change, confrontation avoidance, and insufficient leadership support), and digital (measure used for pain assessment, older patients hesitant to use technology, providers overwhelmed by information). Decreasing reliance on opioids for chronic pain requires a commitment to local availability and provider-facing strategies that increase efficacy in prescribing NPTs. Policies and interventions for decreasing utilization of opioids and increasing use of NPTs should comprehensively consider access barriers. 2017 American Academy of Pain Medicine. This work is written by US Government employees and is in the public domain in the US.

Studies of new perfluoroether elastomeric sealants. [for aircraft fuel tanks

NASA Technical Reports Server (NTRS)

Basiulis, D. I.; Salisbury, D. P.

1981-01-01

Channel and filleting sealants were developed successfully from cyano and diamidoxime terminated perfluoro alkylene ether prepolymers. The prepolymers were polymerized, formulated and tested. The polymers and/or formulations therefrom were evaluated as to their physical, mechanical and chemical properties (i.e., specific gravity, hardness, nonvolatile content, corrosion resistance, stress corrosion, pressure rupture resistance, low temperature flexibility, gap sealing efficiency, tensile strength and elongation, dynamic mechanical behavior, compression set, fuel resistance, thermal properties and processability). Other applications of the formulated polymrs and incorporation of the basic prepolymers into other polymeric systems were investigated. A cyano terminated perfluoro alkylene oxide triazine was formulated and partially evaluated. The channel sealant in its present formulation has excellent pressure rupture resistance and surpasses present MIL specifications before and after fuel and heat aging.

Comparison of the antinociceptive action of crude Fuzei, the root of Aconitum, and its processed products.

PubMed

Liou, Shorong-Shii; Liu, I-Min; Lai, Mei Chou; Cheng, Juei-Tang

2005-07-14

The antinociceptive effects of crude Fuzei, the root of Aconitum carmichaeli and of Fuzei processed by three different methods were determined in mice and rats using the light tail-flick assay. A dose-dependent and significant increase in pain threshold was found at 60 min post treatment, with doses of 20-60 mg/kg crude Fuzei. The analgesic effects of processed Fuzei (20-60 mg/kg) exhibited a dose-dependent inhibition of tail-flick, but the effects were lower than those produced by crude Fuzei in the same tests. The analgesic effect of Yan-Fuzei, the salt baking product, was the most potent of the processed products and was nearly that provided by crude Fuzei. Although the concentrations of aconitine were significantly lower in the processed Fuzei than in the crude Fuzei, a higher oral LD50 was found for all of the processed Fuzei formulations. Moreover, antinociception of crude Fuzei and its processed products was attenuated but not totally blocked by naloxone at doses sufficient to block opioid mu-receptors. Furthermore, the analgesic effect of crude Fuzei and its processed products was decreased in opioid mu-receptor knockout mice, but the effect remained unaltered in mice with opioid mu-receptors, indicating that the analgesic effect of Fuzei is centrally mediated. These results demonstrate that Fuzei processed by salt baking possesses analgesic effects within a large therapeutic range, probably via a mechanism involving central opioid receptors that mediate the antinociception.

Data Hiding and the Statistics of Images

NASA Astrophysics Data System (ADS)

Cox, Ingemar J.

The fields of digital watermarking, steganography and steganalysis, and content forensics are closely related. In all cases, there is a class of images that is considered “natural”, i.e. images that do not contain watermarks, images that do not contain covert messages, or images that have not been tampered with. And, conversely, there is a class of images that is considered to be “unnatural”, i.e. images that contain watermarks, images that contain covert messages, or images that have been tampered with.

The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances

PubMed Central

Dutschmann, M.; Waki, H.; Manzke, T.; Simms, A. E.; Pickering, A. E.; Richter, D. W.; Paton, J. F. R.

2009-01-01

Serotonin receptor (5-HTR) agonists that target 5-HT4(a)R and 5-HT1AR can reverse μ-opioid receptor (μ-OR)-evoked respiratory depression. Here, we have tested whether such rescuing by serotonin agonists also applies to the cardiovascular system. In working heart–brainstem preparations in situ, we have recorded phrenic nerve activity, thoracic sympathetic chain activity (SCA), vascular resistance and heart rate (HR) and in conscious rats, diaphragmatic electromyogram, arterial blood pressure (BP) and HR via radio-telemetry. In addition, the distribution of 5-HT4(a)R and 5-HT1AR in ponto-medullary cardiorespiratory networks was identified using histochemistry. Systemic administration of the μ-OR agonist fentanyl in situ decreased HR, vascular resistance, SCA and phrenic nerve activity. Subsequent application of the 5-HT1AR agonist 8-OH-DPAT further enhanced bradycardia, but partially compensated the decrease in vascular resistance, sympathetic activity and restored breathing. By contrast, the 5-HT4(a)R agonist RS67333 further decreased vascular resistance, HR and sympathetic activity, but partially rescued breathing. In conscious rats, administration of remifentanyl caused severe respiratory depression, a decrease in mean BP accompanied by pronounced bradyarrhythmia. 8-OH-DPAT restored breathing and prevented the bradyarrhythmia; however, BP and HR remained below baseline. In contrast, RS67333 further suppressed cardiovascular functions in vivo and only partially recovered breathing in some cases. The better recovery of μ-OR cardiorespiratory disturbance by 5-HT1AR than 5-HT4(a)R is supported by the finding that 5-HT1AR was more densely expressed in key brainstem nuclei for cardiorespiratory control compared with 5-HT4(a)R. We conclude that during treatment of severe pain, 5-HT1AR agonists may provide a useful tool to counteract opioid-mediated cardiorespiratory disturbances. PMID:19651661

Clinical applications of oxymorphone.

PubMed

Vadivelu, Nalini; Maria, Monisa; Jolly, Suneil; Rosenbloom, Julia; Prasad, Arun; Kaye, Alan David

2013-01-01

Oxymorphone (14-hydroxydihydromorphinone), a pyridine ring unsubstituted pyridomorphinan, a semisynthetic opioid analgesic derived from thebaine, first developed in the year 1914 and has been available as oxymorphone hydrochloride parenteral forms in the United States since 1959, when the US Food and Drug Administration approved it. Over the years, it has been used for the alleviation of moderate-to-severe pain. Pharmacological considerations, new and traditional formulations, clinical indications, and recent study populations are examined in this review. Specific considerations for oxymorphone interactions are focused on as well as specific side effects and end organ considerations. Although discovered many decades ago and used as parenteral formulation, the newer oral preparations of oxymorphone (immediate release and extended release) that were approved in 2006 can provide additional options for customizing therapy to accommodate various patient needs. This newer oral formulation could make this powerful agent an important drug in the armamentarium of the healthcare provider caring for patients with pain.

Substance abuse in anaesthetists.

PubMed

Garcia-Guasch, Roser; Roigé, Jaume; Padrós, Jaume

2012-04-01

Anaesthesiologists have a significantly higher frequency of substance abuse by a factor of nearly 3 when compared with other physicians. This is still a current problem that must be reviewed. Many hypotheses have been formulated to explain why anaesthesiologists appear to be more susceptible to substance abuse than other medical professionals (genetic differences in sensitivity to opioids, stress, the association between chemical dependence and other psychopathology or the second-hand exposure hypothesis). Environmental exposure and sensitization may be an important risk factor in physician addiction. There is a long debate about returning to work for an anaesthetist who has been depending on opioid drugs, and recent debates are discussed. Institutional efforts have been made in many countries and physician health programmes have been developed. As drug abuse among anaesthesiologists has continued, new studies have been conducted to know the theories about susceptibility. Written substance abuse policies and controls must be taken in place and in all countries.

A Corrected Formulation of the Multilayer Model (MLM) for Inferring Gaseous Dry Deposition to Vegetated Surfaces

NASA Technical Reports Server (NTRS)

Saylor, Rick D.; Wolfe, Glenn M.; Meyers, Tilden P.; Hicks, Bruce B.

2014-01-01

The Multilayer Model (MLM) has been used for many years to infer dry deposition fluxes from measured trace species concentrations and standard meteorological measurements for national networks in the U.S., including the U.S. Environmental Protection Agency's Clean Air Status and Trends Network (CASTNet). MLM utilizes a resistance analogy to calculate deposition velocities appropriate for whole vegetative canopies, while employing a multilayer integration to account for vertically varying meteorology, canopy morphology and radiative transfer within the canopy. However, the MLM formulation, as it was originally presented and as it has been subsequently employed, contains a non-physical representation related to the leaf-level quasi-laminar boundary layer resistance that affects the calculation of the total canopy resistance. In this note, the non-physical representation of the canopy resistance as originally formulated in MLM is discussed and a revised, physically consistent, formulation is suggested as a replacement. The revised canopy resistance formulation reduces estimates of HNO3 deposition velocities by as much as 38% during mid-day as compared to values generated by the original formulation. Inferred deposition velocities for SO2 and O3 are not significantly altered by the change in formulation (less than 3%). Inferred deposition loadings of oxidized and total nitrogen from CASTNet data may be reduced by 10-20% and 5-10%, respectively, for the Eastern U. S. when employing the revised formulation of MLM as compared to the original formulation.

From morphine clinics to buprenorphine: regulating opioid agonist treatment of addiction in the United States.

PubMed

Jaffe, Jerome H; O'Keeffe, Charles

2003-05-21

The practice of prescribing opioid drugs for opioid dependent patients in the U.S. has been subjected to special government scrutiny for almost 100 years. From 1920 until 1964, doctors who used opioids to treat addicts risked federal and/or state criminal prosecution. Although that period ended when oral methadone maintenance was established as legitimate medical practice, public concern about methadone diversion and accidental overdose fatalities, combined with political pressure from both hostile bureaucracies and groups committed to drug-free treatments, led to the development of unprecedented and detailed Food and Drug Administration (FDA) regulations that specified the manner in which methadone (and later, levo-alpha-acetyl methadol, or levomethadyl acetate, (LAAM)) could be provided. In 1974, Congress gave the Drug Enforcement Administration (DEA) additional oversight of methadone treatment programs. Efforts to liberalize the FDA regulations over the past 30 years have been resisted by both the DEA and existing treatment providers. Additional flexibility for clinicians may evolve from the most recent effort to create an accreditation system to replace some of the FDA regulations. The development of buprenorphine, a partial opioid agonist, as an effective treatment for opioid addiction reopened the possibility for having a less burdensome oversight process, especially because of its reduced toxicity if ingested by non-tolerant individuals. New legislation, the Drug Addiction Treatment Act (DATA) of 2000, created an opportunity for clinicians with special training to be exempted from both federal methadone regulations and the requirement to obtain a special DEA license when using buprenorphine to treat addicts. Some details of how the DATA was developed, moved through Congress, and signed into law are described.

Peripheral antinociceptive effects of the cyclic endomorphin-1 analog c[YpwFG] in a mouse visceral pain model.

PubMed

Bedini, Andrea; Baiula, Monica; Gentilucci, Luca; Tolomelli, Alessandra; De Marco, Rossella; Spampinato, Santi

2010-11-01

We previously described a novel cyclic endomorphin-1 analog c[Tyr-D-Pro-D-Trp-Phe-Gly] (c[YpwFG]), acting as a mu-opioid receptor (MOR) agonist. This study reports that c[YpwFG] is more lipophilic and resistant to enzymatic hydrolysis than endomorphin-1 and produces preemptive antinociception in a mouse visceral pain model when injected intraperitoneally (i.p.) or subcutaneously (s.c.) before 0.6% acetic acid, employed to evoke abdominal writhing (i.p. ED(50)=1.24 mg/kg; s.c. ED(50)=2.13 mg/kg). This effect is reversed by the selective MOR antagonist β-funaltrexamine and by a high dose of the mu(1)-opioid receptor-selective antagonist naloxonazine. Conversely, the kappa-opioid receptor antagonist nor-binaltorphimine and the delta-opioid receptor antagonist naltrindole are ineffective. c[YpwFG] produces antinociception when injected i.p. after acetic acid (ED(50)=4.80 mg/kg), and only at a dose of 20mg/kg did it elicit a moderate antinociceptive response in the mouse, evaluated by the tail flick assay. Administration of a lower dose of c[YpwFG] (10mg/kg i.p.) apparently produces a considerable part of antinociception on acetic acid-induced writhes through peripheral opioid receptors as this action is fully prevented by i.p. naloxone methiodide, which does not readily cross the blood-brain barrier; whereas this opioid antagonist injected intracerebroventricularly (i.c.v.) is not effective. Antinociception produced by a higher dose of c[YpwFG] (20mg/kg i.p.) is partially reversed by naloxone methiodide i.c.v. administered. Thus, only at the dose of 20mg/kg c[YpwFG] can produce antinociception through both peripheral and central opioid receptors. In conclusion, c[YpwFG] displays sufficient metabolic stability to be effective after peripheral administration and demonstrates the therapeutic potential of endomorphin derivatives as novel analgesic agents to control visceral pain. Copyright © 2010 Elsevier Inc. All rights reserved.

Safety and tolerability of the switch from buprenorphine to buprenorphine/naloxone in an Italian addiction treatment centre.

PubMed

Stimolo, Clementina; Favero, Valentina Del; Zecchinato, Giancarlo; Buson, Roberto; Cusin, Davide; Pellachin, Patrizia; Simonetto, Pamela

2010-01-01

Abuse and misuse of pharmacological therapies represent major challenges in the healthcare system, particularly in patients receiving long-acting opioid drugs for the treatment of heroin or opioid addiction. The partial mu-opioid receptor agonist buprenorphine is used to treat opioid dependence, but diversion and misuse may occur. The sublingual combination formulation of buprenorphine and the opioid receptor antagonist naloxone (buprenorphine/naxolone) is associated with a reduced abuse potential, and has been shown to have promising efficacy for the treatment of opioid dependence. This observational study assessed the safety and efficacy of sublingual buprenorphine/naloxone combination therapy in patients with opioid dependence after therapeutic switch from buprenorphine monotherapy. A total of 94 patients being treated with buprenorphine monotherapy (average dose 8 mg/day; mean duration of therapy 840 days) were switched to buprenorphine/naloxone combination therapy. Patients were asked to rate their level of satisfaction with buprenorphine/naloxone combination treatment with respect to the management of withdrawal symptoms, and urinary toxicology tests were carried out before and 14 days after switching to combination therapy. Within 3 months, 75/94 patients (80%) previously treated with buprenorphine monotherapy had switched to sublingual buprenorphine/naloxone combination treatment (average dose buprenorphine 8 mg). Among patients receiving combination treatment for >3 months, 83% were receiving medication either weekly or fortnightly, based on the results of toxicological testing. A reduction in positive urinary toxicology tests was observed in patients within two weeks after being switched to combination treatment (before switch: 28, 9 and 2 positive tests for heroin, cocaine and heroin + cocaine, respectively vs 11, 3 and 1 after switch) and a total of 64 patients of the 75 who switched to combination therapy (85%) were satisfied with the management of withdrawal symptoms during buprenorphine/naloxone treatment. Few adverse events were reported and no patients dropped out of treatment. This study shows that switching from buprenorphine monotherapy to sublingual buprenorphine/naloxone combination therapy is effective and well tolerated, and associated with good control of withdrawal symptoms in the majority of patients. In addition, combination therapy reduced illicit drug use (based on negative urinary toxicology texts) and allowed the time between clinic visits to be increased.

Pharmaceutical Formulation Facilities as Sources of Opioids and Other Pharmaceuticals to Wastewater Treatment Plant Effluents

PubMed Central

2010-01-01

Facilities involved in the manufacture of pharmaceutical products are an under-investigated source of pharmaceuticals to the environment. Between 2004 and 2009, 35 to 38 effluent samples were collected from each of three wastewater treatment plants (WWTPs) in New York and analyzed for seven pharmaceuticals including opioids and muscle relaxants. Two WWTPs (NY2 and NY3) receive substantial flows (>20% of plant flow) from pharmaceutical formulation facilities (PFF) and one (NY1) receives no PFF flow. Samples of effluents from 23 WWTPs across the United States were analyzed once for these pharmaceuticals as part of a national survey. Maximum pharmaceutical effluent concentrations for the national survey and NY1 effluent samples were generally <1 μg/L. Four pharmaceuticals (methadone, oxycodone, butalbital, and metaxalone) in samples of NY3 effluent had median concentrations ranging from 3.4 to >400 μg/L. Maximum concentrations of oxycodone (1700 μg/L) and metaxalone (3800 μg/L) in samples from NY3 effluent exceeded 1000 μg/L. Three pharmaceuticals (butalbital, carisoprodol, and oxycodone) in samples of NY2 effluent had median concentrations ranging from 2 to 11 μg/L. These findings suggest that current manufacturing practices at these PFFs can result in pharmaceuticals concentrations from 10 to 1000 times higher than those typically found in WWTP effluents. PMID:20521847

In vitro and in vivo evaluation of a sublingual fentanyl wafer formulation

PubMed Central

Lim, Stephen CB; Paech, Michael J; Sunderland, Bruce; Liu, Yandi

2013-01-01

Background The objective of this study was to prepare a novel fentanyl wafer formulation by a freeze-drying method, and to evaluate its in vitro and in vivo release characteristics, including its bioavailability via the sublingual route. Methods The wafer formulation was prepared by freeze-drying an aqueous dispersion of fentanyl containing sodium carboxymethylcellulose and amylogum as matrix formers. Uniformity of weight, friability, and dissolution testing of the fentanyl wafer was achieved using standard methods, and the residual moisture content was measured. The fentanyl wafer was also examined using scanning electron microscopy and x-ray diffraction. The absolute bioavailability of the fentanyl wafer was evaluated in 11 opioid-naïve adult female patients using a randomized crossover design. Results In vitro release showed that almost 90% of the fentanyl dissolved in one minute. In vivo, the first detectable plasma fentanyl concentration was observed after 3.5 minutes and the peak plasma concentration between 61.5 and 67 minutes. The median absolute bioavailability was 53.0%. Conclusion These results indicate that this wafer has potential as an alternative sublingual fentanyl formulation. PMID:23596347

Effect of new auxin herbicide formulations on control of herbicide resistant weeds and on microbial activities in the rhizosphere

USDA-ARS?s Scientific Manuscript database

Widespread distribution of glyphosate-resistant weeds in soybean-growing areas across Mississippi has economically affected soybean planting and follow-up crop management operations. New multiple herbicide-resistant crop (including soybean) technologies with associated formulations will soon be comm...

Watermarking of ultrasound medical images in teleradiology using compressed watermark

PubMed Central

Badshah, Gran; Liew, Siau-Chuin; Zain, Jasni Mohamad; Ali, Mushtaq

2016-01-01

Abstract. The open accessibility of Internet-based medical images in teleradialogy face security threats due to the nonsecured communication media. This paper discusses the spatial domain watermarking of ultrasound medical images for content authentication, tamper detection, and lossless recovery. For this purpose, the image is divided into two main parts, the region of interest (ROI) and region of noninterest (RONI). The defined ROI and its hash value are combined as watermark, lossless compressed, and embedded into the RONI part of images at pixel’s least significant bits (LSBs). The watermark lossless compression and embedding at pixel’s LSBs preserve image diagnostic and perceptual qualities. Different lossless compression techniques including Lempel-Ziv-Welch (LZW) were tested for watermark compression. The performances of these techniques were compared based on more bit reduction and compression ratio. LZW was found better than others and used in tamper detection and recovery watermarking of medical images (TDARWMI) scheme development to be used for ROI authentication, tamper detection, localization, and lossless recovery. TDARWMI performance was compared and found to be better than other watermarking schemes. PMID:26839914

Postgraduate Studies in the Field of HCI

NASA Astrophysics Data System (ADS)

Vainio, Teija; Surakka, Veikko; Raisamo, Roope; Räihä, Kari-Jouko; Isokoski, Poika; Väänänen-Vainio-Mattila, Kaisa; Kujala, Sari

In September of 2007, the Tampere Unit for Computer Human Interaction (TAUCHI) at the University of Tampere and The Unit of Human-Centered Technology (IHTE) at the Tampere University of Technology initiated a joint effort to increase collaboration in the field of human-technology interaction (HTI). One of the main aims was to develop higher quality education for university students and to carry out joint internationally recognized HTI research. Both research units have their own master and postgraduate students while the focus of education is at IHTE on usability and humancentered design of interactive products and services whereas TAUCHI focuses on human-technology interaction developing it by harmonizing the potential of technology with human abilities, needs, and limitations. Based on our joint analysis we know now that together TAUCHI and IHTE are offering an internationally competitive master’s program consisting of more than 40 basic, intermediate and advanced level courses. Although both units are partners in the national Graduate School in User- Centered Information Technology (UCIT) led by TAUCHI we have recognized a clear need for developing and systematizing our doctoral education.

Investigation of the hydrodynamics and emission of a laser heated tamped high-Z target

NASA Astrophysics Data System (ADS)

Gray, William J.; Foord, Mark E.; Schneider, Marilyn B.; Barrios, Maria A.; Brown, Greg V.; Heeter, Robert F.; Jarrott, L. Charlie; Liedahl, Duane A.; Marley, Ed V.; Mauche, Chris W.; Widmann, Klaus

2018-06-01

We investigate the hydrodynamic expansion and x-ray emission of a laser-heated buried-layer target. This work is motivated by our interest in developing an experimental platform for probing plasma properties under relatively uniform conditions, such as ionization and equation of state. Targets consist of a few thousand angstrom-thick layer of material, embedded in a few microns of the tamper material (typically beryllium), which are irradiated on both sides by an intense few-nanosecond laser pulse. The expansion and emission of our target, composed of a homogeneous mixture of iron, vanadium, and gold, are simulated using the 2-D LASNEX code. Reasonable agreement is found with the time history of the x-ray emission traces (DANTE). Both experiments and simulations exhibit an interesting reduction in the radial size of the emission region with time, as measured using face-on imaging. This is shown to be due to the ablation of the beryllium tamper, which affects the radial confinement of the embedded target. Simulations using a larger diameter beryllium tamper are found to mitigate this effect, improving the one-dimensionality of the expansion.

Daily Average Consumption of 2 Long-Acting Opioids: An Interrupted Time Series Analysis

PubMed Central

Puenpatom, R. Amy; Szeinbach, Sheryl L.; Ma, Larry; Ben-Joseph, Rami H.; Summers, Kent H.

2012-01-01

Background Oxycodone controlled release (CR) and oxymorphone extended release (ER) are frequently prescribed long-acting opioids, which are approved for twice-daily dosing. The US Food and Drug Administration approved a reformulated crush-resistant version of oxycodone CR in April 2010. Objective To compare the daily average consumption (DACON) for oxycodone CR and for oxymorphone ER before and after the introduction of the reformulated, crush-resistant version of oxycodone CR. Methods This was a retrospective claims database analysis using pharmacy claims from the MarketScan database for the period from January 2010 through March 2011. The interrupted time series analysis was used to evaluate the impact of the introduction of reformulated oxycodone CR on the DACON of the 2 drugs—oxycodone CR and oxymorphone ER. The source of the databases included private-sector health data from more than 150 medium and large employers. All prescription claims containing oxycodone CR and oxymorphone ER dispensed to members from January 1, 2010, to March 31, 2011, were included in the analysis. Prescription claims containing duplicate National Drug Codes, missing member identification, invalid quantities or inaccurate days supply of either drug, and DACON values of <1 and >500 were removed. Results The database yielded 483,063 prescription claims for oxycodone CR and oxymorphone ER from January 1, 2010, to March 31, 2011. The final sample consisted of 411,404 oxycodone CR prescriptions (traditional and reformulated) dispensed to 85,150 members and 62,656 oxymorphone ER prescriptions dispensed to 11,931 members. Before the introduction of reformulated oxycodone CR, DACON values for the highest strength available for each of the 2 drugs were 0.51 tablets higher for oxycodone CR than for oxymorphone ER, with mean DACON values of 3.5 for oxycodone CR and 3.0 for oxymorphone ER (P <.001). The differences of mean DACON between the 2 drugs for all lower strengths were 0.46 tablets, with mean DACON values of 2.7 for oxycodone CR and 2.3 for oxymorphone ER (P <.001). After the introduction of the new formulation, the difference in mean DACON between the 2 drugs was slightly lower: 0.45 tablets for the highest-strength and 0.40 tablets for the lower-strength pairs. Regression analyses showed that the immediate and overall impact of the reformulation of oxycodone CR on the DACON of oxycodone CR was minimal, whereas no changes were seen in the DACON of oxymorphone ER. The estimated DACON for oxycodone CR decreased by 0.1 tablets, or 3.7% (P <.001), 6 months after the new formulation was introduced. Conclusion The mean DACON was 0.4 tablets per day higher for oxycodone CR compared with oxymorphone ER for all dosage strengths for the entire study period. After the introduction of the reformulated oxycodone CR, the DACON for this drug was slightly mitigated; however, there was a minimal impact on the mean differences between oxycodone CR and oxymorphone ER. PMID:24991311

Effects of Different Heavy-Resistance Exercise Protocols on Plasma Beta-Endorphin Concentrations

DTIC Science & Technology

1993-01-01

of O-EP and cortisol. forms of high-intensity exercise, which is performed well above the level that produces V02 .. but uses multi- anaerobic ; opioid...utilizing the Borg CR- ing the rest period length (i.e., from I to 3 min; or in- 10 scale designed to accommodate primarily anaerobic creasing the resistance...O-EP in response to though short-term anaerobic exercise to exhaustion has high-intensity exercise remain unknown, it has been sug- been shown to

Pain Management: Part 1: Managing Acute and Postoperative Dental Pain

PubMed Central

Becker, Daniel E.

2010-01-01

Abstract Safe and effective management of acute dental pain can be accomplished with nonopioid and opioid analgesics. To formulate regimens properly, it is essential to appreciate basic pharmacological principles and appropriate dosage strategies for each of the available analgesic classes. This article will review the basic pharmacology of analgesic drug classes, including their relative efficacy for dental pain, and will suggest appropriate regimens based on pain intensity. Management of chronic pain will be addressed in the second part of this series. PMID:20553137

Tamper Indicating Device: Initial Training, Course 50112

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bonner, Stephen Ray; Sandoval, Dana M.

Tamper Indicating Device (TID): Initial Training, course #50112, covers Los Alamos National Laboratory (LANL) Material Control & Accountability (MC&A) TID Program procedures for the application and removal of TIDs. LANL’s policy is to comply with Department of Energy (DOE) requirements for the use of TIDs consistent with the graded safeguards described in DOE Manual DOE O 474.2, Nuclear Material Control and Accountability. When you have completed this course, you will: recognize standard practices and procedures of the LANL TID Program; have hands-on experience in the application and removal of LANL TIDs, and; verify the application and removal of LANL TIDs.

Exaggerated acquisition and resistance to extinction of avoidance behavior in treated heroin-dependent males

PubMed Central

Sheynin, Jony; Moustafa, Ahmed A.; Beck, Kevin D.; Servatius, Richard J.; Casbolt, Peter A.; Haber, Paul; Elsayed, Mahmoud; Hogarth, Lee; Myers, Catherine E.

2015-01-01

Objective Addiction is often conceptualized as a behavioral strategy for avoiding negative experiences. In rodents, opioid intake has been associated with abnormal acquisition and extinction of avoidance behavior. Here, we tested the hypothesis that these findings would generalize to human opioid-dependent subjects. Method Adults meeting DSM-IV criteria for heroin-dependence and treated with opioid medication (n=27), and healthy controls (n=26), were recruited between March–October 2013 and given a computer-based task to assess avoidance behavior. On this task, subjects controlled a spaceship and could either gain points by shooting an enemy spaceship, or hide in safe areas to avoid on-screen aversive events. Results While groups did not differ on escape responding (hiding) during the aversive event, heroin-dependent males (but not females) made more avoidance responses during a warning signal that predicted the aversive event (ANOVA, sex × group interaction, p=0.007). This group was also slower to extinguish the avoidance response when the aversive event no longer followed the warning signal (p=0.011). This behavioral pattern resulted in reduced opportunity to obtain reward without reducing risk of punishment. Results suggest that differences in avoidance behavior cannot be easily explained by impaired task performance or by exaggerated motor activity in male patients. Conclusion This study provides evidence for abnormal acquisition and extinction of avoidance behavior in opioid-dependent patients. Interestingly, data suggest abnormal avoidance is demonstrated only by male patients. Findings shed light on cognitive and behavioral manifestations of opioid addiction, and may facilitate development of therapeutic approaches to help affected individuals. PMID:27046310

Abuse and diversion of buprenorphine sublingual tablets and film.

PubMed

Lavonas, Eric J; Severtson, S Geoffrey; Martinez, Erin M; Bucher-Bartelson, Becki; Le Lait, Marie-Claire; Green, Jody L; Murrelle, Lenn E; Cicero, Theodore J; Kurtz, Steven P; Rosenblum, Andrew; Surratt, Hilary L; Dart, Richard C

2014-07-01

Buprenorphine abuse is common worldwide. Rates of abuse and diversion of three sublingual buprenorphine formulations (single ingredient tablets; naloxone combination tablets and film) were compared. Data were obtained from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Poison Center, Drug Diversion, Opioid Treatment (OTP), Survey of Key Informants' Patients (SKIP), and College Survey Programs through December 2012. To control for drug availability, event ratios (rates) were calculated quarterly, based on the number of patients filling prescriptions for each formulation ("unique recipients of a dispensed drug," URDD) and averaged and compared using negative binomial regression. Abuse rates in the OTP, SKIP, and College Survey Programs were greatest for single ingredient tablets, and abuse rates in the Poison Center Program and illicit diversion rates were greatest for the combination tablets. Combination film rates were significantly less than rates for either tablet formulation in all programs. No geographic pattern could be discerned. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Achieving bacterial eradication using pharmacokinetic/pharmacodynamic principles.

PubMed

Dagan, Ron

2003-03-01

Evidence from studies in otitis media indicates that antimicrobials and dosing regimens that have equivalent bacteriologic efficacy against susceptible pathogens can have significantly different bacteriologic success rates against resistant strains of the same species. Unlike macrolide and fluoroquinolone resistance, penicillin resistance can be overcome in Streptococcus pneumoniae by increasing the dose, and hence increasing the time for which the serum concentrations are above the MIC. The new clinical formulation of extra-strength amoxicillin-clavulanate provides 90 mg/kg per day amoxicillin plus 6.4 mg/kg per day clavulanate (14:1) divided every 12 h, compared with 45/6.4 mg/kg per day b.i.d. with conventional dosing. The pharmacokinetic/pharmacodynamic (PK/PD) profiles of extra-strength amoxicillin-clavulanate predict that the new formulation will be more effective than the conventional formulation against S. pneumoniae with elevated amoxicillin MICs and against Haemophilus influenzae. In an open-label, non-comparative study in children with acute otitis media, the extra-strength formulation had high bacteriologic success rates against the major respiratory pathogens, including penicillin-resistant S. pneumoniae. The development of new antimicrobial agents and formulations should be aimed at meeting PK/PD parameters predictive of bacterial eradication of both susceptible and resistant strains.

Is imidacloprid an effective alternative for controlling pyrethroid-resistant populations of Triatoma infestans (Hemiptera: Reduviidae) in the Gran Chaco ecoregion?

PubMed

Carvajal, Guillermo; Picollo, María Inés; Toloza, Ariel Ceferino

2014-09-01

The prevention of Chagas disease is based primarily on the chemical control of Triatoma infestans (Klug) using pyrethroid insecticides. However, high resistance levels, correlated with control failures, have been detected in Argentina and Bolivia. A previous study at our laboratory found that imidacloprid could serve as an alternative to pyrethroid insecticides. We studied the delayed toxicity of imidacloprid and the influence of the blood feeding condition of the insect on the toxicity of this insecticide; we also studied the effectiveness of various commercial imidacloprid formulations against a pyrethroid-resistant T. infestans population from the Gran Chaco ecoregion. Variations in the toxic effects of imidacloprid were not observed up to 72 h after exposure and were not found to depend on the blood feeding condition of susceptible and resistant individuals. Of the three different studied formulations of imidacloprid on glass and filter paper, only the spot-on formulation was effective. This formulation was applied to pigeons at doses of 1, 5, 20 and 40 mg/bird. The nymphs that fed on pigeons treated with 20 mg or 40 mg of the formulation showed a higher mortality rate than the control group one day and seven days post-treatment (p < 0.01). A spot-on formulation of imidacloprid was effective against pyrethroid-resistant T. infestans populations at the laboratory level.

Is imidacloprid an effective alternative for controlling pyrethroid-resistant populations of Triatoma infestans (Hemiptera: Reduviidae) in the Gran Chaco ecoregion?

PubMed Central

Carvajal, Guillermo; Picollo, María Inés; Toloza, Ariel Ceferino

2014-01-01

The prevention of Chagas disease is based primarily on the chemical control of Triatoma infestans (Klug) using pyrethroid insecticides. However, high resistance levels, correlated with control failures, have been detected in Argentina and Bolivia. A previous study at our laboratory found that imidacloprid could serve as an alternative to pyrethroid insecticides. We studied the delayed toxicity of imidacloprid and the influence of the blood feeding condition of the insect on the toxicity of this insecticide; we also studied the effectiveness of various commercial imidacloprid formulations against a pyrethroid-resistant T. infestans population from the Gran Chaco ecoregion. Variations in the toxic effects of imidacloprid were not observed up to 72 h after exposure and were not found to depend on the blood feeding condition of susceptible and resistant individuals. Of the three different studied formulations of imidacloprid on glass and filter paper, only the spot-on formulation was effective. This formulation was applied to pigeons at doses of 1, 5, 20 and 40 mg/bird. The nymphs that fed on pigeons treated with 20 mg or 40 mg of the formulation showed a higher mortality rate than the control group one day and seven days post-treatment (p < 0.01). A spot-on formulation of imidacloprid was effective against pyrethroid-resistant T. infestans populations at the laboratory level. PMID:25141281

Tramadol Extended-Release for the Management of Pain due to Osteoarthritis

PubMed Central

Guetti, Cristiana; Paladini, Antonella; Varrassi, Giustino

2013-01-01

Current knowledge on pathogenesis of osteoarticular pain, as well as the consequent several, especially on the gastrointestinal, renal, and cardiovascular systems, side effects of NSAIDs, makes it difficult to perform an optimal management of this mixed typology of pain. This is especially observable in elderly patients, the most frequently affected by osteoarthritis (OA). Tramadol is an analgesic drug, the action of which has a twofold action. It has a weak affinity to mu opioid receptors and, at the same time, can result in inhibition of the reuptake of noradrenaline and serotonin in nociceptorial descending inhibitory control system. These two mechanisms, “opioidergic” and “nonopioidergic,” are the grounds for contrasting certain types of pain that are generally less responsive to opioids, such as neuropathic pain or mixed OA pain. The extended-release formulation of tramadol has good efficacy and tolerability and acts through a dosing schedule that allows a high level of patients compliance to therapies with a good recovery outcome for the patients' functional status. PMID:27335872

Abuse of reformulated OxyContin: Updated findings from a sentinel surveillance sample of individuals assessed for substance use disorder.

PubMed

Cassidy, Theresa A; Thorley, Eileen; Black, Ryan A; DeVeaugh-Geiss, Angela; Butler, Stephen F; Coplan, Paul

To examine abuse prevalence for OxyContin and comparator opioids over a 6-year period prior to and following market entry of reformulated OxyContin and assess consistency in abuse across treatment settings and geographic regions. An observational study examining longitudinal changes using cross-sectional data from treatment centers for substance use disorder. A total of 874 facilities in 39 states in the United States within the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO®) surveillance system. Adults (72,060) assessed for drug problems using the Addiction Severity Index-Multimedia Version (ASI-MV®) from January 2009 through December 2015 who abused prescription opioids. Percent change in past 30-day abuse. OxyContin had significantly lower abuse 5 years after reformulation compared to levels for original OxyContin. Consistency of magnitude in OxyContin abuse reductions across geographic regions, ranging from 41 to 52 percent with differences in abuse reductions in treatment setting categories occurred. Changes in geographic region and treatment settings across study years did not bias the estimate of lower OxyContin abuse through confounding. In the postmarket setting, limitations and methodologic challenges in abuse measurement exist and it is difficult to isolate singular impacts of any one intervention given the complexity of prescription opioid abuse. Expectations for a reasonable threshold of abuse for any one ADF product or ADF opioids as a class are still uncertain and undefined. A significant decline in abuse prevalence of reformulated OxyContin was observed 5 years after its reformulation among this treatment sample of individuals assessed for substance use disorder that was lower historically for the original formulation of this product.

Civil Society-Driven Drug Policy Reform for Health and Human Welfare-India.

PubMed

Vallath, Nandini; Tandon, Tripti; Pastrana, Tania; Lohman, Diederik; Husain, S Asra; Cleary, James; Ramanath, Ganpati; Rajagopal, M R

2017-03-01

The lack of adequate access to opioids in India as analgesics and for agonist therapies, forces millions to live with severe unalleviated pain, or languish with suffering associated with drug dependence. Although India is a major opium exporter, the excessively prohibitive 1985 narcotics law formulated to control harmful use of drugs, impeded the availability and access to opioids for medical and scientific purposes. Amendment of this law in 2014 established a new national regulatory framework for improved access to essential opioid analgesics. This article reflects on key elements and processes that led to this landmark achievement. Unlike quick timelines associated with effecting policy reforms for law enforcement, realizing the 2014 drug policy change primarily to mitigate human suffering, was a 22-year-long process. The most exacting challenges included recognizing the multilayered complexities of the prior policy framework and understanding their adverse impact on field practices to chart an appropriate and viable path for reform. The evolution of an informal civil society movement involving health care professionals, lawyers, media, policy analysts, government officials, and the public was pivotal in addressing these challenges and garnering momentum for reform. The success of the effort for improving access to opioid medications was underpinned by a three-pronged strategy of 1) persuading the executive arm of the government to take interim enabling measures; 2) leveraging judicial intervention through public interest litigation; and 3) crafting a viable policy document for legislative approval and implementation. We hope our findings are useful for realizing drug policy reforms, given the current transformed global policy mandates emphasizing humanitarian, healthcare, and quality-of-life considerations. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Post-marketing surveillance of methadone and buprenorphine in the United States.

PubMed

Dasgupta, Nabarun; Bailey, Elise J; Cicero, Theodore; Inciardi, James; Parrino, Mark; Rosenblum, Andrew; Dart, Richard C

2010-07-01

There have been recent increases in the use of methadone and buprenorphine in the United States. Methadone is increasingly being used for pain management, and buprenorphine use has expanded to include treatment for opioid addiction, leading to exposures of these drugs in new populations. There is a debate about the relative safety of these two drugs in routine outpatient medical use. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Programs were used to analyze rates of abuse, misuse, and diversion using the Drug Diversion, Key Informant, Poison Center and Opioid Treatment Programs, 2003-2007. National rate and rate ratios were calculated using population and person-time exposed denominators. Detailed data are presented on severity of medical outcome and drug formulations. Between 2003 and 2007, there were steady increases in the rates of abuse, misuse, and diversion of both methadone and buprenorphine. Rate ratios (per 100,000 population per quarter) of abuse, misuse, and diversion were consistently higher for methadone than buprenorphine. RADARS System poison centers received 7,476 calls for methadone and 1,117 calls for buprenorphine. After accounting for availability, there were higher rates of calls for methadone misuse, abuse, and diversion than buprenorphine in three of the four programs. The numbers of exposures requiring medical attention correspond to 46.8% and 25.8% of all calls, for methadone and buprenorphine, respectively. The most commonly diverted form of methadone was solid oral tablets (which are typically dispensed at pharmacies, not at opioid treatment programs), comprising 73% of cases. Buprenorphine appears to have a better safety profile than methadone during routine outpatient medical use. However, both medications have roles in the treatment of pain and opioid addiction, and further research into their respective benefits and risks should be conducted.

Flame-retardant EPDM compounds containing phenanthrene to enhance radiation resistance

NASA Astrophysics Data System (ADS)

Chen, Jian; Huang, Wei; Jiang, Shu-Bin; Li, Xiao-Yan; An, You; Li, Chuang; Gao, Xiao-Ling; Chen, Hong-Bing

2017-01-01

Ethylene propylene diene monomer (EPDM) compounds with good flame-retardant and γ-ray radiation resistant properties were prepared by adding complex flame retardants and phenathrene. The resultant EPDM formulations have a long time to ignition (TTI >46 s), a low peak heat release rate (PHRR 341 kW/m2) and a high limited oxygen index (LOI >30). Effects of γ-ray radiation on the resultant flame-retardant EPDM was investigated. The formulated EPDM is a crosslinking dominated polymer under γ-ray radiation. The γ-ray radiation resistant property of EPDM was enhanced by adding phenanthrene. Elongation at break of EPDM formulated with phenanthrene could retain 91% after being irradiated to 0.3 MGy and still retains 40% elongation even after being irradiated to 0.9 MGy, which is much better the control. It is expected that the formulated flame-retardant and radiation resistant EPDM materials could meet the requirements for use in radiation environments.

New formulation of methadone for opioid dependence in France: acceptability and diversion/misuse liability.

PubMed

Eiden, Céline; Léglise, Yves; Bertomeu, Lisa; Clavel, Vivianne; Faillie, Jean-Luc; Petit, Pierre; Peyrière, Hélène

2013-01-01

A new formulation of methadone as capsules is marketed in France since 2008. Few data are available on the patient acceptability and the risk of misuse of this new formulation. To assess the patient acceptability after the switch methadone syrup/capsules and the diversion/misuse liability of the methadone capsule, a study through an anonymous questionnaire was conducted between March 2011 and May 2012 in two methadone centers of the region. Forty-one patients (men 75.6%) participated, with a median age of 37 years [IQR: 33-43 years]. The median duration of syrup methadone maintenance therapy was 1 year [IQR: 1-3 years]. A majority of patients (80.5%) described side-effects due to the syrup formulation. Median daily dose at the switch to methadone capsules was 75 mg [IQR: 42-105 mg]. Six patients described differences in the pharmacologic effect between the two formulations. Concerning the diversion and misuse liability of methadone capsules, 26.8% of patients reported that the medication was available at the "street market". Three patients have tried to solubilize and eight have tried to snooze it. All patients recognize the contribution of this new formulation concerning the use, side-effects and transport. None of them returned to the syrup. © 2013 Société Française de Pharmacologie et de Thérapeutique.

Tramadol extended-release in the management of chronic pain

PubMed Central

McCarberg, Bill

2007-01-01

Chronic, noncancer pain such as that associated with osteoarthritis of the hip and knee is typically managed according to American College of Rheumatology guidelines. Patients unresponsive to first-line treatment with acetaminophen receive nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors. However, many patients may have chronic pain that is refractory to these agents, or they may be at risk for the gastrointestinal, renal, and cardiovascular complications associated with their use. Tramadol, a mild opioid agonist and norepinephrine and serotonin reuptake inhibitor, is recommended by current guidelines for the treatment of moderate to moderately severe pain in patients who have not responded to previous oral therapy, or in patients who have contraindications to COX-2 inhibitors and nonselective NSAIDs. An extended-release (ER) formulation of tramadol was approved by the US Food and Drug Administration in September 2005. In contrast with immediate-release (IR) tramadol, this ER formulation allows once-daily dosing, providing around-the-clock analgesia. In clinical studies, tramadol ER has demonstrated a lower incidence of adverse events than that reported for IR tramadol. Unlike nonselective NSAIDs and COX-2 inhibitors, tramadol ER is not associated with gastrointestinal, renal, or cardiovascular complications. Although tramadol is an opioid agonist, significant abuse has not been demonstrated after long-term therapy. It is concluded that tramadol ER has an efficacy and safety profile that warrants its early use for the management of chronic pain, either alone or in conjunction with nonselective NSAIDs and COX-2 inhibitors. PMID:18488071

Intranasal Pharmacokinetics of Morphine ARER, a Novel Abuse-Deterrent Formulation: Results from a Randomized, Double-Blind, Four-Way Crossover Study in Nondependent, Opioid-Experienced Subjects

PubMed Central

Pantaleon, Carmela; Iverson, Matthew; Smith, Michael D.; Kinzler, Eric R.; Aigner, Stefan

2018-01-01

Objective To investigate the pharmacokinetics (PK) of Morphine ARER, an extended-release (ER), abuse-deterrent formulation of morphine sulfate after oral and intranasal administration. Methods This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study assessed the PK of morphine and its active metabolite, M6G, from crushed intranasal Morphine ARER and intact oral Morphine ARER compared with crushed intranasal ER morphine following administration to nondependent, recreational opioid users. The correlation between morphine PK and the pharmacodynamic parameter of drug liking, a measure of abuse potential, was also evaluated. Results Mean maximum observed plasma concentration (Cmax) for morphine was lower with crushed intranasal Morphine ARER (26.2 ng/mL) and intact oral Morphine ARER (18.6 ng/mL), compared with crushed intranasal ER morphine (49.5 ng/mL). The time to Cmax (Tmax) was the same for intact oral and crushed intranasal Morphine ARER (1.6 hours) and longer for crushed intranasal morphine ER (1.1 hours). Higher mean maximum morphine Cmax, Tmax, and abuse quotient (Cmax/Tmax) were positively correlated with maximum effect for drug liking (R2 ≥ 0.9795). Conclusion These data suggest that Morphine ARER maintains its ER profile despite physical manipulation and intranasal administration, which may be predictive of a lower intranasal abuse potential compared with ER morphine.

Developmental Potential for Endomorphin Opioidmimetic Drugs

PubMed Central

Okada, Yoshio; Tsuda, Yuko; Salvadori, Severo; Lazarus, Lawrence H.

2012-01-01

Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM)-1 and endomorphin(EM)-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr1 with 2′,6′-dimethyl-l-tyrosine (Dmt) to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt1]EM-1 and [Dmt1]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt1]EM-1 (47) and [N-allyl-Dmt1]EM-2 (48) exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier. PMID:25954530

DYNAMICS OF OPIOID SUBSTITUTION TREATMENTIN DIFFERENT INITIAL SUBSTANCE USER OPIOID DEPENDENT PATIENTS.

PubMed

Todadze, Kh; Mosia, S

2016-05-01

Injecting drug user size estimation studies carried out in 2009, 2012 and 2015 revealed growing trends of drug abuse in Georgia:estimated number of people who inject drugs (PWID) have been increased from 40000 and 45000 to 50000. Since Soviet period the most popular injective narcotics have been opioids: home-made opium, heroine, buprenorphine and home-made desomorphine ("Krokodile") replacing each other on the black market. Self-made desomorphine typically contains big amounts of different toxic substances and causes significant somatic disorders, especially skin, bone, blood infections, liver and kidney failure; is highly addictive, associates with frequent injections that enhance injecting-related harm, including the risk of HIV transmission, in comparison with typical opioids. The aim of the study was to determine the effectiveness of opioid substitution treatment (OST) on depression and anxiety in opioid dependent clients with history of different opioid substance use. 104 opioid drug users undergoing OST with intensive psychological counseling have been divided in 5 groups according to the principal opioid drug that was abused during past 6 months before starting treatment: heroine, desomorphine, illicit methadone injectors, illicit buprenorphine injectors, and multiple drug abusers consuming opioids as primary drugs. Level of depression (Beck Depression Inventory), anxiety (Spielberger Anxiety Inventory) as well as clinical symptoms, risky behavior, quality of life (WHO), and other data were measured before starting and after 3, 9, 15, 21 months of treatment. The illegal use of psychotropic-narcotics was checked through random urine-testing 1-2 times per patient per month. In all five groups remarkable decrease of depression and anxiety was observed in comparison with the starting data. Before inclusion desomorphine and poly-drug users had the highest scores of depression and anxiety while buprenorphine users manifested the lowest rate. Improvement of figures was observed in all groups in three month period that have been continuing during 21 month of treatment process. Study revealed normalization of scores forbothstatesin groups of heroine, desomorphine, methadone and buprenorphine users. The highest scores of depression and anxiety were observed in the group of poly-drug abusers andwhile depression rate hesitated in the range of clear "no-depression", anxiety index still remained close to the clinical important threshold after 21 month of treatment. Urine-testingon psychotropic-narcotic substances indicated remarkable decrease of illegal drug abuse in all studied groups in three month and although abuse of benzodiazepine drugs was highest in desomorphine and poly-drug abusers, the difference between groups was not statistically significant. Although some disparities have been observed in dynamics of subjects with different spectrum of initial opioid substance use, including homemade desomorphine, there is no significant difference between groups and OST effectively supports to improve depression and anxiety indices, and dramatically decreases use of illegal psychotropic-narcotic drugs during treatment. However poly-drug users seems to be the most resistant to achieve stabilization and require more treatment time and targeted interventions.

Pharmacokinetics of ammonium sulfate gradient loaded liposome-encapsulated oxymorphone and hydromorphone in healthy dogs

PubMed Central

Smith, Lesley J.; Kukanich, Butch K.; Krugner-Higby, Lisa A.; Schmidt, Brynn H.; Heath, Timothy D.

2013-01-01

Objective To evaluate the pharmacokinetics, in dogs, of liposome-encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique (ASG). Animals Four healthy purpose-bred Beagles aged 9.5 ± 3.2 months and weighing 13.4 ± 2.3 kg. Study Design Randomized cross-over design. Methods Each dog was given either 4.0 mg kg−1 of ASG-oxymorphone or 8.0 mg kg−1 of ASG-hydromorphone SC on separate occasions with a 3-month washout period. Blood was collected at baseline and at serial time points up to 1032 hours (43 days) after injection for determination of serum opioid concentrations. Serum opioid concentrations were measured with HPLC-MS and pharmacokinetic parameters were calculated using commercial software and non-compartmental methods. Results Serum concentrations of oxymorphone remained above the limit of quantification for 21 days, while those for hydromorphone remained above the limit of quantification for 29 days. Cmax for ASG-oxymorphone was 7.5 ng mL−1; Cmax for ASG-hydromorphone was 5.7 ng mL−1. Conclusions and clinical relevance Oxymorphone and hydromorphone, when encapsulated into liposomes using the ammonium sulfate gradient loading technique, result in measureable serum concentrations for between 3 to 4 weeks. This formulation may have promise in the convenient use of opioids for clinical treatment of chronically painful conditions in dogs. PMID:23601353

Do abuse deterrent opioid formulations work?

PubMed

Dart, Richard C; Iwanicki, Janetta L; Dasgupta, Nabarun; Cicero, Theodore J; Schnoll, Sidney H

We performed a systematic review to answer the question, "Does the introduction of an opioid analgesic with abuse deterrent properties result in reduced overall abuse of the drug in the community?" We included opioid analgesics with abuse deterrent properties (hydrocodone, morphine, oxycodone) with results restricted to the metasearch term "delayed onset," English language, use in humans, and publication years 2009-2016. All articles that contained data evaluating misuse, abuse, overdose, addiction, and death were included. The results were categorized using the Bradford-Hill criteria. We included 44 reports: hydrocodone (n = 7), morphine (n = 5), or oxycodone (n = 32) with Food and Drug Administration-approved Categories 1, 2, or 3 abuse deterrent labeling. The data currently available support the Hill criteria of strength (effect size), consistency (reproducibility), temporality, plausibility, and coherence. There was insufficient or no information available for the criteria of biological gradient, experiment, and analogy. We also assessed confounding factors and bias, which indicated that both were present and substantial in magnitude. Our analysis found that only oxycodone extended release (ER) had information available to evaluate abuse deterrence in the community. In Australia, Canada, and the United States, reformulation of oxycodone ER was followed by marked reduction in measures of abuse. The precise extent of reduced abuse cannot be calculated because of heterogeneous data sets, but the reported reductions ranged from 10 to 90 percent depending on the measure and the duration of follow-up.

Wireless tamper detection sensor and sensing system

NASA Technical Reports Server (NTRS)

Woodard, Stanley E. (Inventor); Taylor, Bryant D. (Inventor)

2011-01-01

A wireless tamper detection sensor is defined by a perforated electrical conductor. The conductor is shaped to form a geometric pattern between first and second ends thereof such that the conductor defines an open-circuit that can store and transfer electrical and magnetic energy. The conductor resonates in the presence of a time-varying magnetic field to generate a harmonic response. The harmonic response changes when the conductor experiences a change in its geometric pattern due to severing of the conductor along at least a portion of the perforations. A magnetic field response recorder is used to wirelessly transmit the time-varying magnetic field and wirelessly detecting the conductor's harmonic response.

Active Time-Domain Reflectometry for Unattended Safeguards Systems: FY16 Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tedeschi, Jonathan R.; Smith, Leon E.; Conrad, Ryan C.

2016-10-21

The International Atomic Energy Agency (IAEA) continues to expand its use of unattended measurement systems. An increasing number of systems and an expanding family of instruments create challenges in terms of deployment efficiency and the implementation of data authentication measures. Traditional data security measures, for example tamper-indicating (TI) conduit, are impractical for the long separation distances (often 100 meters or more) between unattended monitoring system (UMS) components. Pacific Northwest National Laboratory (PNNL) is studying the viability of active time-domain reflectometry (TDR) for the detection of cable tampering in unattended radiation detection systems. The instrument concept under investigation would allow formore » unmanned cable integrity measurements, remote surveillance reporting and locating of cable faults and/or tampers. This report describes PNNL’s FY16 progress and includes: an overview of the TDR methods under investigation; description of the TDR evaluation testbed developed by PNNL; development and testing of advanced signal processing algorithms to extract weak signals from relatively high noise levels; and initial testing of a laboratory prototype intended for IAEA UMS applications and based on a commercially available TDR module. Preliminary viability findings and recommendations for the next stage of development and testing are provided.« less

Reversible Data Hiding in FTIR Microspectroscopy Images with Tamper Indication and Payload Error Correction

PubMed Central

Seppänen, Tapio

2017-01-01

Fourier transform infrared (FTIR) microspectroscopy images contain information from the whole infrared spectrum used for microspectroscopic analyses. In combination with the FTIR image, visible light images are used to depict the area from which the FTIR spectral image was sampled. These two images are traditionally acquired as separate files. This paper proposes a histogram shifting-based data hiding technique to embed visible light images in FTIR spectral images producing single entities. The primary objective is to improve data management efficiency. Secondary objectives are confidentiality, availability, and reliability. Since the integrity of biomedical data is vital, the proposed method applies reversible data hiding. After extraction of the embedded data, the FTIR image is reversed to its original state. Furthermore, the proposed method applies authentication tags generated with keyed Hash-Based Message Authentication Codes (HMAC) to detect tampered or corrupted areas of FTIR images. The experimental results show that the FTIR spectral images carrying the payload maintain good perceptual fidelity and the payload can be reliably recovered even after bit flipping or cropping attacks. It has been also shown that extraction successfully removes all modifications caused by the payload. Finally, authentication tags successfully indicated tampered FTIR image areas. PMID:29259987

Image authentication by means of fragile CGH watermarking

NASA Astrophysics Data System (ADS)

Schirripa Spagnolo, Giuseppe; Simonetti, Carla; Cozzella, Lorenzo

2005-09-01

In this paper we propose a fragile marking system based on Computer Generated Hologram coding techniques, which is able to detect malicious tampering while tolerating some incidental distortions. A fragile watermark is a mark that is readily altered or destroyed when the host image is modified through a linear or nonlinear transformation. A fragile watermark monitors the integrity of the content of the image but not its numerical representation. Therefore the watermark is designed so that the integrity is proven if the content of the image has not been tampered. Since digital images can be altered or manipulated with ease, the ability to detect changes to digital images is very important for many applications such as news reporting, medical archiving, or legal usages. The proposed technique could be applied to Color Images as well as to Gray Scale ones. Using Computer Generated Hologram watermarking, the embedded mark could be easily recovered by means of a Fourier Transform. Due to this fact host image can be tampered and watermarked with the same holographic pattern. To avoid this possibility we have introduced an encryption method using a asymmetric Cryptography. The proposed schema is based on the knowledge of original mark from the Authentication

Development of Damp-Heat Resistant Self-Primed EVA and Non-EVA Encapsulant Formulations at NREL

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pern, F. J.; Jorgensen, G. J.

2005-11-01

Self-primed ethylene-vinyl acetate (EVA) and non-EVA (PMG) encapsulant formulations were developed that have greater resistance to damp heat exposure at 85 deg C and 85% relative humidity (RH) (in terms of adhesion strength to glass substrates) than a commonly used commercial EVA product. The self-primed EVA formulations were developed on the basis of high-performing glass priming formulations that have previously proven to significantly enhance the adhesion strength of unprimed and primed EVA films on glass substrates during damp heat exposure. The PMG encapsulant formulations were based on an ethylene-methylacrylate copolymer containing glycidyl methacrylate.

Recent trends and future of pharmaceutical packaging technology

PubMed Central

Zadbuke, Nityanand; Shahi, Sadhana; Gulecha, Bhushan; Padalkar, Abhay; Thube, Mahesh

2013-01-01

The pharmaceutical packaging market is constantly advancing and has experienced annual growth of at least five percent per annum in the past few years. The market is now reckoned to be worth over $20 billion a year. As with most other packaged goods, pharmaceuticals need reliable and speedy packaging solutions that deliver a combination of product protection, quality, tamper evidence, patient comfort and security needs. Constant innovations in the pharmaceuticals themselves such as, blow fill seal (BFS) vials, anti-counterfeit measures, plasma impulse chemical vapor deposition (PICVD) coating technology, snap off ampoules, unit dose vials, two-in-one prefilled vial design, prefilled syringes and child-resistant packs have a direct impact on the packaging. The review details several of the recent pharmaceutical packaging trends that are impacting packaging industry, and offers some predictions for the future. PMID:23833515

Exaggerated acquisition and resistance to extinction of avoidance behavior in treated heroin-dependent men.

PubMed

Sheynin, Jony; Moustafa, Ahmed A; Beck, Kevin D; Servatius, Richard J; Casbolt, Peter A; Haber, Paul; Elsayed, Mahmoud; Hogarth, Lee; Myers, Catherine E

2016-03-01

Addiction is often conceptualized as a behavioral strategy for avoiding negative experiences. In rodents, opioid intake has been associated with abnormal acquisition and extinction of avoidance behavior. Here, we tested the hypothesis that these findings would generalize to human opioid-dependent subjects. Adults meeting DSM-IV criteria for heroin dependence and treated with opioid medication (n = 27) and healthy controls (n = 26) were recruited between March 2013 and October 2013 and given a computer-based task to assess avoidance behavior. For this task, subjects controlled a spaceship and could either gain points by shooting an enemy spaceship or hide in safe areas to avoid on-screen aversive events. Hiding duration during different periods of the task was used to measure avoidance behavior. While groups did not differ on escape responding (hiding) during the aversive event, heroin-dependent men (but not women) made more avoidance responses during a warning signal that predicted the aversive event (analysis of variance, sex × group interaction, P = .007). Heroin-dependent men were also slower to extinguish the avoidance response when the aversive event no longer followed the warning signal (P = .011). This behavioral pattern resulted in reduced opportunity to obtain reward without reducing risk of punishment. Results suggest that, in male patients, differences in avoidance behavior cannot be easily explained by impaired task performance or by exaggerated motor activity. This study provides evidence for abnormal acquisition and extinction of avoidance behavior in opioid-dependent patients. Interestingly, data suggest that abnormal avoidance is demonstrated only by male patients. Findings shed light on cognitive and behavioral manifestations of opioid addiction and may facilitate development of therapeutic approaches to help affected individuals. © Copyright 2016 Physicians Postgraduate Press, Inc.

Stigma associated with medication treatment for young adults with opioid use disorder: a case series.

PubMed

Hadland, Scott E; Park, Tae Woo; Bagley, Sarah M

2018-05-07

Opioid-related overdose deaths have risen sharply among young adults. Despite this increase, access to evidence-based medication for opioid agonist treatment (OAT) for youth remains low. Among older adults, barriers to OAT include the paucity of buprenorphine-waivered prescribers and low rates of prescribing among waivered physicians. We have increasingly found in our clinical practice significant stigma related to using OAT to treat addiction for young adults. In this series, we describe three cases of young adults who faced significant stigma related to their treatment. The first case is a young male with a history of significant trauma and a severe opioid use disorder. He started buprenorphine and has found a job, stayed abstinent, and began a healthy relationship. At each step in his recovery, he has faced resistance to taking medication from other treatment providers, directors of sober houses, and his parents. The second case is a young woman who presented to a substance use treatment program after a relapse. She was unable to restart buprenorphine despite our calling to ask that it be restarted. Ultimately, she left against medical advice and was stabilized as an outpatient on buprenorphine. The final case is a young woman who stopped buprenorphine after being told she was "not sober" while attending 12-step group but restarted after conversations with her clinical team. In each case, the patient has continued their medication treatment and are stable. Opioid-related deaths continue to rise among all age groups, including young adults. Stigma related to medication treatment can be a substantial barrier for many young adult patients but there are concrete steps that providers and communities can take to address this stigma.

Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue-triggered 'wanting' for reward: entire core and medial shell mapped as substrates for PIT enhancement.

PubMed

Peciña, Susana; Berridge, Kent C

2013-05-01

Pavlovian cues [conditioned stimulus (CS+)] often trigger intense motivation to pursue and consume related reward [unconditioned stimulus (UCS)]. But cues do not always trigger the same intensity of motivation. Encountering a reward cue can be more tempting on some occasions than on others. What makes the same cue trigger more intense motivation to pursue reward on a particular encounter? The answer may be the level of incentive salience ('wanting') that is dynamically generated by mesocorticolimbic brain systems, influenced especially by dopamine and opioid neurotransmission in the nucleus accumbens (NAc) at that moment. We tested the ability of dopamine stimulation (by amphetamine microinjection) vs. mu opioid stimulation [by d-Ala, nMe-Phe, Glyol-enkephalin (DAMGO) microinjection] of either the core or shell of the NAc to amplify cue-triggered levels of motivation to pursue sucrose reward, measured with a Pavlovian-Instrumental Transfer (PIT) procedure, a relatively pure assay of incentive salience. Cue-triggered 'wanting' in PIT was enhanced by amphetamine or DAMGO microinjections equally, and also equally at nearly all sites throughout the entire core and medial shell (except for a small far-rostral strip of shell). NAc dopamine/opioid stimulations specifically enhanced CS+ ability to trigger phasic peaks of 'wanting' to obtain UCS, without altering baseline efforts when CS+ was absent. We conclude that dopamine/opioid stimulation throughout nearly the entire NAc can causally amplify the reactivity of mesocorticolimbic circuits, and so magnify incentive salience or phasic UCS 'wanting' peaks triggered by a CS+. Mesolimbic amplification of incentive salience may explain why a particular cue encounter can become irresistibly tempting, even when previous encounters were successfully resisted before. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Recent advances in 193-nm single-layer photoresists based on alternating copolymers of cycloolefins

NASA Astrophysics Data System (ADS)

Houlihan, Francis M.; Wallow, Thomas I.; Timko, Allen G.; Neria, E.; Hutton, Richard S.; Cirelli, Raymond A.; Nalamasu, Omkaram; Reichmanis, Elsa

1997-07-01

We report on our recent investigations on the formulation and processing of 193 nm single layer photoresists based on alternating copolymers of cycloolefins with maleic anhydride. Resists formulated with cycloolefin copolymers are compatible with 0.262 N tetramethylammonium developers, have excellent adhesion, sensitivity, etch resistance and thermal flow properties. The effect of polymer structure and composition, dissolution inhibitor structure and loading as well as the effect of the photoacid generator on the resist dissolution properties was investigated. Based on the results high contrast formulations were evaluated on a GCA XLS (NA equals 0.53, 4X reduction optics) deep-UV stepper to exhibit 0.27 micrometer L/S pair resolution with excellent photosensitivity. Based on the dissolution properties and a spectroscopic examination of the resist, we have designed materials that show less than 0.17 micrometer L/S pair resolution with 193 nm exposures. In this paper, the formulation methodology is detailed and the most recent results upon both with 248 and 193 nm irradiation are described.

A randomized, double-blind study of hydromorphone hydrochloride extended-release tablets versus oxycodone hydrochloride extended-release tablets for cancer pain: efficacy and safety in Japanese cancer patients (EXHEAL: a Phase III study of EXtended-release HydromorphonE for cAncer pain reLief).

PubMed

Inoue, Satoshi; Saito, Yoji; Tsuneto, Satoru; Aruga, Etsuko; Ide, Azusa; Kakurai, Yasuyuki

2017-01-01

In Japan, there are limited options for switching opioid analgesics. Hydromorphone is an opioid analgesic that is routinely used instead of morphine for cancer pain; however, it is not yet available in Japan. The aim of this study was to assess the efficacy and safety of hydromorphone (DS-7113b) extended-release tablets in opioid-naïve patients with cancer pain not relieved by non-opioid analgesics. This was a multicenter, randomized, double-blind, parallel-group trial. A double-dummy method was used for blinding. Each randomized subject received either hydromorphone extended-release tablets plus placebo oxycodone hydrochloride extended-release tablets 4 mg/day (n=88) or placebo hydromorphone extended-release tablets plus oxycodone hydrochloride extended-release tablets 10 mg/day (n=93) orally for 7 days (once-daily dosing for hydromorphone and twice-daily dosing for oxycodone). The doses were adjusted as necessary. Efficacy was evaluated by change in visual analog scale (VAS) score from baseline to completion of treatment. The between-group difference in least squares mean changes in VAS score from baseline to completion or discontinuation of treatment was -0.4 mm (95% CI -5.9 to 5 mm) by analysis of covariance where the baseline VAS score was used as a covariate. The upper limit of the 95% CI was below 10 mm, which was predefined as the noninferiority limit. This verified the noninferiority of hydromorphone tablets relative to oxycodone tablets. The incidence of adverse events was 80.7% (71 of 88) in the hydromorphone group and 83.7% (77 of 93) in the oxycodone group. The most common adverse events were nausea, vomiting, somnolence, diarrhea, and constipation, most of which are commonly observed with opioid analgesics. The efficacy and safety of hydromorphone extended-release tablets were equivalent to those of the oxycodone extended-release formulation.

Induction of soybean resistance to bacterial pustule disease (Xanthomonas axonopodis pv. glycines) by rhizobacteria and organic material treatment

NASA Astrophysics Data System (ADS)

Khaeruni, A.; Johan, E. A.; Wijayanto, T.; Taufik, M.; Syafar, A. A. R.; Kade Sutariati, G. A.

2018-02-01

This study aimed to evaluate the role of different formulations and types of organic matter in improving yield and resistance of soybean plants to bacterial pustule disease. The study was prepared based on a randomized block design with a factorial pattern. The first factor was the application of rhizobacterial formulation (biofresh), ie F0 = without the application of rhizobacteria, F1 = application of biofresh in solid formulation, and F2 = application of biofresh in liquid formulation. The second factor was the application of organic materials, namely B1 = compost of soybean litter + cow dung, B2 = compost of rice straw + cow dung, B3 = compost of soybean litter + rice straw + cow dung. Observation of disease severity and soybean yield was conducted on five sample plants in each treatment. The results showed that the treatment of biological agent biofresh in solid formulation combined with compos of soybean litter, was the best treatment in increasing plant resistance to bacterial pustule disease and seed weight. Plant resistance induction occurred systemically characterized by salicylic acid increase of 0.3 mg and peroxidase increase of 0.07 unit / mL in the sample plants.

Healthy Adult Male Facial Skin Surface Lipid Pheromone p.o. to Treat Opioid Addiction

ClinicalTrials.gov

2018-03-20

Opioid Addiction; Opioid Abuse, Continuous Use; Opioid Use; Opioid-Related Disorders; Paternal Pheromone Deficiency; Opioid Dependence; Opioid Abuse; Opioid-use Disorder; Opioid Intoxication; Opioid Abuse, Episodic

Community reentry challenges after release from prison among people who inject drugs in St. Petersburg, Russia.

PubMed

Cepeda, Javier A; Vetrova, Marina V; Lyubimova, Alexandra I; Levina, Olga S; Heimer, Robert; Niccolai, Linda M

2015-01-01

Little is known about the context of the post-release risk environment among formerly incarcerated people who inject drugs (PWID) in Russia. The purpose of this paper is to explore these challenges as they relate to reentry, relapse to injection opioid use, and overdose. The authors conducted 25 in-depth semi-structured interviews among PWID living in St Petersburg, Russia who had been incarcerated within the past two years. Participants were recruited from street outreach (n=20) and a drug treatment center (n=5). Emergent themes related to the post-release environment included financial instability, negative interactions with police, return to a drug using community, and reuniting with drug using peers. Many respondents relapsed to opioid use immediately after release. Those whose relapse occurred weeks or months after their release expressed more motivation to resist. Alcohol or stimulant use often preceded the opioid relapse episode. Among those who overdosed, alcohol use was often reported prior to overdosing on opioids. Future post-release interventions in Russia should effectively link PWID to social, medical, and harm reduction services. Particular attention should be focussed on helping former inmates find employment and overdose prevention training prior to leaving prison that should also cover the heightened risk of concomitant alcohol use. In addition to describing a syndemic involving the intersection of incarceration, injection drug use, poverty, and alcohol abuse, the findings can inform future interventions to address these interrelated public health challenges within the Russian setting.

Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers.

PubMed

Jämstorp, Erik; Yarra, Tejaswi; Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne; Strømme, Maria

2012-01-01

Improving acid resistance, while maintaining the excellent mechanical stability is crucial in the development of a sustained and safe oral geopolymer dosage form for highly potent opioids. In the present work, commercially available Methacrylic acid-ethyl acrylate copolymer, Polyethylene-glycol (PEG) and Alginate polymer excipients were included in dissolved or powder form in geopolymer pellets to improve the release properties of Zolpidem, herein acting as a model drug for the highly potent opioid Fentanyl. Scanning electron microscopy, compression strength tests and drug release experiments, in gastric pH 1 and intestinal pH 6.8 conditions, were performed. The polymer excipients, with an exception for PEG, reduced the drug release rate in pH 1 due to their ability to keep the pellets in shape, in combination with the introduction of an insoluble excipient, and thereby maintain a barrier towards drug diffusion and release. Neither geopolymer compression strength nor the release in pH 6.8 was considerably impaired by the incorporation of the polymer excipients. The geopolymer/polymer composites combine high mechanical strength and good release properties under both gastric and intestinal pH conditions, and are therefore promising oral dosage forms for sustained release of highly potent opioids.

Membership and Behavior of Ultra-Low-Diversity Pathogen Communities Present in the Gut of Humans during Prolonged Critical Illness

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zaborin, Alexander; Smith, Daniel; Garfield, Kevin

We analyzed the 16S rRNA amplicon composition in fecal samples of selected patients during their prolonged stay in an intensive care unit (ICU) and observed the emergence of ultra-low-diversity communities (1 to 4 bacterial taxa) in 30% of the patients. Bacteria associated with the genera Enterococcus and Staphylococcus and the family Enterobacteriaceae comprised the majority of these communities. The composition of cultured species from stool samples correlated to the 16S rRNA analysis and additionally revealed the emergence of Candida albicans and Candida glabrata in ~75% of cases. Four of 14 ICU patients harbored 2-member pathogen communities consisting of one Candidamore » taxon and one bacterial taxon. Bacterial members displayed a high degree of resistance to multiple antibiotics. The virulence potential of the 2-member communities was examined in C. elegans during nutrient deprivation and exposure to opioids in order to mimic local conditions in the gut during critical illness. Under conditions of nutrient deprivation, the bacterial members attenuated the virulence of fungal members, leading to a “commensal lifestyle.” However, exposure to opioids led to a breakdown in this commensalism in 2 of the ultra-low-diversity communities. Application of a novel antivirulence agent (phosphate-polyethylene glycol [Pi-PEG]) that creates local phosphate abundance prevented opioid-induced virulence among these pathogen communities, thus rescuing the commensal lifestyle. To conclude, the gut microflora in critically ill patients can consist of ultra-low-diversity communities of multidrug-resistant pathogenic microbes. Local environmental conditions in gut may direct pathogen communities to adapt to either a commensal style or a pathogenic style.« less

Mice lacking the G protein γ3-subunit show resistance to opioids and diet induced obesity

PubMed Central

Schwindinger, William F.; Borrell, Brandon M.; Waldman, Lora C.

2009-01-01

Contributing to the obesity epidemic, there is increasing evidence that overconsumption of high-fat foods may be analogous to drug addiction in that the palatability of these foods is associated with activation of specific reward pathways in the brain. With this perspective, we report that mice lacking the G protein γ3-subunit (Gng3−/− mice) show resistance to high-fat diet-induced weight gain over the course of a 12-wk study. Compared with Gng3+/+ controls, female Gng3−/− mice exhibit a 40% reduction in weight gain and a 53% decrease in fat pad mass, whereas male Gng3−/− mice display an 18% reduction in weight gain and no significant decrease in fat pad mass. The basis for the lowered weight gain is related to reduced food consumption for female and male Gng3−/− mice of 13% and 14%, respectively. Female Gng3−/− mice also show a lesser preference for high-fat chow than their female Gng3+/+ littermates, suggesting an attenuated effect on a reward pathway associated with overconsumption of fat. One possible candidate is the μ-opioid receptor (Oprm1) signaling cascade. Supporting a defect in this signaling pathway, Gng3−/− mice show marked reductions in both acute and chronic morphine responsiveness, as well as increases in endogenous opioid mRNA levels in reward-related regions of the brain. Taken together, these data suggest that the decreased weight gain of Gng3−/− mice may be related to a reduced rewarding effect of the high-fat diet resulting from a defect in Oprm1 signaling and loss of the G protein γ3-subunit. PMID:19759336

Membership and Behavior of Ultra-Low-Diversity Pathogen Communities Present in the Gut of Humans during Prolonged Critical Illness

DOE PAGES

Zaborin, Alexander; Smith, Daniel; Garfield, Kevin; ...

2014-09-23

We analyzed the 16S rRNA amplicon composition in fecal samples of selected patients during their prolonged stay in an intensive care unit (ICU) and observed the emergence of ultra-low-diversity communities (1 to 4 bacterial taxa) in 30% of the patients. Bacteria associated with the genera Enterococcus and Staphylococcus and the family Enterobacteriaceae comprised the majority of these communities. The composition of cultured species from stool samples correlated to the 16S rRNA analysis and additionally revealed the emergence of Candida albicans and Candida glabrata in ~75% of cases. Four of 14 ICU patients harbored 2-member pathogen communities consisting of one Candidamore » taxon and one bacterial taxon. Bacterial members displayed a high degree of resistance to multiple antibiotics. The virulence potential of the 2-member communities was examined in C. elegans during nutrient deprivation and exposure to opioids in order to mimic local conditions in the gut during critical illness. Under conditions of nutrient deprivation, the bacterial members attenuated the virulence of fungal members, leading to a “commensal lifestyle.” However, exposure to opioids led to a breakdown in this commensalism in 2 of the ultra-low-diversity communities. Application of a novel antivirulence agent (phosphate-polyethylene glycol [Pi-PEG]) that creates local phosphate abundance prevented opioid-induced virulence among these pathogen communities, thus rescuing the commensal lifestyle. To conclude, the gut microflora in critically ill patients can consist of ultra-low-diversity communities of multidrug-resistant pathogenic microbes. Local environmental conditions in gut may direct pathogen communities to adapt to either a commensal style or a pathogenic style.« less

Content fragile watermarking for H.264/AVC video authentication

NASA Astrophysics Data System (ADS)

Ait Sadi, K.; Guessoum, A.; Bouridane, A.; Khelifi, F.

2017-04-01

Discrete cosine transform is exploited in this work to generate the authentication data that are treated as a fragile watermark. This watermark is embedded in the motion vectors. The advances in multimedia technologies and digital processing tools have brought with them new challenges for the source and content authentication. To ensure the integrity of the H.264/AVC video stream, we introduce an approach based on a content fragile video watermarking method using an independent authentication of each group of pictures (GOPs) within the video. This technique uses robust visual features extracted from the video pertaining to the set of selected macroblocs (MBs) which hold the best partition mode in a tree-structured motion compensation process. An additional security degree is offered by the proposed method through using a more secured keyed function HMAC-SHA-256 and randomly choosing candidates from already selected MBs. In here, the watermark detection and verification processes are blind, whereas the tampered frames detection is not since it needs the original frames within the tampered GOPs. The proposed scheme achieves an accurate authentication technique with a high fragility and fidelity whilst maintaining the original bitrate and the perceptual quality. Furthermore, its ability to detect the tampered frames in case of spatial, temporal and colour manipulations is confirmed.

Electrophysiological evidence for different release mechanism of ATP and NO as inhibitory NANC transmitters in guinea-pig colon.

PubMed Central

Zagorodnyuk, V.; Maggi, C. A.

1994-01-01

1. The effect of the P2-purinoceptor antagonist, suramin, the specific N-type voltage-dependent calcium channel blocker, omega-conotoxin GVIA (omega-CgTx) and the delta-opioid receptor agonist [D-Pen2,D-Pen5] enkephalin (DPDPE) on the apamin-sensitive and apamin-resistant inhibitory junction potentials (i.j.ps) produced by electrical field stimulation (EFS) were investigated by means of a sucrose-gap technique in the circular muscle of the guinea-pig colon. 2. After incubation of muscle strips in either atropine (1 microM), guanethidine (3 microM) and NG-nitro-L-arginine (L-NOARG, 30 microM) or atropine, guanethidine and apamin (0.3 microM), the addition of the NK1 receptor antagonist, SR 140,333 (1 microM) abolished the non-adrenergic, non-cholinergic (NANC) excitatory junction potential (e.j.p.) and unmasked a pure apamin-sensitive i.j.p. (in the presence of L-NOARG) or a pure apamin-resistant i.j.p. (in the presence of apamin). Both types of i.j.p. were abolished by tetrodotoxin. 3. Suramin (30-300 microM) concentration-dependently inhibited the apamin-sensitive i.j.p., while the apamin-resistant i.j.p. was not significantly affected by suramin (up to 300 microM). L-NOARG (30 microM) markedly reduced the apamin-resistant i.j.p. 4. The delta-opioid receptor agonist, DPDPE (0.03-3 microM) concentration-dependently reduced the apamin-sensitive i.j.p., while leaving the apamin-resistant i.j.p. unaffected. Naloxone (1 microM) prevented the i.j.p. inhibition evoked by DPDPE (0.3 microM). 5. omega-CgTx (0.3 microM) markedly reduced the apamin-sensitive but not the apamin-resistant i.j.p.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7952866

Developing Items to Measure Theory of Planned Behavior Constructs for Opioid Administration for Children: Pilot Testing.

PubMed

Vincent, Catherine; Riley, Barth B; Wilkie, Diana J

2015-12-01

The Theory of Planned Behavior (TpB) is useful to direct nursing research aimed at behavior change. As proposed in the TpB, individuals' attitudes, perceived norms, and perceived behavior control predict their intentions to perform a behavior and subsequently predict their actual performance of the behavior. Our purpose was to apply Fishbein and Ajzen's guidelines to begin development of a valid and reliable instrument for pediatric nurses' attitudes, perceived norms, perceived behavior control, and intentions to administer PRN opioid analgesics when hospitalized children self-report moderate to severe pain. Following Fishbein and Ajzen's directions, we were able to define the behavior of interest and specify the research population, formulate items for direct measures, elicit salient beliefs shared by our target population and formulate items for indirect measures, and prepare and test our questionnaire. For the pilot testing of internal consistency of measurement items, Cronbach alphas were between 0.60 and 0.90 for all constructs. Test-retest reliability correlations ranged from 0.63 to 0.90. Following Fishbein and Ajzen's guidelines was a feasible and organized approach for instrument development. In these early stages, we demonstrated good reliability for most subscales, showing promise for the instrument and its use in pain management research. Better understanding of the TpB constructs will facilitate the development of interventions targeted toward nurses' attitudes, perceived norms, and/or perceived behavior control to ultimately improve their pain behaviors toward reducing pain for vulnerable children. Copyright © 2015 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Evaluation of the Relative Abuse of an OROS® Extended-release Hydromorphone HCI Product: Results from three Post-market Surveillance Studies.

PubMed

Butler, Stephen F; McNaughton, Emily C; Black, Ryan A; Cassidy, Theresa A

2018-01-02

Formulating prescription opioids to limit abuse remains a priority. OROS® extended-release (ER) hydromorphone HCl (EXALGO®) may have low abuse potential. Three post-marketing studies of the relative abuse liability of OROS hydromorphone ER were conducted. Estimates of abuse, unadjusted and adjusted for prescription volume, were generated for OROS hydromorphone ER and comparators from Q2 2010 through Q2 2014 for a high-risk, substance abuse treatment population and the general population using poison control center data. Comparators were selected for compound, market penetration, and route of administration (ROA) profile. ROA comparisons were made among the substance abuse treatment population. Internet discussion was examined to determine abusers' interest in and desire for the OROS formulation. Examination of abuse prevalence among adults within substance abuse treatment, intentional poison exposures and Internet discussion levels generally support the hypothesis that OROS hydromorphone ER may have lower abuse potential than many other opioid products. OROS hydromorphone ER also appears to be abused less often by alternate ROAs (e.g., snorting and injection). Lower levels of online discussion were observed along with relatively low endorsement for abuse. Abuse of OROS hydromorphone ER was observed in high-risk substance abuse and general population samples but at a very low relative prevalence. Evidence suggests it may be less often abused by alternate ROAs than some comparators. Online data did not find evidence of high levels of desire for OROS hydromorphone ER by recreational abusers. Continued monitoring of this product's abuse liability is warranted.

Effects of a sustained-release naloxone pellet on luteinizing hormone secretion in female rats.

PubMed

Gabriel, S M; Simpkins, J W

1983-11-01

Studies were undertaken to develop a naloxone implant capable of chronically blocking opioid receptors for several weeks in an effort to evaluate the effect of this prolonged narcotic antagonism on luteinizing hormone (LH) secretion in female rats. Antagonism of opiate receptors was achieved with a tablet formulation which contained 75 mg naloxone free base and a high content of the insoluble binding material, Mg stearate. Subcutaneous placement of this implant prevented morphine-induced analgesia for 2 weeks and antagonized the LH suppressory effects of morphine (15 or 30 mg/kg) administration. Thus, this naloxone delivery system is capable of chronically occupying the opioid receptors which mediate morphine's effects on analgesia and LH secretion. Despite this, the naloxone pellet only moderately enhanced the initial rate of increase in LH secretion following ovariectomy (day 1) and was ineffective in further augmenting LH secretion at 3 and 7 days after implantation. In rats which were ovariectomized and implanted immediately with estradiol-containing Silastic capsules, the naloxone pellet was ineffective in altering LH secretion 1, 3 or 7 days later. Thus, while chronic exposure to naloxone persistently antagonizes the pharmacologic actions of morphine, the naloxone pellet only transiently blocked the tonic inhibitory effect of endogenous opioid peptides. The mechanism by which the LH secretory effects of naloxone are lost following chronic exposure to the antagonist are at present unknown, but may involve the activation of compensatory mechanisms which are inhibitory to LH secretion.

Variable Effects of Exposure to Formulated Microbicides on Antibiotic Susceptibility in Firmicutes and Proteobacteria

PubMed Central

Forbes, Sarah; Knight, Christopher G.; Cowley, Nicola L.; Amézquita, Alejandro; McClure, Peter; Humphreys, Gavin

2016-01-01

ABSTRACT Microbicides are broad-spectrum antimicrobial agents that generally interact with multiple pharmacological targets. While they are widely deployed in disinfectant, antiseptic, and preservative formulations, data relating to their potential to select for microbicide or antibiotic resistance have been generated mainly by testing the compounds in much simpler aqueous solutions. In the current investigation, antibiotic susceptibility was determined for bacteria that had previously exhibited decreased microbicide susceptibility following repeated exposure to microbicides either in formulation with sequestrants and surfactants or in simple aqueous solution. Statistically significant increases in antibiotic susceptibility occurred for 12% of bacteria after exposure to microbicides in formulation and 20% of bacteria after exposure to microbicides in aqueous solutions, while 22% became significantly less susceptible to the antibiotics, regardless of formulation. Of the combinations of a bacterium and an antibiotic for which British Society for Antimicrobial Chemotherapy breakpoints are available, none became resistant. Linear modeling taking into account phylogeny, microbicide, antibiotic, and formulation identified small but significant effects of formulation that varied depending on the bacterium and microbicide. Adaptation to formulated benzalkonium chloride in particular was more likely to increase antibiotic susceptibility than adaptation to the simple aqueous solution. In conclusion, bacterial adaptation through repeated microbicide exposure was associated with both increases and decreases in antibiotic susceptibility. Formulation of the microbicide to which the bacteria had previously adapted had an identifiable effect on antibiotic susceptibility, but it effect was typically small relative to the differences observed among microbicides. Susceptibility changes resulting in resistance were not observed. IMPORTANCE The safety of certain microbicide applications has been questioned due to the possibility that microbicide exposure could select for microbicide and antibiotic resistance. Evidence that this may happen is based mainly on in vitro experiments where bacteria have been exposed to microbicides in aqueous solution. Microbicides are, however, normally deployed in products formulated with surfactants, sequestrants, and other compounds. While this may influence the frequency and extent of susceptibility changes, few studies reported in the literature have assessed this. In the current investigation, therefore, we have investigated changes in antibiotic susceptibility in bacteria which exhibited decreased microbicide susceptibility following repeated exposure to microbicides in simple aqueous solutions and in formulation. We report that the microbicide formulation had an identifiable effect on antibiotic susceptibility, but it was typically small relative to the differences observed among microbicides. We did not observe susceptibility changes resulting in resistance. PMID:27060123

Bioavailability of curcumin and curcumin glucuronide in the central nervous system of mice after oral delivery of nano-curcumin.

PubMed

Szymusiak, Magdalena; Hu, Xiaoyu; Leon Plata, Paola A; Ciupinski, Paulina; Wang, Zaijie Jim; Liu, Ying

2016-09-10

Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography-mass spectrometry (LC-MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

Fentanyl patches: preventable overdose.

PubMed

2010-02-01

Fentanyl is a potent opioid analgesic marketed for the treatment of stable intense chronic pain, particularly in the form of a transdermal patch. These delivery devices carry the same risk of adverse effects and drug interactions as conventional formulations of opioids. The patches carry an added risk of fentanyl overdose because they contain very high doses, both before and after use. High-risk situations for overdose were identified by examining the results of pharmacovigilance studies and medication error prevention programmes, as well as an observational study, case reports, and a French legal action. The main situations exposing patients to a risk of overdose are: confusion between two dose strengths, forgetting to remove the patch; accidental transfer of the patch to another person, application of more than one patch, cutting the patches, self-medication, and ingestion. Increased skin temperature facilitates fentanyl absorption and thus increases the risk of overdose; high-risk situations include fever, electric blankets, and intense physical exercise. In practice, the precautions for treatment and patch disposal must be followed exactly if this delivery system is to serve as a valid alternative to morphine for selected patients with stable intense chronic pain.

Secure Web-Site Access with Tickets and Message-Dependent Digests

USGS Publications Warehouse

Donato, David I.

2008-01-01

Although there are various methods for restricting access to documents stored on a World Wide Web (WWW) site (a Web site), none of the widely used methods is completely suitable for restricting access to Web applications hosted on an otherwise publicly accessible Web site. A new technique, however, provides a mix of features well suited for restricting Web-site or Web-application access to authorized users, including the following: secure user authentication, tamper-resistant sessions, simple access to user state variables by server-side applications, and clean session terminations. This technique, called message-dependent digests with tickets, or MDDT, maintains secure user sessions by passing single-use nonces (tickets) and message-dependent digests of user credentials back and forth between client and server. Appendix 2 provides a working implementation of MDDT with PHP server-side code and JavaScript client-side code.

Secure and Efficient Reactive Video Surveillance for Patient Monitoring.

PubMed

Braeken, An; Porambage, Pawani; Gurtov, Andrei; Ylianttila, Mika

2016-01-02

Video surveillance is widely deployed for many kinds of monitoring applications in healthcare and assisted living systems. Security and privacy are two promising factors that align the quality and validity of video surveillance systems with the caliber of patient monitoring applications. In this paper, we propose a symmetric key-based security framework for the reactive video surveillance of patients based on the inputs coming from data measured by a wireless body area network attached to the human body. Only authenticated patients are able to activate the video cameras, whereas the patient and authorized people can consult the video data. User and location privacy are at each moment guaranteed for the patient. A tradeoff between security and quality of service is defined in order to ensure that the surveillance system gets activated even in emergency situations. In addition, the solution includes resistance against tampering with the device on the patient's side.

Secure and Efficient Reactive Video Surveillance for Patient Monitoring

PubMed Central

Braeken, An; Porambage, Pawani; Gurtov, Andrei; Ylianttila, Mika

2016-01-01

Video surveillance is widely deployed for many kinds of monitoring applications in healthcare and assisted living systems. Security and privacy are two promising factors that align the quality and validity of video surveillance systems with the caliber of patient monitoring applications. In this paper, we propose a symmetric key-based security framework for the reactive video surveillance of patients based on the inputs coming from data measured by a wireless body area network attached to the human body. Only authenticated patients are able to activate the video cameras, whereas the patient and authorized people can consult the video data. User and location privacy are at each moment guaranteed for the patient. A tradeoff between security and quality of service is defined in order to ensure that the surveillance system gets activated even in emergency situations. In addition, the solution includes resistance against tampering with the device on the patient’s side. PMID:26729130

Identification of Dmt-D-Lys-Phe-Phe-OH as a highly antinociceptive tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20.

PubMed

Kleczkowska, Patrycja; Bojnik, Engin; Leśniak, Anna; Kosson, Piotr; Van den Eynde, Isabelle; Ballet, Steven; Benyhe, Sandor; Tourwé, Dirk; Lipkowski, Andrzej W

2013-01-01

Recently, we presented a novel compound (PK20, Dmt-D-Lys-Phe-Phe-Lys-Lys-Pro-Phe-Tle-Leu-OH) that targets single entity opioid and neurotensin pharmacophores. This endomorphin-2-like opioid peptide was introduced as a highly active analgesic because it elicited a strong dose- and time-dependent antinociceptive response when administered centrally and peripherally. Its pain-relieving activity was observed as rapidly as 5 min after drug injection. Such promising results led us to perform further studies, such as determining the resistance to enzymatic degradation, which resulted in obtaining a very stable opioid pharmacore PK20 metabolite. The synthesis of PK20 and its N-terminal tetrapeptide fragment has been accomplished using solid phase peptide chemistry. The biological stability of peptides has been measured in human serum and analyzed by HPLC/MS. Peptides were pharmacologically characterized in in vitro MOP and DOP receptor binding as well as [(35)S]GTPγS receptor binding assays. Antinociceptive properties of compounds were measured by in vivo assays in C57Bl6 mice after intravenous or intrathecal applications. Dmt-D-Lys-Phe-Phe-OH (PK20M), an N-terminal tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20, is characterized by a long duration of action, as demonstrated by a preserved, long-lasting analgesic effect even 2 h post-injection (average % MPE = 69.33). In rat brain membranes, PK20M efficiently displaced both the MOP and DOP receptor selective radioprobes [(3)H]DAMGO and [(3)H]DIDI (pKi of 9.52 and 7.86, respectively) and potently stimulated [(35)S]GTPγS binding, proving full agonism at both receptor types. In the [(35)S]GTPγS assay, which measured the agonist-mediated G protein activation, PK20M together with PK20 and Met-enkephalin were potent stimulators of the regulatory G proteins. The relative affinities of PK20M for the μ and δ receptor subtypes revealed μ-receptor selectivity. The novel MOP receptor selective metabolite has been shown to possess opioid subtype receptor selectivity, high potency, and effective analgesic activities as measured in various bioassays.

Formulation of stable Bacillus subtilis AH18 against temperature fluctuation with highly heat-resistant endospores and micropore inorganic carriers.

PubMed

Chung, Soohee; Lim, Hyung Mi; Kim, Sang-Dal

2007-08-01

To survive the commercial market and to achieve the desired effect of beneficial organisms, the strains in microbial products must be cost-effectively formulated to remain dormant and hence survive through high and low temperatures of the environment during transportation and storage. Dormancy and stability of Bacillus subtilis AH18 was achieved by producing endospores with enhanced heat resistance and using inorganic carriers. Heat stability assays, at 90 degrees C for 1 h, showed that spores produced under a sublethal temperature of 57 degrees C was 100 times more heat-resistant than the ones produced by food depletion at the growing temperature of 37 degrees C. When these highly heat-resistant endospores were formulated with inorganic carriers of natural and synthetic zeolite or kaolin clay minerals having substantial amount of micropores, the dormancy of the endospores was maintained for 6 months at 15-25 degrees C. Meanwhile, macroporous perlite carriers with average pore diameter larger than 3.7 microm stimulated the germination of the spores and rapid proliferation of the bacteria. These results indicated that a B. subtilis AH18 product that can remain dormant and survive through environmental temperature fluctuation can be formulated by producing heat-stressed endospores and incorporating inorganic carriers with micropores in the formulation step.

The Concentration of Opioid Prescriptions by Providers and Among Patients in the Oregon Medicaid Program.

PubMed

Kim, Hyunjee; Hartung, Daniel M; Jacob, Reside L; McCarty, Dennis; McConnell, K John

2016-04-01

This study examined the distribution of opioid prescribing across providers and patients and the extent to which concentrated distribution predicts opioid misuse. Using 2013 Oregon Medicaid claims and the National Provider Identifier Registry, this study identified patients who filled at least one opioid prescription and providers who prescribed opioids for those patients (N=61,477 Medicaid beneficiaries). This study examined the distribution of opioid prescriptions by provider and patient, the extent to which high-volume opioid use was associated with potential opioid misuse, and how this association changed when patients received opioids from providers in the top decile of morphine-equivalent doses (MEQ) prescribed in 2013. This study used four indicators of opioid misuse: doctor and pharmacy shopping for opioid prescriptions, opioid prescription overlap, and opioid and benzodiazepine prescription overlap. Opioid use and prescriptions were heavily concentrated among the top 10% of opioid users and prescribers. Those high-volume opioid users and prescribers accounted for, respectively, 83.2% and 80.8% in MEQ of entire opioids prescribed. Patients' increasing use of opioids (by MEQ) was associated with most measures of opioid misuse. Patients receiving opioids from high-volume prescribers had a higher probability of opioid prescription overlap and opioid and benzodiazepine prescription overlap compared with other patients, but the difference was significant only among patients who received high doses of opioids, and the size of the difference was modest. Whereas current policies emphasize reducing opioid prescriptions across all patients and providers, study results suggest that focusing policies on high-volume opioid users and prescribers may be more beneficial.

Insecticide resistance and diminished secondary kill performance of bait formulations against German cockroaches (Dictyoptera: Blattellidae)

PubMed Central

Ko, Alexander E.; Bieman, Donald N.; Schal, Coby; Silverman, Jules

2015-01-01

BACKGROUND Bait formulations are considered the most effective method for reducing German cockroach infestations. An important property of some bait formulations is secondary kill, whereby active ingredient is translocated in insect-produced residues throughout the cockroach population, especially affecting relatively sedentary early instar nymphs. RESULTS Blattella germanica was collected from a location where baits containing hydramethylnon, fipronil, or indoxacarb became ineffective, and these AIs were topically applied to adult males. Results revealed the first evidence for hydramethylnon resistance, moderate resistance to fipronil and extremely high resistance to indoxacarb. Insecticide residues excreted by field-collected males that ingested commercial baits effectively killed nymphs of an insecticide-susceptible laboratory strain of B. germanica but failed to kill most nymphs of the field-collected strain. CONCLUSIONS We report three novel findings: 1) The first evidence for hydramethylnon resistance in any insect; 2) extremely high levels of indoxacarb resistance in a field population; and 3) reduced secondary mortality in an insecticide-resistant field-collected strain of B. germanica. We suggest that while secondary mortality is considered to be advantageous in cockroach interventions, the ingestion of sublethal doses of AI by nymphs may select for high insecticide resistance by increasing the frequency of AI resistance alleles within the population. PMID:26689433

Attentional bias for prescription opioid cues among opioid dependent chronic pain patients.

PubMed

Garland, Eric L; Froeliger, Brett E; Passik, Steven D; Howard, Matthew O

2013-12-01

Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioid-related cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200. vs. 2,000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2,000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior.

Fenitrothion: an alternative insecticide for the control of deltamethrin-resistant populations of Triatoma infestans in northern Argentina.

PubMed

Germano, M; Picollo, M I; Spillmann, C; Mougabure-Cueto, G

2014-03-01

Deltamethrin-based campaigns to control Triatoma infestans (Klug) (Hemiptera: Reduviidae) have decreased in success as a result of the development of insecticide resistance. We compared the in vitro effects of the pyrethroid deltamethrin and two doses of the organophosphate fenitrothion, presented on different materials, on T. infestans from La Esperanza, Argentina. Laboratory tests demonstrated a decrease in susceptibility to deltamethrin in the field population [LD50 : 30.32 nanograms per insect (ng/i)] compared with the reference population (LD50 : 0.13 ng/i), giving a high resistance ratio of 233.42. By contrast, similar susceptibility to fenitrothion was assessed in both the field and reference populations (LD50 : 21.65 ng/i and 21.38 ng/i, respectively). The effectiveness of the formulated insecticides varied according to the surfaces to which they were applied. The application of fenitrothion formulations to glass or brick resulted in mortality of 90-100%. The application of fenitrothion formulations to wood or mud caused mortality in the range of 6.7-56.7%. Resistant insects presented low mortality when exposed to the deltamethrin formulation and high mortality when exposed to fenitrothion formulations. Moreover, the insecticides demonstrated residual activity only when applied to glass. The present work demonstrates that fenitrothion is an alternative to pyrethroids for the management of deltamethrin-resistant insects in La Esperanza. However, this effectiveness is not sustained over time. © 2013 The Royal Entomological Society.

Comparative in vitro anti-tick efficacy of commercially available products and newly developed phyto-formulations against field collected and resistant tick lines of Rhipicephalus (Boophilus) microplus.

PubMed

Ajith Kumar, K G; Sharma, Anil Kumar; Kumar, Sachin; Ray, D D; Rawat, A K S; Srivastava, Sharad; Ghosh, Srikant

2016-12-01

Rhipicephalus ( Boophilus ) microplus is considered as one of the most widely distributed tick species ecto-parasitizing on livestock and causes fatal diseases with significant production loss. To address the problem of controlling acaricide resistant tick infestations on animals, attention has been paid to develop eco-friendly phyto-acaricides. The present study was undertaken to evaluate the comparative anti-tick activities of commercially available herbal and chemical products with chemically characterized phyto-formulations developed recently against field ticks and resistant tick lines of R. ( B. ) microplus . The chemical product Butox ® Vet was found nearly passive against all the tested resistant tick lines. However, one of the commercial polyherbal product, Zerokeet ® showed an efficacy (E%) of 41.8-75.4 % ([Formula: see text]) using recommended dilution (1:2) against field ticks and resistant tick lines. However, the other commercial product, Erina ® EP has very limited efficacy against all the tested tick. In comparison, the newly developed phyto-formulation, NBA/13/B/2 and NAC-01 conferred an E% of 82.4-91.3 % ([Formula: see text]) and 62.3-94.6 % ([Formula: see text]), respectively, against tested resistant ticks. Results indicated higher marketing potentiality of newly developed formulation in the existing tick problem scenario.

76 FR 19829 - Clean Alternative Fuel Vehicle and Engine Conversions

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-08

...EPA is streamlining the process by which manufacturers of clean alternative fuel conversion systems may demonstrate compliance with vehicle and engine emissions requirements. Specifically, EPA is revising the regulatory criteria for gaining an exemption from the Clean Air Act prohibition against tampering for the conversion of vehicles and engines to operate on a clean alternative fuel. This final rule creates additional compliance options beyond certification that protect manufacturers of clean alternative fuel conversion systems against a tampering violation, depending on the age of the vehicle or engine to be converted. The new options alleviate some economic and procedural impediments to clean alternative fuel conversions while maintaining environmental safeguards to ensure that acceptable emission levels from converted vehicles are sustained.

An Invisible Text Watermarking Algorithm using Image Watermark

NASA Astrophysics Data System (ADS)

Jalil, Zunera; Mirza, Anwar M.

Copyright protection of digital contents is very necessary in today's digital world with efficient communication mediums as internet. Text is the dominant part of the internet contents and there are very limited techniques available for text protection. This paper presents a novel algorithm for protection of plain text, which embeds the logo image of the copyright owner in the text and this logo can be extracted from the text later to prove ownership. The algorithm is robust against content-preserving modifications and at the same time, is capable of detecting malicious tampering. Experimental results demonstrate the effectiveness of the algorithm against tampering attacks by calculating normalized hamming distances. The results are also compared with a recent work in this domain

Apparatus and method for detecting tampering in flexible structures

DOEpatents

Maxey, Lonnie C [Knoxville, TN; Haynes, Howard D [Knoxville, TN

2011-02-01

A system for monitoring or detecting tampering in a flexible structure includes taking electrical measurements on a sensing cable coupled to the structure, performing spectral analysis on the measured data, and comparing the spectral characteristics of the event to those of known benign and/or known suspicious events. A threshold or trigger value may used to identify an event of interest and initiate data collection. Alternatively, the system may be triggered at preset intervals, triggered manually, or triggered by a signal from another sensing device such as a motion detector. The system may be used to monitor electrical cables and conduits, hoses and flexible ducts, fences and other perimeter control devices, structural cables, flexible fabrics, and other flexible structures.

The Concentration of Opioid Prescriptions by Providers and Patients in the Oregon Medicaid Program

PubMed Central

Kim, Hyunjee; Hartung, Daniel; Jacob, Lorie; McCarty, Dennis; McConnell, K. John

2016-01-01

Objective This study seeks to understand the distribution of opioid prescribing across providers and patients, and examines how this concentration predicts opioid misuse. Methods Using 2013 Oregon Medicaid claims and National Provider ID registry, this study identified patients who filled at least one opioid prescription and providers who prescribed opioids for those patients (N=61,477 Medicaid patients). This study examined the distribution of opioid prescriptions by provider and patient, the extent to which high-volume opioid use was associated with potential opioid misuse, and how this association changes when patients received opioids from providers in the top decile of morphine equivalents (MEQ) prescribed in 2013. This study used four indicators of opioid misuse: doctor and pharmacy shopping for opioid prescriptions, opioid prescription overlap, and opioid and benzodiazepine prescription overlap. Results Opioid use and prescriptions were heavily concentrated among the top 10% opioid users and prescribers. Those high-volume opioid users and prescribers accounted for 83.2% and 80.8% in MEQ of entire opioids prescribed. Patients’ increasing use of MEQ was associated with most measures of opioid misuse. Patients receiving opioids from high-volume prescribers had a higher probability of opioid prescription overlap and opioid and benzodiazepine prescription overlap, but the increase was significant only among patients who received high doses of opioids and the size of the increase was modest. Conclusions Whereas current policies emphasize reducing opioid prescriptions across all patients and providers, study results suggest potential for policies that focus on high-volume opioid users and prescribers. PMID:26766755

Attentional Bias For Prescription Opioid Cues Among Opioid Dependent Chronic Pain Patients

PubMed Central

Garland, Eric L.; Froeliger, Brett; Passik, Steven D.; Howard, Matthew O.

2012-01-01

Recurrent use of prescription opioid analgesics by chronic pain patients may result in opioid dependence, which involves implicit neurocognitive operations that organize and impel craving states and compulsive drug taking behavior. Prior studies have identified an attentional bias (AB) towards heroin among heroin dependent individuals. The aim of this study was to determine whether opioid-dependent chronic pain patients exhibit an AB towards prescription opioidrelated cues. Opioid-dependent chronic pain patients (n = 32) and a comparison group of non-dependent opioid users with chronic pain (n = 33) completed a dot probe task designed to measure opioid AB. Participants also rated their opioid craving and self-reported arousal associated with opioid-related and neutral images, pain severity, and relief from pain treatments. Repeated-measures ANOVA revealed a significant group (opioid-dependent vs. non-dependent opioid user) × presentation duration (200 ms. vs. 2000 ms.) interaction, such that opioid-dependent individuals evidenced a significant AB towards opioid cues presented for 200 ms but not for cues presented for 2000 ms, whereas non-dependent opioid users did not exhibit a significant mean AB at either stimulus duration. Among opioid-dependent individuals, 200 ms opioid AB was significantly associated with opioid craving, while among non-dependent opioid users, 200 ms opioid AB was significantly associated with relief from pain treatments. Furthermore, dependent and non-dependent opioid users experienced opioid cues as significantly more arousing than neutral cues. Opioid dependence among chronic pain patients appears to involve an automatic AB towards opioid-related cues. When coupled with chronic pain, attentional fixation on opioid cues may promote compulsive drug use and addictive behavior. PMID:22968666

Use of opioid substitution therapies in the treatment of opioid use disorder: results of a UK cost-effectiveness modelling study.

PubMed

Kenworthy, James; Yi, Yunni; Wright, Antony; Brown, Jim; Maria Madrigal, Ana; Dunlop, William C N

2017-07-01

This study investigated the cost-effectiveness of buprenorphine maintenance treatment (BMT) and methadone maintenance treatment (MMT) vs no opioid substitution therapy (OST) for the treatment of opioid use disorder, from the UK National Health Service (NHS)/personal social services (PSS) and societal perspectives over 1 year. Cost-effectiveness of OST vs no OST was evaluated by first replicating and then expanding an existing UK health technology assessment model. The expanded model included the impact of OST on infection rates of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. Versus no OST, incremental cost-effectiveness ratios (ICERs) for BMT and MMT were £13,923 and £14,206 per quality-adjusted life year (QALY), respectively, from a NHS/PSS perspective. When total costs (NHS/PSS and societal) are considered, there are substantial savings associated with adopting OST; these savings are in excess of £14,032 for BMT vs no OST and £17,174 for MMT vs no OST over 1 year. This is primarily driven by a reduction in victim costs. OST treatment also impacted other aspects of criminality and healthcare resource use. The model's 1-year timeframe means long-term costs and benefits, and the influence of changes over time are not captured. OST can be considered cost-effective vs no OST from the UK NHS/PSS perspective, with a cost per QALY well below the UK's willingness-to-pay threshold. There were only small differences between BMT and MMT. The availability of two or more cost-effective options is beneficial to retaining patients in OST programs. From a societal perspective, OST is estimated to save over £14,032 and £17,174 per year for BMT and MMT vs no OST, respectively, due to savings in victim costs. Further work is required to fully quantify the clinical and health economic impacts of different OST formulations and their societal impact over the long-term.

Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats.

PubMed

Merlos, Manuel; Portillo-Salido, Enrique; Brenchat, Alex; Aubel, Bertrand; Buxens, Jordi; Fisas, Angels; Codony, Xavier; Romero, Luz; Zamanillo, Daniel; Vela, José Miguel

2018-06-19

Drug combination for the treatment of pain is common clinical practice. Co-crystal of Tramadol-Celecoxib (CTC) consists of two active pharmaceutical ingredients (APIs), namely the atypical opioid tramadol and the preferential cyclooxygenase-2 inhibitor celecoxib, at a 1:1 molecular ratio. In this study, a non-formulated 'raw' form of CTC administered in suspension (referred to as ctc susp ) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model. For comparison, the strong opioids morphine and oxycodone, and a tramadol plus acetaminophen combination at a molecular ratio of 1:17 were also tested. Isobolographic analyses showed that ctc susp exerted synergistic mechanical antiallodynic (experimental ED 50 =2.0±0.5mg/kg, i.p.; theoretical ED 50 =3.8±0.4mg/kg, i.p.) and thermal (experimental ED 50 =2.3±0.5mg/kg, i.p.; theoretical ED 50 =9.8±0.8mg/kg, i.p.) antihyperalgesic effects in the postoperative pain model. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on locomotor activity, motor coordination, ulceration potential and gastrointestinal transit were observed after the administration of ctc susp . Overall, rat efficacy and safety data revealed that ctc susp provided synergistic analgesic effects compared with each API alone, without enhancing adverse effects. Moreover, ctc susp showed similar efficacy but improved safety ratio (80, measured as gastrointestinal transit vs postoperative pain ED 50 ratios) compared with the strong opioids morphine (2.5) and oxycodone (5.8). The overall in vivo profile of ctc susp supports the further investigation of CTC in the clinical management of moderate-to-severe acute pain as an alternative to strong opioids. Copyright © 2018. Published by Elsevier B.V.

The Mixed Opioid Receptor Antagonist Naltrexone Mitigates Stimulant-Induced Euphoria: A Double-Blind, Placebo-Controlled Trial of Naltrexone.

PubMed

Spencer, Thomas J; Bhide, Pradeep; Zhu, Jinmin; Faraone, Stephen V; Fitzgerald, Maura; Yule, Amy M; Uchida, Mai; Spencer, Andrea E; Hall, Anna M; Koster, Ariana J; Feinberg, Leah; Kassabian, Sarah; Storch, Barbara; Biederman, Joseph

Supratherapeutic doses of methylphenidate activate μ-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed μ-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention-deficit/hyperactivity disorder (ADHD). We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to ~1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH. Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (χ² = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (χ² = 0.22, P = .64) of SODAS-MPH treatment. Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential. ClinicalTrials.gov identifier: NCT01673594. © Copyright 2018 Physicians Postgraduate Press, Inc.

Opioid Attentional Bias and Cue-Elicited Craving Predict Future Risk of Prescription Opioid Misuse Among Chronic Pain Patients*

PubMed Central

Garland, Eric L.; Howard, Matthew O.

2014-01-01

Background Some chronic pain patients receiving long-term opioid analgesic pharmacotherapy are at risk for misusing opioids. Like other addictive behaviors, risk of opioid misuse may be signaled by an attentional bias (AB) towards drug-related cues. The purpose of this study was to examine opioid AB as a potential predictor of opioid misuse among chronic pain patients following behavioral treatment. Methods Chronic pain patients taking long-term opioid analgesics (N = 47) completed a dot probe task designed to assess opioid AB, as well as self-report measures of opioid misuse and pain severity, and then participated in behavioral treatment. Regression analyses examined opioid AB and cue-elicited craving as predictors of opioid misuse at 3-months posttreatment follow-up. Results Patients who scored high on a measure of opioid misuse risk following treatment exhibited significantly greater opioid AB scores than patients at low risk for opioid misuse. Opioid AB for 200 ms cues and cue-elicited craving significantly predicted opioid misuse risk 20 weeks later, even after controlling for pre-treatment opioid dependence diagnosis, opioid misuse, and pain severity (Model R2 = .50). Conclusion Biased initial attentional orienting to prescription opioid cues and cue-elicited craving may reliably signal future opioid misuse risk following treatment. These measures may therefore provide potential prognostic indicators of treatment outcome. PMID:25282309

Low efficacy of non-opioid drugs in opioid withdrawal symptoms.

PubMed

Hermann, Derik; Klages, Eckard; Welzel, Helga; Mann, Karl; Croissant, Bernhard

2005-06-01

Opioid withdrawal, stress or cues associated with opioid consumption can induce opioid craving. If opioids are not available, opioid-dependent patients usually search for alternative drugs. Because several non-opioid drugs stimulate the endogenous opioidergic system, this concept may explain their frequent use by opioid-dependent patients. We hypothesized that non-opioid drugs alleviate opioid withdrawal symptoms and are therefore consumed by opioid addicts. We asked 89 opioid-dependent patients participating in an out-patient opioid maintenance program to estimate the potential of several non-opioid drugs in being able to alleviate opioid withdrawal. We applied a five-point Lickert scale (1 = very good reduction of opioid withdrawal; 5 = no reduction of opioid withdrawal). Patients could also indicate a worsening of opioid withdrawal. Values (mean +/- SD) were: for benzodiazepines, 3.2 +/- 1.1; tricyclic antidepressants, 3.6 +/- 1.1; cannabis, 3.6 +/- 1.0; alcohol, 4.1 +/- 1.1; cocaine, 4.2 +/- 1.1; amphetamine, 4.4 +/- 0.9; nicotine, 4.7 +/- 0.7; and caffeine, 4.9 +/- 0.5. A worsening of opioid withdrawal was reported by 62% of the patients for cocaine, 62% for amphetamine, 50% for caffeine, 37.5% for cannabis, 27% for nicotine, 26% for alcohol, 8% for tricyclic antidepressants and 3% for benzodiazepines. Our study shows a low efficacy of non-opioid drugs in alleviating opioid withdrawal symptoms. The data basis of this study was good and the sample was suitable to be asked for estimations of drug-drug interactions. Of the patients, 26 - 62% even reported a worsening of opioid withdrawal for cannabis, alcohol, cocaine and amphetamine. Only benzodiazepines and tricyclic antidepressants were reported to have a moderate positive effect on opioid withdrawal.

Pinhão starch and coat extract as new natural cosmetic ingredients: Topical formulation stability and sensory analysis.

PubMed

Daudt, Renata Moschini; Back, Patrícia Inês; Cardozo, Nilo Sérgio Medeiros; Marczak, Ligia Damasceno Ferreira; Külkamp-Guerreiro, Irene Clemes

2015-12-10

The objective of this study was to use pinhão derivatives, starch and coat extract, as new natural ingredients to develop cosmetic formulations. Two types of formulation, gel and emulgel, and their controls were developed. The formulations were characterized by stability studies using thermal stress. The parameters analyzed were resistance to centrifugation, pH, spreadability, rheology, content of phenolic compounds and antioxidant activity. Sensory analysis was also performed to verify the acceptability of the ingredients to potential consumers. The pH was kept the same after heating/freezing cycles for all formulations, and the formulations showed stability by resistance to centrifugation. The formulations did not induce any skin irritation or cutaneous pH alteration. The pinhão starch addition improved spreadability stability and increased viscosity when compared with control formulations. The pinhão coat extract used in these formulations is a good source of phenolic compounds and antioxidant activity. Moreover, sensory analysis indicates that the emulgel formulation is the best vehicle for adding pinhão starch and pinhão coat extract. Copyright © 2015 Elsevier Ltd. All rights reserved.

Relative bioavailability and comparative clinical efficacy of different ivermectin oral formulations in lambs

PubMed Central

2013-01-01

Background Several oral ivermectin (IVM) formulations for use in sheep are available in the pharmaceutical veterinary market in different countries. All of them are indicated at the same dose rate to treat the gastrointestinal nematodes. However, there is a lack of information on the relative systemic exposure (plasma bioavailability) and clinical efficacy among oral formulations routinely used in sheep. The main goal of the work reported here was to perform a pharmaco-parasitological assessment of three different IVM oral formulations in lambs infected with multiple resistant gastrointestinal nematodes. The comparative drug systemic exposure (IVM plasma concentrations) and nematodicidal efficacies (clinical efficacy) in lambs were determined for a reference (RF) and two different test (T1, T2) IVM oral formulations. One hundred and fifty six (n= 156) healthy Corriedale lambs, naturally infected with multiple resistant gastrointestinal nematodes were allocated into four experimental groups (n=39). Animals in each group received treatment (200 μg/kg) with either the RF, one of the test IVM formulations or were kept as untreated control. Blood samples were collected over 15 days post-treatment (n=8). The IVM plasma concentrations were measured by high performance liquid chromatography with fluorescence detection. The faecal nematode egg count reduction test (FECRT) (n=39) and evaluation of the clinical efficacy were performed at day 14 post-treatment (n=6), where a predominance of IVM highly resistant nematodes was observed. Results and conclusions Neither the overall kinetic behaviour nor the IVM systemic exposure differed among all the tested oral formulations. Equivalent efficacy results were obtained for the different preparations, with an evident therapeutic failure to control Haemonchus spp. and Teladorsagia circumcincta, which correlates with a high degree of nematode resistance to IVM. PMID:23398629

Systematic review of the effects of fascia iliaca compartment block on hip fracture patients before operation.

PubMed

Steenberg, J; Møller, A M

2018-06-01

Fascia iliaca compartment block is used for hip fractures in order to reduce pain, the need for systemic analgesia, and prevent delirium, on this basis. This systematic review was conducted to investigate the analgesic and adverse effects of fascia iliaca block on hip fracture in adults when applied before operation. Nine databases were searched from inception until July 2016 yielding 11 randomised and quasi-randomised controlled trials, all using loss of resistance fascia iliaca compartment block, with a total population of 1062 patients. Meta-analyses were conducted comparing the analgesic effect of fascia iliaca compartment block on nonsteroidal anti-inflammatory drugs (NSAIDs), opioids and other nerve blocks, preoperative analgesia consumption, and time to perform spinal anaesthesia compared with opioids and time for block placement. The analgesic effect of fascia iliaca compartment block was superior to that of opioids during movement, resulted in lower preoperative analgesia consumption and a longer time for first request, and reduced time to perform spinal anaesthesia. Block success rate was high and there were very few adverse effects. There is insufficient evidence to conclude anything on preoperative analgesic consumption or first request thereof compared with NSAIDs and other nerve blocks, postoperative analgesic consumption for preoperatively applied fascia iliaca compartment block compared with NSAIDs, opioids and other nerve blocks, incidence and severity of delirium, and length of stay or mortality. Fascia iliaca compartment block is an effective and relatively safe supplement in the preoperative pain management of hip fracture patients. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Community reentry challenges after release from prison among people who inject drugs in St. Petersburg, Russia

PubMed Central

Cepeda, Javier A.; Vetrova, Marina V.; Lyubimova, Alexandra I.; Levina, Olga S.; Heimer, Robert; Niccolai, Linda M.

2016-01-01

Purpose Little is known about the context of the post-release risk environment among formerly incarcerated people who inject drugs (PWID) in Russia. The purpose of this paper is to explore these challenges as they relate to reentry, relapse to injection opioid use, and overdose. Design/methodology/approach The authors conducted 25 in-depth semi-structured interviews among PWID living in St Petersburg, Russia who had been incarcerated within the past two years. Participants were recruited from street outreach (n = 20) and a drug treatment center (n = 5). Findings Emergent themes related to the post-release environment included financial instability, negative interactions with police, return to a drug using community, and reuniting with drug using peers. Many respondents relapsed to opioid use immediately after release. Those whose relapse occurred weeks or months after their release expressed more motivation to resist. Alcohol or stimulant use often preceded the opioid relapse episode. Among those who overdosed, alcohol use was often reported prior to overdosing on opioids. Practical implications Future post-release interventions in Russia should effectively link PWID to social, medical, and harm reduction services. Particular attention should be focussed on helping former inmates find employment and overdose prevention training prior to leaving prison that should also cover the heightened risk of concomitant alcohol use. Originality/value In addition to describing a syndemic involving the intersection of incarceration, injection drug use, poverty, and alcohol abuse, the findings can inform future interventions to address these interrelated public health challenges within the Russian setting. PMID:26277925

Prescription of Opioid and Non-opioid Analgesics for Dental Care in Emergency Departments: Findings from the National Hospital Ambulatory Medical Care Survey

PubMed Central

Okunseri, Christopher; Okunseri, Elaye; Xiang, Qun; Thorpe, Joshua M.; Szabo, Aniko

2014-01-01

Objective The aim of this study was to examine trends and associated factors in the prescription of opioid analgesics, non-opioid analgesics, opioid and non-opioid analgesic combinations and no analgesics by emergency physicians for nontraumatic dental condition (NTDC)-related visits. Our secondary aim was to investigate whether race/ethnicity is a possible predictor of receiving a prescription for either type of medication for NTDC visits in emergency departments (EDs) after adjustment for potential covariates. Methods We analyzed data from the National Hospital Ambulatory Medical Care Survey for 1997–2000 and 2003–2007, and used multinomial multivariate logistic regression to estimate the probability of receiving a prescription for opioid analgesics, non-opioid analgesics, or a combination of both compared to receiving no analgesics for NTDC-related visits. Results During 1997–2000 and 2003–2007, prescription of opioid analgesics and combinations of opioid and non-opioid analgesics increased and that of no analgesics decreased over time. The prescription rates for opioid analgesics, non-opioid analgesics, opioid and non-opioid analgesic combinations and no analgesics for NTDC-related visits in EDs were 43%, 20%, 12% and 25% respectively. Majority of patients categorized as having severe pain received prescriptions for opioids for NTDC-related visits in EDs. After adjusting for covariates, patients with self-reported dental reasons for visit and severe pain had a significantly higher probability of receiving prescriptions for opioid analgesics and opioid and non-opioid analgesic combinations. Conclusion Prescription of opioid analgesics increased over time. ED physicians were more likely to prescribe opioid analgesics and opioid and non-opioid analgesic combinations for NTDC-related visits with reported severe pain. PMID:24863407

Investigation of the interaction between the atypical agonist c[YpwFG] and MOR.

PubMed

Gentilucci, Luca; Squassabia, Federico; De Marco, Rossella; Artali, Roberto; Cardillo, Giuliana; Tolomelli, Alessandra; Spampinato, Santi; Bedini, Andrea

2008-05-01

Endogenous and exogenous opiates are currently considered the drugs of choice for treating different kinds of pain. However, their prolonged use produces several adverse symptoms, and in addition, many forms of pain are resistant to any kind of therapy. Therefore, the discovery of compounds active towards mu-opioid receptors (MORs) by alternative pharmacological mechanisms could be of value for developing novel classes of analgesics. There is evidence that some unusual molecules can bind opioid receptors, albeit lacking some of the typical opioid pharmacophoric features. In particular, the recent discovery of a few compounds that showed agonist behavior even in the absence of the primary pharmacophore, namely a protonable amine, led to a rediscussion of the importance of ionic interactions in stabilizing the ligand-receptor complex and in activating signal transduction. Very recently, we synthesized a library of cyclic analogs of the endogenous, MOR-selective agonist endomorphin-1 (YPWF-NH(2)), containing a Gly5 bridge between Tyr1 and Phe4. The cyclopeptide c[YpwFG] showed good affinity and agonist behavior. This atypical MOR agonist does not have the protonable Tyr amine. In order to gain more information about plausible mechanisms of interaction between c[YpwFG] and the opioid receptor, we synthesized a selected set of derivatives containing different bridges between Tyr1 and Phe4, and tested their affinities towards mu-opioid receptors. We performed conformational analysis of the cyclopeptides by NMR spectroscopy and molecular dynamics, and investigated plausible, unprecedented modes of interaction with the MOR by molecular docking. The successive quantum mechanics/molecular mechanics investigation of the complexes obtained by the molecular docking procedure furnished a more detailed description of the binding mode and the electronic properties of the ligands. The comparison with the binding mode of the potent agonist JOM-6 seems to indicate that the cyclic endomorphin-1 analogs interact with the receptor by way of an alternative mechanism, still maintaining the ability to activate the receptor.

Pharmacokinetics of a new, nasal formulation of naloxone.

PubMed

Tylleskar, Ida; Skulberg, Arne Kristian; Nilsen, Turid; Skarra, Sissel; Jansook, Phatsawee; Dale, Ola

2017-05-01

Nasal naloxone is wanted for bystander administration in opioid overdose and as a needle-free alternative for emergency medical personnel. Epidemiologic studies have indicated a therapeutic effect of bystander administration of low-concentration/high-volume formulations. The objective for this study was to describe the nasal pharmacokinetics of a new high-concentration/low-volume nasal formulation of naloxone. This was an open, randomized triple crossover trial in healthy, human volunteers (n = 12) where two doses of nasal naloxone (0.8 and 1.6 mg) and one intravenous dose (1.0 mg) were compared. Fifteen serum samples were collected before and until 6 h after naloxone administration. Quantification of naloxone was performed by a validated liquid chromatography-tandem mass spectrometry method. Bioavailability was 0.54 (0.45-0.63) for the 0.8 mg and 0.52 (0.37-0.67) for the 1.6 mg nasal naloxone formulation. Maximum concentration levels (C max ) were 1.45 ng/ml (1.07-1.84) for 0.8 mg and 2.57 ng/ml (1.49-3.66) for the 1.6 mg. Time to maximum concentrations (T max ) were reached at 17.9 min (11.4-24.5) and 18.6 min (14.4-22.9) for the 0.8 mg and the 1.6 mg doses, respectively. This nasal naloxone formulation had a rapid, systemic uptake and higher bioavailability than naloxone formulations not designed for IN use. This indicates that an optimized high-concentration/low-volume nasal spray formulation may deliver a therapeutic dose. The 1.6 mg nasal dose provided serum concentrations that surpassed those of 1.0 mg IV after 15-20 min and stayed above for the rest of the study period.

Tamper asymmetry and its effect on transmission for x-ray driven opacity simulations

DOE PAGES

Morris, H. E.; Tregillis, I. L.; Hoffman, N. M.; ...

2017-08-01

This paper reports on synthetic transmission results from Lasnex [1] radiation-hydrodynamics simulations of opacity experiments carried out at Sandia National Laboratories' recently upgraded ZR facility. The focus is on experiments utilizing disk targets composed of a half-moon Fe/Mg mixture tamped on either end with 10- m CH and an additional 35- m beryllium tamper accessory on the end facing the spectrometer. Five x-ray sources with peak power ranging from 10 to 24 TW were used in the simulations to heat and backlight the opacity target. The dominant effect is that the beryllium behind the Fe/Mg mixture is denser and moremore » opaque than the beryllium unshielded by metal during the times of greatest importance for the transmission measurement for all drives. This causes the simulated transmission to be lower than expected, and this is most pronounced for the case using the lowest drive power. While beryllium has a low opacity, its areal density is sufficiently high such that the expected reduction of the measured transmission is significant. This situation leads to an overestimate of iron opacity by 10-215% for a photon energy range of 975- 1775 eV for the 10-TW case. It is shown that if the tamper conditions are known, the transmission through each component of the target can be calculated and the resulting opacity can be corrected.« less

Security inspection in ports by anomaly detection using hyperspectral imaging technology

NASA Astrophysics Data System (ADS)

Rivera, Javier; Valverde, Fernando; Saldaña, Manuel; Manian, Vidya

2013-05-01

Applying hyperspectral imaging technology in port security is crucial for the detection of possible threats or illegal activities. One of the most common problems that cargo suffers is tampering. This represents a danger to society because it creates a channel to smuggle illegal and hazardous products. If a cargo is altered, security inspections on that cargo should contain anomalies that reveal the nature of the tampering. Hyperspectral images can detect anomalies by gathering information through multiple electromagnetic bands. The spectrums extracted from these bands can be used to detect surface anomalies from different materials. Based on this technology, a scenario was built in which a hyperspectral camera was used to inspect the cargo for any surface anomalies and a user interface shows the results. The spectrum of items, altered by different materials that can be used to conceal illegal products, is analyzed and classified in order to provide information about the tampered cargo. The image is analyzed with a variety of techniques such as multiple features extracting algorithms, autonomous anomaly detection, and target spectrum detection. The results will be exported to a workstation or mobile device in order to show them in an easy -to-use interface. This process could enhance the current capabilities of security systems that are already implemented, providing a more complete approach to detect threats and illegal cargo.

Role of vagal afferents in the ventilatory response to naloxone during loaded breathing in the rabbit.

PubMed

Delpierre, S; Pugnat, C; Duté, N; Jammes, Y

1995-02-15

It was previously shown that inspiratory resistive loading (IRL) increases the cerebrospinal fluid (CSF) level of beta endorphin in awake goats, and also that the slower ventilation induced by injection of this substance into the CSF of anesthetized dogs is suppressed after vagotomy. In the present study, performed on anesthetized rabbits, we evaluated the part played by vagal afferents in the ventilatory response to IRL after opioid receptor blockade by naloxone. During unloaded breathing, naloxone injection did not modify baseline ventilation. Conversely, naloxone partially reversed IRL-induced hypoventilation through an increase in respiratory rate. This effect was abolished after either vagotomy or cold blockade of large vagal fibers, but it persisted after procaine blockade of thin vagal fibers. These results suggest that pulmonary stretch receptors, which are connected to some large vagal afferent fibers, would play a major role in the ventilatory response to IRL under opioid receptor inhibition.

LC-MS-sMRM Method Development and Validation of Different Classes of Pain Panel Drugs and Analysis of Clinical Urine Samples.

PubMed

Athar Masood, M; Veenstra, Timothy D

2017-08-26

Urine Drug Testing (UDT) is an important analytical/bio-analytical technique that has inevitably become an integral and vital part of a testing program for diagnostic purposes. This manuscript presents a tailor-made LC-MS/MS quantitative assay method development and validation for a custom group of 33 pain panel drugs and their metabolites belonging to different classes (opiates, opioids, benzodiazepines, illicit, amphetamines, etc.) that are prescribed in pain management and depressant therapies. The LC-MS/MS method incorporates two experiments to enhance the sensitivity of the assay and has a run time of about 7 min. with no prior purification of the samples required and a flow rate of 0.7 mL/min. The method also includes the second stage metabolites for some drugs that belong to different classes but have first stage similar metabolic pathways that will enable to correctly identify the right drug or to flag the drug that might be due to specimen tampering. Some real case examples and difficulties in peak picking were provided with some of the analytes in subject samples. Finally, the method was deliberated with some randomly selected de-identified clinical subject samples, and the data evaluated from "direct dilute and shoot analysis" and after "glucuronide hydrolysis" were compared. This method is now used to run routinely more than 100 clinical subjects samples on a daily basis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Serratia marcescens Bacteremia: Nosocomial Cluster Following Narcotic Diversion.

PubMed

Schuppener, Leah M; Pop-Vicas, Aurora E; Brooks, Erin G; Duster, Megan N; Crnich, Christopher J; Sterkel, Alana K; Webb, Aaron P; Safdar, Nasia

2017-09-01

OBJECTIVE To describe the investigation and control of a cluster of Serratia marcescens bacteremia in a 505-bed tertiary-care center. METHODS Cluster cases were defined as all patients with S. marcescens bacteremia between March 2 and April 7, 2014, who were found to have identical or related blood isolates determined by molecular typing with pulsed-field gel electrophoresis. Cases were compared using bivariate analysis with controls admitted at the same time and to the same service as the cases, in a 4:1 ratio. RESULTS In total, 6 patients developed S. marcescens bacteremia within 48 hours after admission within the above period. Of these, 5 patients had identical Serratia isolates determined by molecular typing, and were included in a case-control study. Exposure to the post-anesthesia care unit was a risk factor identified in bivariate analysis. Evidence of tampered opioid-containing syringes on several hospital units was discovered soon after the initial cluster case presented, and a full narcotic diversion investigation was conducted. A nurse working in the post-anesthesia care unit was identified as the employee responsible for the drug diversion and was epidemiologically linked to all 5 patients in the cluster. No further cases were identified once the implicated employee's job was terminated. CONCLUSION Illicit drug use by healthcare workers remains an important mechanism for the development of bloodstream infections in hospitalized patients. Active mechanisms and systems should remain in place to prevent, detect, and control narcotic drug diversions and associated patient harm in the healthcare setting. Infect Control Hosp Epidemiol 2017;38:1027-1031.

Comparative Study of Different Nano-Formulations of Curcumin for Reversal of Doxorubicin Resistance in K562R Cells.

PubMed

Dash, Tapan K; Konkimalla, V Badireenath

2017-02-01

Curcumin is very well established as a chemo-therapeutic, chemo-preventive and chemo-sensitizing agent in diverse disease conditions. As the isolated pure form has poor solubility and pharmacokinetic problems, therefore it is encapsulated in to several nano-formulations to improve its bioavailability. Here in the current study, we aim to compare different nano-formulations of curcumin for their chemo-sensitizing activity in doxorubicin (DOX) resistant K562 cells. Four different curcumin formulations were prepared namely DMSO assisted curcumin nano-dispersion (CurD, 260 nm), liposomal curcumin (CurL, 165 nm), MPEG-PCL micellar curcumin (CurM, 18 nm) and cyclodextrin encapsulated curcumin (CurN, 37 nm). The formulations were subjected to particle characterizations (size, zeta potential, release studies), followed by biological assays such as cellular uptake, P-gp inhibitory activity and reversal of DOX resistance by co-treatment with DOX. Curcumin uptake in K562N and K562R cells was mildly reduced when treated with CurL and CurM, while for CurD and CurN the uptake remained equivalent. However, CurL retained P-gp inhibitory activity of curcumin and with a considerable chemo-sensitizing effect but CurM showed no P-gp inhibitory activity. CurN retained above biological activities, but requires a secondary carrier under in vivo conditions. From the results, CurM was found to be most suitable for solubilization of curcumin where as CurL can be considered as most suitable nano-formulation for reversal of DOX resistance.

Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers

PubMed Central

Jämstorp, Erik; Yarra, Tejaswi; Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne; Strømme, Maria

2012-01-01

Improving acid resistance, while maintaining the excellent mechanical stability is crucial in the development of a sustained and safe oral geopolymer dosage form for highly potent opioids. In the present work, commercially available Methacrylic acid–ethyl acrylate copolymer, Polyethylene-glycol (PEG) and Alginate polymer excipients were included in dissolved or powder form in geopolymer pellets to improve the release properties of Zolpidem, herein acting as a model drug for the highly potent opioid Fentanyl. Scanning electron microscopy, compression strength tests and drug release experiments, in gastric pH 1 and intestinal pH 6.8 conditions, were performed. The polymer excipients, with an exception for PEG, reduced the drug release rate in pH 1 due to their ability to keep the pellets in shape, in combination with the introduction of an insoluble excipient, and thereby maintain a barrier towards drug diffusion and release. Neither geopolymer compression strength nor the release in pH 6.8 was considerably impaired by the incorporation of the polymer excipients. The geopolymer/polymer composites combine high mechanical strength and good release properties under both gastric and intestinal pH conditions, and are therefore promising oral dosage forms for sustained release of highly potent opioids. PMID:25755991

Discharge prescribing of enteral opioids after initiation as a weaning strategy from continuous opioid infusions in the Intensive Care Unit.

PubMed

Kram, Bridgette; Weigel, Kylie M; Kuhrt, Michelle; Gilstrap, Daniel L

To evaluate the proportion of patients receiving a hospital discharge prescription for a scheduled enteral opioid following initiation as a weaning strategy from a continuous opioid infusion in the Intensive Care Unit (ICU). Retrospective, observational study. Five adult ICUs at a large, quaternary care academic medical center. Endotracheally intubated, opioid-naive adults receiving a continuous opioid infusion with a concomitant scheduled enteral opioid initiated. Exclusion criteria were receipt of fewer than two enteral opioid doses, documentation of a long-acting opioid as a home medication, the indication for the enteral opioid was not a weaning strategy, death during hospital admission or discharge to hospice. None. The proportion of ICU and hospital survivors who received a discharge prescription for a scheduled enteral opioid, total duration of continuous opioid infusion, duration of continuous opioid infusion after initiation of an enteral opioid therapy, total duration of enteral therapy, ICU and hospital length of stay. Of 62 included patients, 19 patients (30.6 percent) received a new prescription for a scheduled enteral opioid at hospital discharge. The median duration of enteral opioid therapy was longer for patients who received a discharge prescription compared to those who did not (20.09 vs 8.89 days, p = 0.02), though the remaining endpoints were not different. Utilizing scheduled enteral opioids as a weaning strategy from continuous opioid infusions may place patients at risk of ICU-acquired physical dependence on opioids.

Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

PubMed Central

Anand, Kanwaljeet J. S.; Willson, Douglas F.; Berger, John; Harrison, Rick; Meert, Kathleen L.; Zimmerman, Jerry; Carcillo, Joseph; Newth, Christopher J. L.; Prodhan, Parthak; Dean, J. Michael; Nicholson, Carol

2012-01-01

OBJECTIVE After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS Relevant manuscripts published in the English language were searched in Medline by using search terms “opioid,” “opiate,” “sedation,” “analgesia,” “child,” “infant-newborn,” “tolerance,” “dependency,” “withdrawal,” “analgesic,” “receptor,” and “individual opioid drugs.” Clinical and preclinical studies were reviewed for data synthesis. RESULTS Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal. PMID:20403936

Targeted nanoparticles that mimic immune cells in pain control inducing analgesic and anti-inflammatory actions: a potential novel treatment of acute and chronic pain condition.

PubMed

Hua, Susan; Cabot, Peter J

2013-01-01

The peripheral immune-derived opioid analgesic pathway has been well established as a novel target in the clinical pain management of a number of painful pathologies, including acute inflammatory pain, neuropathic pain, and rheumatoid arthritis. Our objective was to engineer targeted nanoparticles that mimic immune cells in peripheral pain control to deliver opioids, in particular loperamide HCl, specifically to peripheral opioid receptors to induce analgesic and anti-inflammatory actions for use in painful inflammatory conditions. This peripheral analgesic system is devoid of central opioid mediated side effects (e.g., respiratory depression, sedation, dependence, tolerance). A randomized, double blind, controlled animal trial. Thirty-six adult male Wistar rats (200 - 250 g) were randomly divided into 6 groups: loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, naloxone methiodide + loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, loperamide HCl-encapsulated liposomes, empty anti-ICAM-1 immunoliposomes, empty liposomes, and loperamide solution. Animals received an intraplantar injection of 150 μL Complete Freund's Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All formulations were administered intravenously via tail vein injection. The dose administered was 200 μL, which equated to 0.8 mg of loperamide HCl for the loperamide HCl treatment groups (sub-therapeutic dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to loperamide-encapsulated anti-ICAM-1 immunoliposomes. An investigator blinded to the treatment administered assessed the time course of the antinociceptive and anti-inflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively. Biodistribution studies were performed 5 days post-CFA injection with anti-ICAM-1 immunoliposomes and control liposomes via tail vein injection using liquid scintillation counting (LSC). Administration of liposomes loaded with loperamide HCl, and conjugated with antibody to intercellular adhesion molecule-1 (anti-ICAM-1), exerted analgesic and anti-inflammatory effects exclusively in peripheral painful inflamed tissue. These targeted nanoparticles produced highly significant analgesic and anti-inflammatory effects over the 48 hour time course studied following intravenous administration in rats with Complete Freund's Adjuvant-induced inflammation of the paw. All control groups showed no significant antinociceptive or anti-inflammatory effects. Our biodistribution study demonstrated specific localization of the targeted nanoparticles to peripheral inflammatory tissue and no significant uptake into the brain. In vivo studies were performed in the well-established rodent model of acute inflammatory pain. We are currently studying this approach in chronic pain models known to have clinical activation of the peripheral immune-derived opioid response. The study presents a novel approach of opioid delivery specifically to injured tissues for pain control. The study also highlights a novel anti-inflammatory role for peripheral opioid targeting, which is of clinical relevance. The potential also exists for the modification of these targeted nanoparticles with other therapeutic compounds for use in other painful conditions.

Non-analgesic effects of opioids: opioids and the endocrine system.

PubMed

Elliott, Jennifer A; Opper, Susan E; Agarwal, Sonali; Fibuch, Eugene E

2012-01-01

Opioids are among the oldest known and most widely used analgesics. The application of opioids has expanded over the last few decades, especially in the treatment of chronic non-malignant pain. This upsurge in opioid use has been accompanied by the increasingly recognized occurrence of opioid-associated endocrinopathy. This may arise after exposure to enteral, parenteral, or neuraxial opioids. Opioid-associated endocrinopathy consists primarily of hypothalamic-pituitary-gonadal axis or hypothalamic-pituitary-adrenal axis dysfunction and may manifest with symptoms of hypogonadism, adrenal dysfunction, and other hormonal disturbances. Additionally, opioid related endocrine dysfunction may be coupled with such disorders as osteoporosis and mood disturbances including depression. Undesirable changes in pain sensitivity such as opioid-induced hyperalgesia, and reduced potency of opioid analgesia may also be potential consequences of chronic opioid consumption. Few studies to date have been able to establish what degree of opioid exposure, in terms of dose or duration of therapy, may predispose patients to opioid-associated endocrinopathy. This article will review the currently available literature concerning opioid-associated endocrinopathy and will provide recommendations for the evaluation, monitoring, and management of opioid-associated endocrinopathy and its other accompanying undesired effects.

A comparison between pre-operative carprofen and a long-acting sufentanil formulation for analgesia after ovariohysterectomy in dogs.

PubMed

Slingsby, Louisa S; Murison, Pamela J; Goossens, Lieve; Engelen, Marc; Waterman-Pearson, Avril E

2006-09-01

To assess the analgesic efficacy and adverse effects of a novel, long-acting sufentanil preparation in dogs undergoing ovariohysterectomy (OHE). Blinded, positively controlled, randomized field trial with four parallel treatment groups. Eighty client owned dogs undergoing elective OHE randomly allocated into four treatment groups (each n = 20). Three groups received intramuscular (IM) sufentanil (at 10, 15 and 25 microg kg(-1), respectively) and the control group received subcutaneous (SC) carprofen 4 mg kg(-1) SC plus acepromazine 0.05 mg kg(-1) IM as pre-anaesthetic medication. OHE was performed under thiopental/halothane anaesthesia. Visual Analogue Scale (VAS) scores for pain and sedation were awarded and mechanical nociceptive thresholds were measured at the wound and hock before surgery and up to 24 hours after tracheal extubation. Serum cortisol was measured before surgery, during surgery and up to 24 hours after tracheal extubation. Animals with inadequate post-operative analgesia were given rescue medication. In the carprofen group, VAS pain scores were significantly higher, wound tenderness was greater and requirement for rescue analgesia was more than in the sufentanil-treated groups. Sufentanil produced dose dependent analgesia and sedation. All treatment groups showed similar patterns of change for cortisol concentrations. Use of the sufentanil preparation was associated with a relatively high incidence of adverse events. The long-acting preparation of sufentanil provided excellent post-operative analgesia that was significantly better than that provided by carprofen. However, use of this formulation, in the anaesthetic technique used in the study, resulted in a relatively high incidence of adverse effects. Full mu (MOP) opioid agonists provide significantly better post-operative analgesia than nonsteroidal anti-inflammatory drugs after moderately painful surgery. However, the widely recognized adverse effects of opioids may preclude the use of these agents.

Intranasal abuse potential of an abuse-deterrent oxycodone formulation compared to oxycodone immediate release and placebo in nondependent, recreational opioid users.

PubMed

Setnik, Beatrice; Schoedel, Kerri; Bartlett, Cindy; Dick, Chris; Hakim, Nasrat; Geoffroy, Pierre

To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone. Randomized, double-blind, double-dummy, active and placebo-controlled, five-way crossover study. Pharmacodynamics, safety, and pharmacokinetics (PKs) were evaluated for up to 36 hours postdose. Single site in Canada (INC Research Toronto). Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test. Single IN dose of ground ELI-200 (30-mg oxycodone hydrochloride [HCl]/3-mg naltrexone HCl), crushed 30-mg oxycodone HCl IR (Roxicodone®), placebo, fixed placebo, and single oral dose of intact ELI-200 (30mg/3mg). Peak effect (E max ) for bipolar Drug Liking (0-100 point visual analog scale). Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p<0.001) median Drug Liking E max relative to placebo. Significant reductions (p<0.001) in median Drug Liking [E max ] were observed for IN ELI-200 [56.0] compared to IN oxycodone IR [100.0]. Secondary positive or objective measures (High, Good Drug Effects, Overall Drug Liking, Take Drug Again, and maximum pupil constriction) showed significantly lower E max for IN ELI-200 (p<0.001) compared to IN oxycodone IR. IN administration of ELI-200 demonstrated significantly decreased effects on subjective and physiologic measures, and greater nasal irritation, compared to IN oxycodone IR. These findings, along with the PK profile of naltrexone, demonstrated that when ELI-200 capsules were ground and administered intranasally, the naltrexone component was rapidly released and conferred meaningful abuse-deterrent properties.

Employment-Based Reinforcement of Adherence to Depot Naltrexone in Unemployed Opioid-Dependent Adults: A Randomized Controlled Trial

PubMed Central

Everly, Jeffrey J.; DeFulio, Anthony; Koffarnus, Mikhail N.; Leoutsakos, Jeannie-Marie S.; Donlin, Wendy D.; Aklin, Will M.; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E.; Silverman, Kenneth

2011-01-01

Aims Naltrexone can be used to treat opioid dependence, but patients refuse to take it. Extended-release depot formulations may improve adherence, but long-term adherence rates to depot naltrexone are not known. This study determined long-term rates of adherence to depot naltrexone and whether employment-based reinforcement can improve adherence. Design Participants who were inducted onto oral naltrexone were randomly assigned to Contingency (n=18) or Prescription (n=17) groups. Participants were offered six depot naltrexone injections and invited to work at the therapeutic workplace weekdays for 26 weeks where they earned stipends for participating in job skills training. Contingency participants were required to accept naltrexone injections to maintain workplace access and to maintain maximum pay. Prescription participants could work independent of whether they accepted injections. Setting The therapeutic workplace, a model employment-based intervention for drug addiction and unemployment. Participants Opioid-dependent unemployed adults. Measurements Depot naltrexone injections accepted and opiate-negative urine samples. Findings Contingency participants accepted significantly more naltrexone injections than Prescription participants (81% versus 42%), and were more likely to accept all injections (66% versus 35%). At monthly assessments (with missing urine samples imputed as positive), the groups provided similar percentages of samples negative for opiates (74% versus 62%) and for cocaine (56% versus 54%). Opiate positive samples were more likely when samples were also positive for cocaine. Conclusions Employment-based reinforcement can maintain adherence to depot naltrexone. Future research should determine whether persistent cocaine use compromises naltrexone's effect on opiate use. Workplaces may be useful for promoting sustained adherence to depot naltrexone. PMID:21320227

Unintended impacts of regulatory changes to British Columbia Methadone Maintenance Program on addiction and HIV-related outcomes: an interrupted time series analysis

PubMed Central

Socías, M. Eugenia; Wood, Evan; McNeil, Ryan; Kerr, Thomas; Dong, Huiru; Shoveller, Jean; Montaner, Julio; Milloy, M-J

2018-01-01

Background In February 2014, several regulatory reforms were introduced to the methadone maintenance treatment (MMT) program in British Columbia, Canada, including a switch to a ten-times more concentrated methadone formulation and restrictions in pharmacy delivery services. We evaluated possible unintended effects of these changes on illicit drug use patterns and HIV treatment outcomes among HIV-positive opioid users. Methods Data was drawn from ACCESS, a prospective community-recruited cohort of HIV-positive people who use illicit drugs in Vancouver, Canada. Interrupted time series analyses were used to evaluate impacts of the policy change on monthly rates of MMT enrollment, illicit heroin injection, antiretroviral therapy (ART) adherence, and HIV viral suppression among HIV-positive opioid users between November 2012 and May 2015. Results A total of 331 HIV-positive opioid users were included. The MMT policy change led to a significant immediate 11.5% increase in heroin injection, and 15.9% drop in optimal ART adherence. A gradual increase in the prevalence of MMT enrolment after the policy change was also documented (0.9% per month). No changes in viral suppression rates were observed. Conclusions We observed immediate increases in illicit heroin injection and decreases in ART adherence in the wake of regulatory changes to the local MMT program. These findings underscore the need to consider potential unintended effects of altering health programmes for vulnerable populations, the need to develop appropriate mitigation strategies, as well as to involve all relevant stakeholders in the planning and implementations of new policies. PMID:28454044

Unintended impacts of regulatory changes to British Columbia Methadone Maintenance Program on addiction and HIV-related outcomes: An interrupted time series analysis.

PubMed

Socías, M Eugenia; Wood, Evan; McNeil, Ryan; Kerr, Thomas; Dong, Huiru; Shoveller, Jean; Montaner, Julio; Milloy, M-J

2017-07-01

In February 2014, several regulatory reforms were introduced to the methadone maintenance treatment (MMT) program in British Columbia, Canada, including a switch to a ten-times more concentrated methadone formulation and restrictions in pharmacy delivery services. We evaluated possible unintended effects of these changes on illicit drug use patterns and HIV treatment outcomes among HIV-positive opioid users. Data was drawn from ACCESS, a prospective community-recruited cohort of HIV-positive people who use illicit drugs in Vancouver, Canada. Interrupted Time Series Analyses were used to evaluate impacts of the policy change on monthly rates of MMT enrolment, illicit heroin injection, antiretroviral therapy (ART) adherence, and HIV viral suppression among HIV-positive opioid users between November 2012 and May 2015. A total of 331 HIV-positive opioid users were included. The MMT policy change led to a significant immediate 11.5% increase in heroin injection, and 15.9% drop in optimal ART adherence. A gradual increase in the prevalence of MMT enrolment after the policy change was also documented (0.9% per month). No changes in viral suppression rates were observed. We observed immediate increases in illicit heroin injection and decreases in ART adherence in the wake of regulatory changes to the local MMT program. These findings underscore the need to consider potential unintended effects of altering health programmes for vulnerable populations, the need to develop appropriate mitigation strategies, as well as to involve all relevant stakeholders in the planning and implementations of new policies. Copyright © 2017 Elsevier B.V. All rights reserved.

Rapid pain relief using transdermal film forming polymeric solution of ketorolac.

PubMed

Ammar, H O; Ghorab, M; Mahmoud, A A; Makram, T S; Ghoneim, A M

2013-01-01

Ketorolac is one of the most potent nonsteroidal anti-inflammatory drugs and is an attractive alternative to opioids for pain management. Development and evaluation of transdermal ketorolac film forming polymeric solution. Eudragits(®) RLPO, RSPO and E100 as well as polyvinyl pyrrolidone K30 dissolved in ethanol were used as film forming solutions. In vitro experiments were conducted to optimize formulation parameters. Different permeation enhancers were monitored for potentiality of enhancing drug permeation across excised pigskin. The use of 10% oleic acid, Lauroglycol(®) 90 or Azone(®) with 5% Eudragit(®) RSPO, showed the highest enhancement effect on ketorolac skin permeation and showed faster analgesic effect compared to the ketorolac tablet. The formula comprising 5% Eudragit(®) RSPO and 10% Lauroglycol(®) 90 showed the greatest pharmacodynamic effect and thus was subjected to pharmacokinetic studies. The pharmacodynamic and pharmacokinetic results didn't run paralleled to each other, as the ketorolac tablets showed higher plasma concentrations compared to the selected ketorolac transdermal formulation. This might be due to the induction of analgesia by the available ethanol in the transdermal preparation. Optimized transdermal ketorolac formulation showed marked ability to ensure fast and augmented analgesic effect that is an essential request in pain management.

10 CFR 73.70 - Records.

Code of Federal Regulations, 2012 CFR

2012-01-01

... copy throughout the required retention period. The record may also be stored in electronic media with..., alarm check, and tamper indication that identifies the type of alarm, location, alarm circuit, date, and...

Reappraisal deficits promote craving and emotional distress among chronic pain patients at risk for prescription opioid misuse.

PubMed

Garland, Eric L; Hanley, Adam W; Bedford, Carter E; Zubieta, Jon-Kar; Howard, Matthew O; Nakamura, Yoshio; Donaldson, Gary W; Froeliger, Brett

2018-06-04

A subset of chronic pain patients misuse prescription opioids as a means of regulating negative emotions. However, opioid misuse may result in deficits in emotion regulation strategies like reappraisal by virtue of the deleterious effects of chronic opioid exposure. The aim of this study was to characterize differences in reappraisal use among chronic pain patients at risk for opioid misuse and those who report taking opioids as prescribed. A sample of 127 pain patients receiving chronic opioid analgesic pharmacotherapy were classified as at risk for opioid misuse (n = 62) or taking opioids as prescribed (n = 65) using the Current Opioid Misuse Measure (COMM). The Emotion Regulation Questionnaire (ERQ) characterized use of emotion regulation strategies including reappraisal and expressive suppression. Participants also reported levels of opioid craving, emotional distress, and pain severity. Patients at risk for opioid misuse reported significantly less reappraisal use (M = 25.31, SD = 7.33) than those who reportedly took opioids as prescribed (M = 30.28, SD = 7.50), p<.001, but did differ with regard to suppression strategies. Reduced reappraisal use was associated with higher opioid craving and emotional distress that mediated the association between reappraisal deficits and opioid misuse risk. Further, there was a significant indirect effect of opioid misuse on emotional distress via reappraisal use. Opioid misuse risk was associated with reduced use of reappraisal, which in turn was associated with dysregulated negative emotions and increased appetitive drive towards consuming opioids. Studying individual differences in emotion regulation may yield efficacious intervention and prevention approaches to stem the rising tide of the prescription opioid crisis.

Opioid Analgesics for Chronic Non-Cancer Pain: A Guideline on Opioid Prescribing.

PubMed

Van Demark, Robert; Chang, Peter; Heinemann, Daniel

2016-01-01

Over the past decade, the use of opioid analgesics has risen dramatically both in the U.S. and South Dakota. Opioids have been increasingly used to treat chronic non-cancer pain; however, the utilization of opioids for this role has limited and questionable utility. The U.S. has also seen a rise of opioid abuse, addiction, misuse, and overdose. The various pharmacological and non-pharmacological strategies to help physicians manage chronic non-cancer pain and a guideline on appropriate opioid prescribing are presented. Before the decision is made to begin opioid therapy for chronic non-cancer pain, other pharmacological and non-pharmacological therapeutic strategies should be explored. The schema for responsible opioid prescribing can be dived into the following: the initial assessment, initiating opioid therapy, maintenance therapy, and the discontinuation of opioid treatment. These categories are explored, and a general approach to prescribing opioids for chronic non-cancer pain is presented. The Centers for Disease Control and Prevention (CDC) has declared opioid prescription abuse an "epidemic." There are a variety of methods clinicians can utilize to relieve chronic non-cancer pain. If opioid therapy is sought, clinicians should be mindful of the current state of opioid abuse and misuse. This guideline may aid clinicians in appropriate opioid prescribing.

Opioid dependence - management in general practice.

PubMed

Frei, Matthew

2010-08-01

Addiction to opioids, or opioid dependence, encompasses the biopsychosocial dysfunction seen in illicit heroin injectors, as well as aberrant behaviours in patients prescribed opioids for chronic nonmalignant pain. To outline the management of opioid dependence using opioid pharmacotherapy as part of a comprehensive chronic illness management strategy. The same principles and skills general practitioners employ in chronic illness management underpin the care of patients with opioid dependence. Opioid pharmacotherapy, with the substitution medications methadone and buprenorphine, is an effective management of opioid dependence. Training and regulatory requirements for prescribing opioid pharmacotherapies vary between jurisdictions, but this treatment should be within the scope of most Australian GPs.

Opioids in Preclinical and Clinical Trials

NASA Astrophysics Data System (ADS)

Nagase, Hiroshi; Fujii, Hideaki

Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug [1]. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs [2]. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues [3] established types of opioid receptors (these are now classified into μ, δ, and κ types). Later, Portoghese discovered a highly selective μ type opioid receptor antagonist, β-funaltrexamine [4]. This led to the finding that the μ type opioid receptor was correlated to drug dependence [5]. Consequently, δ, and particularly κ, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we provide a short survey of opioid ligands in development and describe the discovery of the two most promising drugs, TRK-851 [6] and TRK-820 (nalfurafine hydrochloride) [7].

Fatal and non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone.

PubMed

Kelty, Erin; Hulse, Gary

2017-08-01

Illicit opioid use is associated with high rates of fatal and non-fatal opioid overdose. This study aims to compare rates of fatal and serious but non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone, and to identify risk factors for fatal opioid overdose. Opioid dependent patients treated with methadone (n=3515), buprenorphine (n=3250) or implant naltrexone (n=1461) in Western Australia for the first time between 2001 and 2010, were matched against state mortality and hospital data. Rates of fatal and non-fatal serious opioid overdoses were calculated and compared for the three treatments. Risk factors associated with fatal opioid overdose were examined using multivariate cox proportional hazard models. No significant difference was observed between the three groups in terms of crude rates of fatal or non-fatal opioid overdoses. During the first 28days of treatment, rates of non-fatal opioid overdose were high in all three groups, as were fatal opioid overdoses in patients treated with methadone. However, no fatal opioid overdoses were observed in buprenorphine or naltrexone patients during this period. Following the first 28 days, buprenorphine was shown to be protective, particularly in terms of non-fatal opioid overdoses. After the cessation of treatment, rates of fatal and non-fatal opioid overdoses were similar between the groups, with the exception of lower rates of non-fatal opioid overdose in the naltrexone treated patients compared with the methadone treated patients. After the commencement of treatment, gender, and hospitalisations with a diagnosis of opioid poisoning, cardiovascular or mental health problems were significant predictors of subsequent fatal opioid overdose. Rates of fatal and non-fatal opioid overdose were not significantly different in patients treated with methadone, buprenorphine or implant naltrexone. Gender and prior cause-specific hospitalisations can be used to identify patients at a high risk of fatal opioid overdose. Copyright © 2017 Elsevier B.V. All rights reserved.

Uniquely identifiable tamper-evident device using coupling between subwavelength gratings

NASA Astrophysics Data System (ADS)

Fievre, Ange Marie Patricia

Reliability and sensitive information protection are critical aspects of integrated circuits. A novel technique using near-field evanescent wave coupling from two subwavelength gratings (SWGs), with the input laser source delivered through an optical fiber is presented for tamper evidence of electronic components. The first grating of the pair of coupled subwavelength gratings (CSWGs) was milled directly on the output facet of the silica fiber using focused ion beam (FIB) etching. The second grating was patterned using e-beam lithography and etched into a glass substrate using reactive ion etching (RIE). The slightest intrusion attempt would separate the CSWGs and eliminate near-field coupling between the gratings. Tampering, therefore, would become evident. Computer simulations guided the design for optimal operation of the security solution. The physical dimensions of the SWGs, i.e. period and thickness, were optimized, for a 650 nm illuminating wavelength. The optimal dimensions resulted in a 560 nm grating period for the first grating etched in the silica optical fiber and 420 nm for the second grating etched in borosilicate glass. The incident light beam had a half-width at half-maximum (HWHM) of at least 7 microm to allow discernible higher transmission orders, and a HWHM of 28 microm for minimum noise. The minimum number of individual grating lines present on the optical fiber facet was identified as 15 lines. Grating rotation due to the cylindrical geometry of the fiber resulted in a rotation of the far-field pattern, corresponding to the rotation angle of moire fringes. With the goal of later adding authentication to tamper evidence, the concept of CSWGs signature was also modeled by introducing random and planned variations in the glass grating. The fiber was placed on a stage supported by a nanomanipulator, which permitted three-dimensional displacement while maintaining the fiber tip normal to the surface of the glass substrate. A 650 nm diode laser was fixed to a translation mount that transmitted the light source through the optical fiber, and the output intensity was measured using a silicon photodiode. The evanescent wave coupling output results for the CSWGs were measured and compared to the simulation results.

Innovative Formulation Combining Al, Zr and Si Precursors to Obtain Anticorrosion Hybrid Sol-Gel Coating.

PubMed

Genet, Clément; Menu, Marie-Joëlle; Gavard, Olivier; Ansart, Florence; Gressier, Marie; Montpellaz, Robin

2018-05-10

The aim of our study is to improve the aluminium alloy corrosion resistance with Organic-Inorganic Hybrid (OIH) sol-gel coating. Coatings are obtained from unusual formulation with precursors mixing: glycidoxypropyltrimethoxysilane (GPTMS), zirconium (IV) propoxide (TPOZ) and aluminium tri-sec-butoxide (ASB). This formulation was characterized and compared with sol formulations GPTMS/TPOZ and GPTMS/ASB. In each formulation, a corrosion inhibitor, cerium (III) nitrate hexahydrate, is employed to improve the corrosion performance. Coatings obtained from sol based on GPTMS/TPOZ/ASB have good anti-corrosion performances with Natural Salt Spray (NSS) resistance of 500 h for a thickness lower than 4 µm. Contact angle measurement showed a coating hydrophobic behaviour. To understand these performances, nuclear magnetic resonance (NMR) analyses were performed, results make sol-gel coating condensation evident and are in very good agreement with previous results.

Pharmacokinetics of buprenorphine: a comparison of sublingual tablet versus liquid after chronic dosing.

PubMed

Compton, Peggy; Ling, Walter; Chiang, C Nora; Moody, David E; Huber, Alice; Ling, Debbie; Charuvastra, Charles

2007-06-01

Although buprenorphine is approved for use in the outpatient treatment of opioid addiction in 2 tablet formulations, a monoproduct containing buprenorphine only (Subutex) and a buprenorphine/naloxone combination product (Suboxone), much of the clinical data that support the approval by the U.S. Food and Drug Administration were generated by using a sublingual liquid. To interpret the literature in prescribing parameters for tablet buprenorphine, this study was designed to determine steady state buprenorphine plasma levels for the 2 formulations and to assess the relative bioavailability of each. A randomized, double-blind, crossover study with dose increases was conducted during a 12-week period at an outpatient treatment clinic. Of the 184 subjects initially randomized to treatment, 133 (72.3%) were evaluated for the steady-state trough plasma concentration, 16 (8.7%) for relative bioavailability, and 31 (16.8%) for dose proportionality. At steady state, differences in the trough plasma concentrations of buprenorphine between the 2 formulations were found across all the dose levels. Average plasma concentration (Cavg) of the tablet at twice the milligram dose of the liquid was twice that of the liquid; intersubject variability was greater for the tablet. At double the dose of tablet, there is no difference in steady state plasma concentrations. The bioavailability seems equivalent for the 2 formulations across all the dose levels.

Are Prescription Opioids Driving the Opioid Crisis? Assumptions vs Facts.

PubMed

Rose, Mark Edmund

2018-04-01

Sharp increases in opioid prescriptions, and associated increases in overdose deaths in the 2000s, evoked widespread calls to change perceptions of opioid analgesics. Medical literature discussions of opioid analgesics began emphasizing patient and public health hazards. Repetitive exposure to this information may influence physician assumptions. While highly consequential to patients with pain whose function and quality of life may benefit from opioid analgesics, current assumptions about prescription opioid analgesics, including their role in the ongoing opioid overdose epidemic, have not been scrutinized. Information was obtained by searching PubMed, governmental agency websites, and conference proceedings. Opioid analgesic prescribing and associated overdose deaths both peaked around 2011 and are in long-term decline; the sharp overdose increase recorded in 2014 was driven by illicit fentanyl and heroin. Nonmethadone prescription opioid analgesic deaths, in the absence of co-ingested benzodiazepines, alcohol, or other central nervous system/respiratory depressants, are infrequent. Within five years of initial prescription opioid misuse, 3.6% initiate heroin use. The United States consumes 80% of the world opioid supply, but opioid access is nonexistent for 80% and severely restricted for 4.1% of the global population. Many current assumptions about opioid analgesics are ill-founded. Illicit fentanyl and heroin, not opioid prescribing, now fuel the current opioid overdose epidemic. National discussion has often neglected the potentially devastating effects of uncontrolled chronic pain. Opioid analgesic prescribing and related overdoses are in decline, at great cost to patients with pain who have benefited or may benefit from, but cannot access, opioid analgesic therapy.

Relationship of opioid prescription sales and overdoses, North Carolina.

PubMed

Modarai, F; Mack, K; Hicks, P; Benoit, S; Park, S; Jones, C; Proescholdbell, S; Ising, A; Paulozzi, L

2013-09-01

In the United States, fatal drug overdoses have tripled since 1991. This escalation in deaths is believed to be driven primarily by prescription opioid medications. This investigation compared trends and patterns in sales of opioids, opioid drug overdoses treated in emergency departments (EDs), and unintentional overdose deaths in North Carolina (NC). Our ecological study compared rates of opioid sales, opioid related ED overdoses, and unintentional drug overdose deaths in NC. Annual sales data, provided by the Drug Enforcement Administration, for select opioids were converted into morphine equivalents and aggregated by zip code. These opioid drug sales rates were trended from 1997 to 2010. In addition, opioid sales were correlated and compared to opioid related ED visits, which came from a Centers for Disease Control and Prevention syndromic surveillance system, and unintentional overdose deaths, which came from NC Vital Statistics, from 2008 to 2010. Finally, spatial cluster analysis was performed and rates were mapped by zip code in 2010. Opioid sales increased substantially from 1997 to 2010. From 2008 to 2010, the quarterly rates of opioid drug overdoses treated in EDs and opioid sales correlated (r=0.68, p=0.02). Specific regions of the state, particularly in the southern and western corners, had both high rates of prescription opioid sales and overdoses. Temporal trends in sales of prescription opioids correlate with trends in opioid related ED visits. The spatial correlation of opioid sales with ED visit rates shows that opioid sales data may be a timely way to identify high-risk communities in the absence of timely ED data. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Comparative in vitro activity of a pharmacokinetically enhanced oral formulation of amoxicillin/clavulanic acid (2000/125 mg twice daily) against 9172 respiratory isolates collected worldwide in 2000.

PubMed

Koeth, Laura M; Jacobs, Michael R; Good, Caryn E; Bajaksouzian, Saralee; Windau, Anne; Jakielaszek, Charles; Saunders, Kay A

2004-11-01

A new, pharmacokinetically enhanced, oral formulation of amoxicillin/clavulanic acid has been developed to overcome resistance in the major bacterial respiratory pathogen Streptococcus pneumoniae, while maintaining excellent activity against Haemophilus influenzae and Moraxella catarrhalis, including beta-lactamase producing strains. This study was conducted to provide in vitro susceptibility data for amoxicillin/clavulanic acid and 16 comparator agents against the key respiratory tract pathogens. Susceptibility testing was performed on 9172 isolates collected from 95 centers in North America, Europe, Australia, and Hong Kong by broth microdilution MIC determination, according to NCCLS methods, using amoxicillin/clavulanic acid and 16 comparator antimicrobial agents. Results were interpreted according to NCCLS breakpoints and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints based on oral dosing regimens. Overall, 93.5% of Streptococcus pneumoniae isolates were susceptible to amoxicillin/clavulanic acid at the current susceptible breakpoint of < or =2 microg/mL and 97.3% at the PK/PD susceptible breakpoint of < or =4 microg/mL for the extended release formulation. Proportions of isolates that were penicillin intermediate and resistant were 13% and 16.5%, respectively, while 25% were macrolide resistant and 21.8% trimethoprim/sulfamethoxazole resistant. 21.9% of Haemophilus influenzae were beta-lactamase producers and 16.8% trimethoprim/sulfamethoxazole resistant, >99% of isolates were susceptible to amoxicillin/clavulanic acid, cefixime, ciprofloxacin and levofloxacin at NCCLS breakpoints. The most active agents against Moraxella catarrhalis were amoxicillin/clavulanic acid, macrolides, cefixime, fluoroquinolones, and doxycycline. Overall, 13% of Streptococcus pyogenes were resistant to macrolides. The extended release formulation of amoxicillin/clavulanic acid has potential for empiric use against many respiratory tract infections worldwide due to its activity against species resistant to many agents currently in use.

Opioid Stewardship in Otolaryngology: State of the Art Review.

PubMed

Cramer, John D; Wisler, Brad; Gouveia, Christopher J

2018-05-01

Objective The United States is facing an epidemic of opioid addiction. Deaths from opioid overdose have quadrupled in the past 15 years and now surpass annual deaths during the height of the human immunodeficiency virus epidemic. There is a link between opioid prescriptions after surgery, opioid misuse, opioid diversion, and use of other drugs of abuse. As surgeons, otolaryngologists contribute to this crisis. Our objective is to outline the risk of abuse from opioids in the management of acute postoperative pain in otolaryngology-head and neck surgery (OHNS) and strategies to avoid misuse. Data Sources PubMed/MEDLINE. Review Methods We conducted a review of the literature on the rate of opioid abuse after surgery, methods of safe opioid use, and strategies to minimize the dangers of opioids. Conclusions Otolaryngologists have a responsibility to treat pain. This begins preoperatively by discussing perioperative pain control and developing a personalized pain control plan. Patients should be aware that opioids carry significant risks of adverse events and abuse. Perioperative use of multimodal nonopioid agents enables pain control and avoidance of opioids in many otolaryngologic cases. When this approach is inadequate, opioids should be used in short duration under close surveillance. Institutional standards for opioid prescribing after common procedures can minimize misuse. Implications for Practice Otolaryngologists need to acknowledge the potential harm that opioids cause. It is essential that we evaluate our practices to ensure that opioids are used responsibly. Furthermore, opioid stewardship should become a priority in otolaryngology.

Something for pain: Responsible opioid use in emergency medicine.

PubMed

Strayer, Reuben J; Motov, Sergey M; Nelson, Lewis S

2017-02-01

The United States is currently experiencing a public health crisis of opioid addiction, which has its genesis in an industry marketing effort that successfully encouraged clinicians to prescribe opioids liberally, and asserted the safety of prescribing opioids for chronic non-cancer pain, despite a preponderance of evidence demonstrating the risks of dependence and misuse. The resulting rise in opioid use has pushed drug overdose deaths in front of motor vehicle collisions to become the leading cause of accidental death in the country. Emergency providers frequently treat patients for complications of opioid abuse, and also manage patients with acute and chronic pain, for which opioids are routinely prescribed. Emergency providers are therefore well positioned to both prevent new cases of opioid misuse and initiate appropriate treatment of existing opioid addicts. In opioid-naive patients, this is accomplished by a careful consideration of the likelihood of benefit and harm of an opioid prescription for acute pain. If opioids are prescribed, the chance of harm is reduced by matching the number of pills prescribed to the expected duration of pain and selecting an opioid preparation with low abuse liability. Patients who present to acute care with exacerbations of chronic pain or painful conditions associated with opioid misuse are best managed by treating symptoms with opioid alternatives and encouraging treatment for opioid addiction. Copyright © 2016 Elsevier Inc. All rights reserved.

Pain Control in the Presence of Drug Addiction.

PubMed

Vadivelu, Nalini; Lumermann, Leandro; Zhu, Richard; Kodumudi, Gopal; Elhassan, Amir O; Kaye, Alan David

2016-05-01

Drug addiction is present in a significant proportion of the population in the USA and worldwide. Drug addiction can occur with the abuse of many types of substances including cocaine, marijuana, stimulants, alcohol, opioids, and tranquilizers. There is a high likelihood that clinicians will encounter patients with substance abuse disorders on a regular basis with the prevalence of the use of illicit substances and the high rate of abuse of prescription drugs. The use of abuse deterrent formulations of prescription opioid agents, pill counts, and urine drug abuse screenings are all useful strategies. Optimum pain management of patients with addiction in the outpatient and inpatient setting is essential to minimize pain states. Careful selection of medications and appropriate oversight, including drug agreements, can reduce drug-induced impairments, including sleep deficits and diminished physical, social, and sexual functioning. This review, therefore, discusses the prevalence of illicit and prescription drug addiction, the challenges of achieving optimum pain control, and the therapeutic approaches to be considered in this challenging population. More research is warranted to develop improved therapies and routes of treatments for optimum pain relief and to prevent the development of central sensitization, chronic pain, and impaired physical and social functioning in patients with drug addiction.

The association between negative affect and prescription opioid misuse in patients with chronic pain: The mediating role of opioid craving

PubMed Central

Martel, MO; Dolman, AJ; Edwards, RR; Jamison, RN; Wasan, AD

2013-01-01

Over the past decade, considerable research has accumulated showing that chronic pain patients experiencing high levels of negative affect (i.e., anxiety, depression) are at increased risk for prescription opioid misuse. The primary objective of the present study was to examine the factors that underlie the association between negative affect (NA) and prescription opioid misuse among patients with chronic pain. In this study, 82 patients with chronic musculoskeletal pain being prescribed opioid medication completed the Current Opioid Misuse Measure (COMM), a well-validated self-report questionnaire designed to assess prescription opioid misuse. Patients were also asked to complete self-report measures of pain intensity, NA, and opioid craving. A bootstrapped multiple mediation analysis was used to examine the mediating role of patients’ pain intensity and opioid craving in the association between NA and prescription opioid misuse. Consistent with previous research, we found a significant association between NA and prescription opioid misuse. Interestingly, results revealed that opioid craving, but not pain intensity, mediated the association between NA and opioid misuse. Discussion addresses the potential psychological and neurobiological factors that might contribute to the inter-relationships between NA, opioid craving, and prescription opioid misuse in patients with pain. The clinical implications of our findings are also discussed. PMID:24295876

10 CFR 70.51 - Records requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... licensed materials in soil before January 28, 1981, without specific Commission authorization. See § 20.304... adequate safeguards against tampering with and loss of records. (2) If there is a conflict between the...

Cloning, expression and functional role of a nociceptin/orphanin FQ receptor in the porcine gastrointestinal tract.

PubMed

Osinski, M A; Pampusch, M S; Murtaugh, M P; Brown, D R

1999-01-22

The heptadecapeptide nociceptin/orphanin FQ is the cognate ligand for the opioid receptor-like orphanin FQ (OFQ) receptor, a member of the G protein-coupled receptor superfamily. The gastrointestinal tract is a major site of opioid action, and preliminary evidence suggests that an OFQ receptor may be expressed in rat small intestine. We addressed the hypothesis that this receptor is expressed in the gastrointestinal tract of the pig, a model for the human digestive system. A 1205-bp cDNA was isolated from porcine forebrain which contained the 370 amino acid open reading frame encoding the OFQ receptor. The receptor mRNA is likely to arise from a single gene, as determined by Southern blotting of porcine genomic DNA restriction digests using a porcine OFQ receptor cDNA probe. A semi-nested reverse transcriptase-polymerase chain reaction survey of receptor mRNA indicates that it is expressed in the porcine cerebral cortex and kidney, and along the length of the gastrointestinal tract. OFQ decreased initial contractile responses of porcine ileal smooth muscle strips to trains of electrical field stimulation with an IC50 value of 1.3 nM; its effects were resistant to the opioid antagonist, naloxone. The peptide, at concentrations > or =3 nM, also attenuated Isc elevations evoked by electrical transmural stimulation of mucosa-submucosa sheets from porcine ileum. The actions of OFQ appeared to differ from those previously reported for opioid receptor agonists in these tissue preparations. These results indicate that an OFQ receptor is expressed in the porcine intestine which modulates the neural control of intestinal smooth muscle contractility and mucosal transport.

Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target

PubMed Central

Yin, Kathleen; Deuis, Jennifer R; Lewis, Richard J

2016-01-01

Burn injury is a cause of significant mortality and morbidity worldwide and is frequently associated with severe and long-lasting pain that remains difficult to manage throughout recovery. We characterised a mouse model of burn-induced pain using pharmacological and transcriptomic approaches. Mechanical allodynia elicited by burn injury was partially reversed by meloxicam (5 mg/kg), gabapentin (100 mg/kg) and oxycodone (3 and 10 mg/kg), while thermal allodynia and gait abnormalities were only significantly improved by amitriptyline (3 mg/kg) and oxycodone (10 mg/kg). The need for relatively high opioid doses to elicit analgesia suggested a degree of opioid resistance, similar to that shown clinically in burn patients. We thus assessed the gene expression changes in dorsal root ganglion neurons and pathophysiological mechanisms underpinning burn injury-induced pain using a transcriptomic approach. Burn injury was associated with significantly increased expression of genes associated with axon guidance, neuropeptide signalling, behavioural defence response and extracellular signalling, confirming a mixed neuropathic and inflammatory aetiology. Notably, among the pain-related genes that were upregulated post-injury was the cholecystokinin 2 receptor (Cckbr), a G protein-coupled receptor known as a pain target involved in reducing opioid effectiveness. Indeed, the clinically used cholecystokinin receptor antagonist proglumide (30 mg/kg) was effective at reversing mechanical allodynia, with additional analgesia evident in combination with low-dose oxycodone (1 mg/kg), including significant reversal of thermal allodynia. These findings highlight the complex pathophysiological mechanisms underpinning burn injury-induced pain and suggest that cholecystokinin-2 receptor antagonists may be useful clinically as adjuvants to decrease opioid requirements and improve analgesic management. PMID:27573516

Brief Opioid Overdose Knowledge (BOOK): A Questionnaire to Assess Overdose Knowledge in Individuals Who Use Illicit or Prescribed Opioids.

PubMed

Dunn, Kelly E; Barrett, Frederick S; Yepez-Laubach, Claudia; Meyer, Andrew C; Hruska, Bryce J; Sigmon, Stacey C; Fingerhood, Michael; Bigelow, George E

2016-01-01

Opioid overdose is a public health crisis. This study describes efforts to develop and validate the Brief Opioid Overdose Knowledge (BOOK) questionnaire to assess patient knowledge gaps related to opioid overdose risks. Two samples of illicit opioid users and a third sample of patients receiving an opioid for the treatment of chronic pain (total N = 848) completed self-report items pertaining to opioid overdose risks. A 3-factor scale was established, representing Opioid Knowledge (4 items), Opioid Overdose Knowledge (4 items), and Opioid Overdose Response Knowledge (4 items). The scale had strong internal and face validity. Patients with chronic pain performed worse than illicit drug users in almost all items assessed, highlighting the need to increase knowledge of opioid overdose risk to this population. This study sought to develop a brief, internally valid method for quickly assessing deficits in opioid overdose risk areas within users of illicit and prescribed opioids, to provide an efficient metric for assessing and comparing educational interventions, facilitate conversations between physicians and patients about overdose risks, and help formally identify knowledge deficits in other patient populations.

Efficacy of Biocides Used in the Modern Food Industry To Control Salmonella enterica, and Links between Biocide Tolerance and Resistance to Clinically Relevant Antimicrobial Compounds

PubMed Central

Condell, Orla; Iversen, Carol; Cooney, Shane; Power, Karen A.; Walsh, Ciara; Burgess, Catherine

2012-01-01

Biocides play an essential role in limiting the spread of infectious disease. The food industry is dependent on these agents, and their increasing use is a matter for concern. Specifically, the emergence of bacteria demonstrating increased tolerance to biocides, coupled with the potential for the development of a phenotype of cross-resistance to clinically important antimicrobial compounds, needs to be assessed. In this study, we investigated the tolerance of a collection of susceptible and multidrug-resistant (MDR) Salmonella enterica strains to a panel of seven commercially available food-grade biocide formulations. We explored their abilities to adapt to these formulations and their active biocidal agents, i.e., triclosan, chlorhexidine, hydrogen peroxide, and benzalkonium chloride, after sequential rounds of in vitro selection. Finally, cross-tolerance of different categories of biocidal formulations, their active agents, and the potential for coselection of resistance to clinically important antibiotics were investigated. Six of seven food-grade biocide formulations were bactericidal at their recommended working concentrations. All showed a reduced activity against both surface-dried and biofilm cultures. A stable phenotype of tolerance to biocide formulations could not be selected. Upon exposure of Salmonella strains to an active biocidal compound, a high-level of tolerance was selected for a number of Salmonella serotypes. No cross-tolerance to the different biocidal agents or food-grade biocide formulations was observed. Most tolerant isolates displayed changes in their patterns of susceptibility to antimicrobial compounds. Food industry biocides are effective against planktonic Salmonella. When exposed to sublethal concentrations of individual active biocidal agents, tolerant isolates may emerge. This emergence was associated with changes in antimicrobial susceptibilities. PMID:22367085

Efficacy of biocides used in the modern food industry to control salmonella enterica, and links between biocide tolerance and resistance to clinically relevant antimicrobial compounds.

PubMed

Condell, Orla; Iversen, Carol; Cooney, Shane; Power, Karen A; Walsh, Ciara; Burgess, Catherine; Fanning, Séamus

2012-05-01

Biocides play an essential role in limiting the spread of infectious disease. The food industry is dependent on these agents, and their increasing use is a matter for concern. Specifically, the emergence of bacteria demonstrating increased tolerance to biocides, coupled with the potential for the development of a phenotype of cross-resistance to clinically important antimicrobial compounds, needs to be assessed. In this study, we investigated the tolerance of a collection of susceptible and multidrug-resistant (MDR) Salmonella enterica strains to a panel of seven commercially available food-grade biocide formulations. We explored their abilities to adapt to these formulations and their active biocidal agents, i.e., triclosan, chlorhexidine, hydrogen peroxide, and benzalkonium chloride, after sequential rounds of in vitro selection. Finally, cross-tolerance of different categories of biocidal formulations, their active agents, and the potential for coselection of resistance to clinically important antibiotics were investigated. Six of seven food-grade biocide formulations were bactericidal at their recommended working concentrations. All showed a reduced activity against both surface-dried and biofilm cultures. A stable phenotype of tolerance to biocide formulations could not be selected. Upon exposure of Salmonella strains to an active biocidal compound, a high-level of tolerance was selected for a number of Salmonella serotypes. No cross-tolerance to the different biocidal agents or food-grade biocide formulations was observed. Most tolerant isolates displayed changes in their patterns of susceptibility to antimicrobial compounds. Food industry biocides are effective against planktonic Salmonella. When exposed to sublethal concentrations of individual active biocidal agents, tolerant isolates may emerge. This emergence was associated with changes in antimicrobial susceptibilities.

Co-morbid pain and opioid addiction: Long term effect of opioid maintenance on acute pain

PubMed Central

Wachholtz, Amy; Gonzalez, Gerardo

2014-01-01

Introduction Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. Method 120 individuals with chronic pain were recruited in 4 groups (n=30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M=121 weeks; SD=23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. Results A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (Log rank=15.50; p<.001) and tolerance (Log rank=20.11; p<.001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p’s<.01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p<.05), with the highest tolerance found among opioid naïve control group participants (p’s<.001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R=.37; p<.05); but duration of abstinence did not alter sensitivity (ns). Conclusion Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. PMID:25456326

Co-morbid pain and opioid addiction: long term effect of opioid maintenance on acute pain.

PubMed

Wachholtz, Amy; Gonzalez, Gerardo

2014-12-01

Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. 120 Individuals with chronic pain were recruited in 4 groups (N = 30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M = 121 weeks; SD = 23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (log rank = 15.50; p < .001) and tolerance (log rank = 20.11; p < .001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p's < .01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p < .05), with the highest tolerance found among opioid naïve control group participants (p's < .001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R = .37; p < .05); but duration of abstinence did not alter sensitivity (ns). Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Personality as a risk factor for illicit opioid use and a protective factor for illicit opioid dependence.

PubMed

Zaaijer, Eline R; Bruijel, Jessica; Blanken, Peter; Hendriks, Vincent; Koeter, Maarten W J; Kreek, Mary Jeanne; Booij, Jan; Goudriaan, Anna E; van Ree, Jan M; van den Brink, Wim

2014-12-01

Most studies investigating the role of personality as a risk factor for the development of opioid dependence compare dependent opioid users with healthy controls who never used heroin. In order to understand the potential protective role of personality, it is crucial to compare illicit opioid users who never became dependent with dependent opioid users. This study aims to examine the role of personality as a risk factor for opioid use and as a protective factor for the development of opioid dependence. Comparing personality factors between three groups: (1) 161 never-dependent illicit opioid users who have been using illicit opioids but never became opioid dependent; (2) 402 dependent opioid users in methadone maintenance treatment or heroin-assisted treatment; and (3) 135 healthy controls who never used heroin. Personality was assessed with a short version of Cloninger's Temperament and Character Inventory. Never-dependent opioid users reported more Novelty Seeking and Harm Avoidance and less Self-Directedness and Cooperativeness than healthy controls and more Reward Dependence and Self-Directedness, and less Harm Avoidance than dependent opioid users. Furthermore, never-dependent opioid users reported more Self-Transcendence than both dependent opioid users and healthy controls. Never-dependent opioid users may have started to use opioids partly due to their tendency to seek novel and/or spiritual experiences (high Novelty Seeking, high Self-Transcendence) and their tendency to avoid aversive stimuli (high Harm Avoidance), whereas they may have been protected against the development of dependence by their need for social approval (high Reward Dependence) and their self-efficacy (high Self-Directedness). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis

PubMed Central

Regan, Patrick M.; Langford, T. Dianne; Khalili, Kamel

2015-01-01

Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the predications of a four opioid receptor model. Instead, current studies of opioid pharmacology suggest the existence of additional receptor subtypes; however, no additional opioid receptor subtype has been identified to date. It is now understood that this discrepancy is due to the generation of multiple isoforms of opioid receptor subtypes. While several mechanisms are utilized to generate these isoforms, the primary mechanism involves alternative splicing of the pre-mRNA transcript. Extensive alternative splicing patterns for opioid receptors have since been identified and discrepancies in opioid pharmacology are now partially attributed to variable expression of these isoforms. Recent studies have been successful in characterizing the localization of these isoforms as well as their specificity in ligand binding; however, the regulation of opioid receptor splicing specificity is poorly characterized. Furthermore, the functional significance of individual receptor isoforms and the extent to which opioid- and/or HIV-mediated changes in the opioid receptor isoform profile contributes to altered opioid pharmacology or the well-known physiological role of opioids in the exacerbation of HIV neurocognitive dysfunction is unknown. As such, the current review details constitutive splicing mechanisms as well as the specific architecture of opioid receptor genes, transcripts, and receptors in order to highlight the current understanding of opioid receptor isoforms, potential mechanisms of their regulation and signaling, and their functional significance in both opioid pharmacology and HIV-associated neuropathology. PMID:26529364

Past-year Prescription Drug Monitoring Program Opioid Prescriptions and Self-reported Opioid Use in an Emergency Department Population With Opioid Use Disorder.

PubMed

Hawk, Kathryn; D'Onofrio, Gail; Fiellin, David A; Chawarski, Marek C; O'Connor, Patrick G; Owens, Patricia H; Pantalon, Michael V; Bernstein, Steven L

2017-11-22

Despite increasing reliance on prescription drug monitoring programs (PDMPs) as a response to the opioid epidemic, the relationship between aberrant drug-related behaviors captured by the PDMP and opioid use disorder is incompletely understood. How PDMP data should guide emergency department (ED) assessment has not been studied. The objective was to evaluate a relationship between PDMP opioid prescription records and self-reported nonmedical opioid use of prescription opioids in a cohort of opioid-dependent ED patients enrolled in a treatment trial. PDMP opioid prescription records during 1 year prior to study enrollment on 329 adults meeting Diagnostic and Statistical Manual IV criteria for opioid dependence entering a randomized clinical trial in a large, urban ED were cross-tabulated with data on 30-day nonmedical prescription opioid use self-report. The association among these two types of data was assessed by the Goodman and Kruskal's gamma; a logistic regression was used to explore characteristics of participants who had PDMP record of opioid prescriptions. During 1 year prior to study enrollment, 118 of 329 (36%) patients had at least one opioid prescription (range = 1-51) in our states' PDMP. Patients who reported ≥15 of 30 days of nonmedical prescription opioid use were more likely to have at least four PDMP opioid prescriptions (20/38; 53%) than patients reporting 1 to 14 days (14/38, 37%) or zero days of nonmedical prescription opioid use (4/38, 11%; p = 0.002). Female sex and having health insurance were significantly more represented in the PDMP (p < 0.05 for both). PDMPs may be helpful in identifying patients with certain aberrant drug-related behavior, but are unable to detect many patients with opioid use disorder. The majority of ED patients with opioid use disorder were not captured by the PDMP, highlighting the importance of using additional methods such as screening and clinical history to identify opioid use disorders in ED patients and the limitations of PDMPs to detect opioid use disorders. © 2017 by the Society for Academic Emergency Medicine.

Fiber Optic Tamper Indicating Enclosure (TIE); A Case Study in Authentication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anheier, Norman C.; Benz, Jacob M.; Tanner, Jennifer E.

2015-07-15

A robust fiber optic-based tamper-indicating enclosure (TIE) has been developed by PNNL through funding by the National Nuclear Security Administration Office of Nuclear Verification over the past few years. The objective of this work is to allow monitors to have confidence in both the authenticity and integrity of the TIE and the monitoring equipment inside, throughout the time it may be located at a host facility. Incorporating authentication features into the design were the focus of fiscal year 2014 development efforts. Throughout the development process, modifications have been made to the physical TIE design based on lessons learned via exercisesmore » and expert elicitation. The end result is a robust and passive TIE which can be utilized to protect monitoring party equipment left in a host facility.« less

Implosion-driven technique to create fast shockwaves in high-density gas

NASA Astrophysics Data System (ADS)

Serge, Matthew; Loiseau, Jason; Huneault, Justin; Szirti, Daniel; Higgins, Andrew; Tanguay, Vincent

2012-03-01

Pressurized tubes surrounded by either one or two layers (separated by a secondary tube) of sensitized nitromethane and encased in a thick-walled tube (the tamper) were imploded. The distance between the detonation wave in the explosive and shock wave in the innermost tube were measured (the standoff). A simple model based on hoop stress and acoustic interactions between the tubing was developed and used to predict the standoff distance. At low initial pressures (on the order of 7MPa), results indicate that the secondary tube and two layers of explosive did not prove to significantly increase the standoff. However, at higher pressures (on the order of 10 MPa), standoff was noticeably greater when the secondary tube was inserted between the pressurized tube and the tamper. The measured values are in reasonable agreement with the predictions of the model.

Apparatus for safeguarding a radiological source

DOEpatents

Bzorgi, Fariborz M

2014-10-07

A tamper detector is provided for safeguarding a radiological source that is moved into and out of a storage location through an access porthole for storage and use. The radiological source is presumed to have an associated shipping container approved by the U.S. Nuclear Regulatory Commission for transporting the radiological source. The tamper detector typically includes a network of sealed tubing that spans at least a portion of the access porthole. There is an opening in the network of sealed tubing that is large enough for passage therethrough of the radiological source and small enough to prevent passage therethrough of the associated shipping cask. Generally a gas source connector is provided for establishing a gas pressure in the network of sealed tubing, and a pressure drop sensor is provided for detecting a drop in the gas pressure below a preset value.

Tamper asymmetry and its effect on transmission for x-ray driven opacity simulations

NASA Astrophysics Data System (ADS)

Morris, H. E.; Tregillis, I. L.; Hoffman, N. M.; Sherrill, M. E.; Fontes, C. J.; Marshall, A. J.; Urbatsch, T. J.; Bradley, P. A.

2017-09-01

This paper reports on synthetic transmission results from Lasnex [Zimmerman and Kruer, Comments Plasma Phys. 2, 51 (1975)] radiation-hydrodynamics simulations of opacity experiments carried out at Sandia National Laboratories' recently upgraded ZR facility. The focus is on experiments utilizing disk targets composed of a half-moon Fe/Mg mixture tamped on either end with 10-μm CH and an additional 35-μm beryllium tamper accessory on the end facing the spectrometer. Five x-ray sources with peak power ranging from 10 to 24 TW were used in the simulations to heat and backlight the opacity target. The dominant effect is that the beryllium behind the Fe/Mg mixture is denser and more opaque than the beryllium unshielded by metal during the times of greatest importance for the transmission measurement for all drives. This causes the simulated transmission to be lower than expected, and this is most pronounced for the case using the lowest drive power. While beryllium has a low opacity, its areal density is sufficiently high such that the expected reduction of the measured transmission is significant. This situation leads to an overestimate of iron opacity by 10%-215% for a photon energy range of 975-1775 eV for the 10-TW case. It is shown that if the tamper conditions are known, the transmission through each component of the target can be calculated and the resulting opacity can be corrected.

Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, anti-hypertensives, opioid analgesics, and a large term request.

PubMed

Hogan, William R; Hanna, Josh; Hicks, Amanda; Amirova, Samira; Bramblett, Baxter; Diller, Matthew; Enderez, Rodel; Modzelewski, Timothy; Vasconcelos, Mirela; Delcher, Chris

2017-03-03

The Drug Ontology (DrOn) is an OWL2-based representation of drug products and their ingredients, mechanisms of action, strengths, and dose forms. We originally created DrOn for use cases in comparative effectiveness research, primarily to identify historically complete sets of United States National Drug Codes (NDCs) that represent packaged drug products, by the ingredient(s), mechanism(s) of action, and so on contained in those products. Although we had designed DrOn from the outset to carefully distinguish those entities that have a therapeutic indication from those entities that have a molecular mechanism of action, we had not previously represented in DrOn any particular therapeutic indication. In this work, we add therapeutic indications for three research use cases: resistant hypertension, malaria, and opioid abuse research. We also added mechanisms of action for opioid analgesics and added 108 classes representing drug products in response to a large term request from the Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda (PRISM) project. The net result is a new version of DrOn, current to May 2016, that represents three major therapeutic classes of drugs and six new mechanisms of action. A therapeutic indication of a drug product is represented as a therapeutic function in DrOn. Adverse effects of drug products, as well as other therapeutic uses for which the drug product was not designed are dispositions. Our work provides a framework for representing additional therapeutic indications, adverse effects, and uses of drug products beyond their design. Our work also validated our past modeling decisions for specific types of mechanisms of action, namely effects mediated via receptor and/or enzyme binding. DrOn is available at: http://purl.obolibrary.org/obo/dron.owl . A smaller version without NDCs is available at: http://purl.obolibrary.org/obo/dron/dron-lite.owl.

In vitro characterization of a formulation of butorphanol tartrate in a poloxamer 407 base intended for use as a parenterally administered slow-release analgesic agent.

PubMed

Laniesse, Delphine; Smith, Dale A; Knych, Heather K; Mosley, Cornelia; Guzman, David Sanchez-Migallon; Beaufrère, Hugues

2017-06-01

OBJECTIVE To assess rheological properties and in vitro diffusion of poloxamer 407 (P407) and butorphanol-P407 (But-P407) hydrogels and to develop a sustained-release opioid formulation for use in birds. SAMPLE P407 powder and a commercially available injectable butorphanol tartrate formulation (10 mg/mL). PROCEDURES P407 and But-P407 gels were compounded by adding water or butorphanol to P407 powder. Effects of various concentrations of P407 (20%, 25% and 30% [{weight of P407/weight of diluent} × 100]), addition of butorphanol, and sterilization through a microfilter on rheological properties of P407 were measured by use of a rheometer. In vitro diffusion of butorphanol from But-P407 25% through a biological membrane was compared with that of a butorphanol solution. RESULTS P407 20% and 25% formulations were easily compounded, whereas it was difficult to obtain a homogenous P407 30% formulation. The P407 was a gel at avian body temperature, although its viscosity was lower than that at mammalian body temperature. The But-P407 25% formulation (butorphanol concentration, 8.3 mg/mL) was used for subsequent experiments. Addition of butorphanol to P407 as well as microfiltration did not significantly affect viscosity. Butorphanol diffused in vitro from But-P407, and its diffusion was slower than that from a butorphanol solution. CONCLUSIONS AND CLINICAL RELEVANCE But-P407 25% had in vitro characteristics that would make it a good candidate for use as a sustained-release analgesic medication. Further studies are needed to characterize the pharmacokinetic and pharmacodynamic properties of But-P407 25% in vivo before it can be recommended for use in birds.

Using behavioral economics to predict opioid use during prescription opioid dependence treatment.

PubMed

Worley, Matthew J; Shoptaw, Steven J; Bickel, Warren K; Ling, Walter

2015-03-01

Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N=353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR=1.30, p<.001) and a greater proportion of their income on drugs (OR=1.31, p<.001) were more likely to use opioids during treatment. Individual differences in drug reinforcement value, as indicated by pre-treatment allocation of economic resources to drugs, reflects propensity for continued opioid use during treatment among individuals with prescription opioid addiction. Future studies should examine disrupted decision-making and reward-processing in prescription opioid users more directly and test whether reinforcer pathology can be remediated in this population. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Using behavioral economics to predict opioid use during prescription opioid dependence treatment

PubMed Central

Worley, Matthew J.; Shoptaw, Steven J.; Bickel, Warren K.; Ling, Walter

2015-01-01

Background Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. Methods Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N = 353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. Results Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR = 1.30, p < .001) and a greater proportion of their income on drugs (OR = 1.31, p < .001) were more likely to use opioids during treatment. Conclusions Individual differences in drug reinforcement value, as indicated by pre-treatment allocation of economic resources to drugs, reflects propensity for continued opioid use during treatment among individuals with prescription opioid addiction. Future studies should examine disrupted decision-making and reward-processing in prescription opioid users more directly and test whether reinforcer pathology can be remediated in this population. PMID:25622776

Increased use of heroin as an initiating opioid of abuse.

PubMed

Cicero, Theodore J; Ellis, Matthew S; Kasper, Zachary A

2017-11-01

Given the relatively recent growth in access to heroin and a more permissive atmosphere surrounding its use, we hypothesized that an increasing number of persons with limited experience and tolerance to opioids would experiment with heroin as their first opioid rather than more common prescription opioid analgesics. Individuals entering substance abuse treatment for an opioid use disorder in the period 2010-2016 (N=5885) were asked about the specific opioid they first regularly used to get high. To limit long-term recall and survival bias, analyses was restricted to opioid initiation that occurred in the past ten years (2005-2015). In 2005, only 8.7% of opioid initiators started with heroin, but this sharply increased to 33.3% (p<0.001) in 2015, with no evidence of stabilization. The use of commonly prescribed opioids, oxycodone and hydrocodone, dropped from 42.4% and 42.3% of opioid initiators, respectively, to 24.1% and 27.8% in 2015, such that heroin as an initiating opioid was now more frequently endorsed than prescription opioid analgesics. Our data document that, as the most commonly prescribed opioids - hydrocodone and oxycodone - became less accessible due to supply-side interventions, the use of heroin as an initiating opioid has grown at an alarming rate. Given that opioid novices have limited tolerance to opioids, a slight imprecision in dosing inherent in heroin use is likely to be an important factor contributing to the growth in heroin-related over dose fatalities in recent years. Copyright © 2017. Published by Elsevier Ltd.

Accelerated weathering of natural fiber-filled polyethylene composites

Treesearch

Thomas Lundin; Steven M. Cramer; Robert H. Falk; Colin Felton

2004-01-01

The resistance of natural fiber-filled high-density polyethylene composite specimens to ultraviolet- (UV) and moisture-induced degradation was evaluated by measuring changes to flexural properties. High-density polyethylene (HDPE) served as the polymer matrix for four formulations: two formulations without fiber filler and two formulations one containing wood flour and...

Opioid Abuse and Addiction - Multiple Languages

MedlinePlus

... Opioid addiction, part 8 - español (Spanish) MP4 Healthy Roads Media Comorbidity or dual diagnosis - Opioid addiction, part 9 - English PDF Comorbidity or ... addiction, part 9 - English MP4 Comorbidity or dual diagnosis - Opioid ... MP4 Healthy Roads Media Pregnancy and opioids - Opioid addiction, part 10 - ...

Risk of Prolonged Opioid Use Among Opioid-Naïve Patients Following Common Hand Surgery Procedures.

PubMed

Johnson, Shepard P; Chung, Kevin C; Zhong, Lin; Shauver, Melissa J; Engelsbe, Michael J; Brummett, Chad; Waljee, Jennifer F

2016-10-01

To evaluate prolonged opioid use in opioid-naïve patients after common hand surgery procedures in the United States. We studied insurance claims from the Truven MarketScan databases to identify opioid-naïve adult patients (no opioid exposure 11 months before the perioperative period) who underwent an elective (carpal tunnel release, carpometacarpal arthroplasty/arthrodesis, cubital tunnel release, or trigger finger release) or trauma-related (closed distal radius fracture fixation, flexor tendon repair, metacarpal fracture fixation, or phalangeal fracture fixation) hand surgery procedure between 2010 and 2012 (N = 77,573 patients). Patients were observed for 6 months to determine the number, timing, duration, and oral morphine equivalent dosage of postoperative opioid prescriptions. We assessed prolonged postoperative opioid use, defined as patients who filled a perioperative opioid prescription followed by a prescription between 90 and 180 days after surgery, and evaluated associated risk factors using multivariable logistic regression. In this cohort, 59,725 opioid-naïve patients (77%) filled a perioperative opioid prescription. Of these, 13% of patients continued to fill prescriptions between 90 and 180 days after surgery. Elective surgery patients were more likely to continue to fill opioid prescriptions after 90 days compared with trauma patients (13.5% vs 10.5%). Younger age, female gender, lower income, comprehensive insurance, higher Elixhauser comorbidity index, mental health disorders, and tobacco dependence or abuse were associated with prolonged opioid use. Approximately 13% of opioid-naïve patients continue to fill opioid prescriptions after hand surgery procedures 90 days after surgery. Preoperative interventions centered on opioid alternatives and early cessation, particularly among patients at risk for long-term use, is critical to addressing the prescription opioid crisis in the United States. The current national opioid use epidemic requires an assessment of the prevalence of hand surgery patients who receive and fill opioid prescriptions after common hand surgery procedures. Copyright © 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Opioid Utilization and Opioid-Related Adverse Events in Non-Surgical Patients in U.S. Hospitals

PubMed Central

Herzig, Shoshana J.; Rothberg, Michael B.; Cheung, Michael; Ngo, Long H.; Marcantonio, Edward R.

2014-01-01

Background Recent studies in the outpatient setting have demonstrated high rates of opioid prescribing and overdose-related deaths. Prescribing practices in hospitalized patients are unexamined. Objective To investigate patterns and predictors of opioid utilization in non-surgical admissions to U.S. hospitals, variation in use, and the association between hospital-level use and rates of severe opioid-related adverse events. Design, Setting, and Patients Adult non-surgical admissions to 286 U.S. hospitals. Measurements Opioid exposure and severe opioid-related adverse events during hospitalization, defined using hospital charges and ICD-9-CM codes. Results Of 1.14 million admissions, opioids were used in 51%. The mean ± s.d. daily dose received in oral morphine equivalents (OME) was 68 ± 185 mg; 23% of exposed received a total daily dose of ≥ 100 mg OME. Opioid prescribing rates ranged from 5% in the lowest to 72% in the highest prescribing hospital (mean 51% ± 10%). After adjusting for patient characteristics, the adjusted opioid prescribing rates ranged from 33–64% (mean 50% ± s.d. 4%). Among exposed, 0.97% experienced severe opioid-related adverse events. Hospitals with higher opioid prescribing rates had higher adjusted relative risk of a severe opioid-related adverse event per patient exposed (RR 1.23 [1.14–1.33] for highest compared to lowest prescribing quartile). Conclusions The majority of hospitalized non-surgical patients were exposed to opioids, often at high doses. Hospitals that used opioids most frequently had increased adjusted risk of a severe opioid-related adverse event per patient exposed. Interventions to standardize and enhance the safety of opioid prescribing in hospitalized patients should be investigated. PMID:24227700

Characteristics of Opioid-Users Whose Death Was Related to Opioid-Toxicity: A Population-Based Study in Ontario, Canada

PubMed Central

Madadi, Parvaz; Hildebrandt, Doris; Lauwers, Albert E.; Koren, Gideon

2013-01-01

Background The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity. Methods This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed. Results Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer. Significance/Conclusion These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users. PMID:23577131

A Clinical Study on Administration of Opioid Antagonists in Terminal Cancer Patients: 7 Patients Receiving Opioid Antagonists Following Opioids among 2443 Terminal Cancer Patients Receiving Opioids.

PubMed

Uekuzu, Yoshihiro; Higashiguchi, Takashi; Futamura, Akihiko; Ito, Akihiro; Mori, Naoharu; Murai, Miyo; Ohara, Hiroshi; Awa, Hiroko; Chihara, Takeshi

2017-03-01

There have been few detailed reports on respiratory depression due to overdoses of opioids in terminal cancer patients. We investigated the situation of treatment with opioid antagonists for respiratory depression that occurred after administration of opioid at optimal doses in terminal cancer patients, to clarify pathological changes as well as causative factors. In 2443 terminal cancer patients receiving opioids, 7 patients (0.3%) received opioid antagonists: 6, morphine (hydrochloride, 5; sulfate, 1); 1, oxycodone. The median dosage of opioids was 13.3 mg/d, as converted to morphine injection. Respiratory depression occurred on this daily dose in 4 patients and after changed dose and route in 3 patients. Opioids were given through the vein in 6 patients and by the enteral route in 1 patient. Concomitant drugs included nonsteroidal anti-inflammatory drugs in 3 patients and zoledronic acid in 2 patients. In morphine-receiving patients, renal functions were significantly worsened at the time of administration of an opioid antagonist than the day before the start of opioid administration. These findings indicate that the proper use of opioids was safe and acceptable in almost all terminal cancer patients. In rare cases, however, a risk toward respiratory depression onset is indicated because morphine and morphine-6-glucuronide become relatively excessive owing to systemic debility due to disease progression, especially respiratory and renal dysfunctions. At the onset of respiratory depression, appropriate administration of an opioid antagonist mitigated the symptoms. Thereafter, opioid switching or continuous administration at reduced dosages of the same opioids prevented the occurrence of serious adverse events.

Opioid errors in inpatient palliative care services: a retrospective review.

PubMed

Heneka, Nicole; Shaw, Tim; Rowett, Debra; Lapkin, Samuel; Phillips, Jane L

2018-06-01

Opioids are a high-risk medicine frequently used to manage palliative patients' cancer-related pain and other symptoms. Despite the high volume of opioid use in inpatient palliative care services, and the potential for patient harm, few studies have focused on opioid errors in this population. To (i) identify the number of opioid errors reported by inpatient palliative care services, (ii) identify reported opioid error characteristics and (iii) determine the impact of opioid errors on palliative patient outcomes. A 24-month retrospective review of opioid errors reported in three inpatient palliative care services in one Australian state. Of the 55 opioid errors identified, 84% reached the patient. Most errors involved morphine (35%) or hydromorphone (29%). Opioid administration errors accounted for 76% of reported opioid errors, largely due to omitted dose (33%) or wrong dose (24%) errors. Patients were more likely to receive a lower dose of opioid than ordered as a direct result of an opioid error (57%), with errors adversely impacting pain and/or symptom management in 42% of patients. Half (53%) of the affected patients required additional treatment and/or care as a direct consequence of the opioid error. This retrospective review has provided valuable insights into the patterns and impact of opioid errors in inpatient palliative care services. Iatrogenic harm related to opioid underdosing errors contributed to palliative patients' unrelieved pain. Better understanding the factors that contribute to opioid errors and the role of safety culture in the palliative care service context warrants further investigation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Daily home opioid use in adults with sickle cell disease: The PiSCES project.

PubMed

Smith, Wally R; McClish, Donna K; Dahman, Bassam A; Levenson, James L; Aisiku, Imoigele P; de A Citero, Vanessa; Bovbjerg, Viktor E; Roberts, John D; Penberthy, Lynne T; Roseff, Susan D

2015-01-01

Although opioid prescribing in sickle cell disease (SCD) can be controversial, little is published about patterns of opioid use. To report on home opioid use among adults with SCD. Cohort study. Adults with SCD (n=219) who completed daily pain diaries for up to 6 months and had at least one home pain day. Use of long-acting or short-acting opioids, other analgesics, or adjuvants; the proportion of home days, home pain days, and home crisis days with opioid use; these two outcomes according to patient characteristics. Patients used opioids on 12,311 (78 percent) of 15,778 home pain days. Eighty-five patients (38.8 percent) used long-acting opioids with or without short-acting opioids and 103 (47.0 percent) used only short-acting opioids. Twenty-one (9.6 percent) patients used only non-opioid analgesics and 10 (4.6 percent) used no analgesics. Both pain intensity and pain frequency were higher among opioid users (analysis of variance [ANOVA], p<0.0001). Opioid users used hydroxyurea more often than nonusers, even when controlling for mean pain on pain days. Among all patients, significant relationships were found between any opioid use and somatic symptom burden, SCD stress, negative coping, and physical and mental quality of life (QOL); the relationship with SCD stress and physical QOL remained when controlled for mean pain. Among opioid users, similar associations were found between frequency of opioid use and some disease-related and psychosocial variables. In this adult SCD sample, opioids were used by the majority of patients. Pain was the overwhelming characteristic associated with use, but disease-related and psychosocial variables were also associated.

Characteristics of opioid-users whose death was related to opioid-toxicity: a population-based study in Ontario, Canada.

PubMed

Madadi, Parvaz; Hildebrandt, Doris; Lauwers, Albert E; Koren, Gideon

2013-01-01

The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity. This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed. Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer. These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users.

Advances in membrane technology for the NASA redox energy storage system

NASA Technical Reports Server (NTRS)

Ling, J. S.; Charleston, J.

1980-01-01

Anion exchange membranes used in the system serve as a charge transferring medium as well as a reactant separator and are the key enabling component in this storage technology. Each membrane formulation undergoes a series of screening tests for area-resistivity, static (non-flow) diffusion rate determination, and performance in Redox systems. The CDIL series of membranes has, by virtue of its chemical stability and high ion exchange capacity, demonstrated superior properties in the redox environment. Additional resistivity results at several acid and iron solution concentrations, iron diffusion rates, and time dependent iron fouling of the various membrane formulations are presented in comparison to past standard formulations.

Evidence that opioids may have toll-like receptor 4 and MD-2 effects.

PubMed

Hutchinson, Mark R; Zhang, Yingning; Shridhar, Mitesh; Evans, John H; Buchanan, Madison M; Zhao, Tina X; Slivka, Peter F; Coats, Benjamen D; Rezvani, Niloofar; Wieseler, Julie; Hughes, Travis S; Landgraf, Kyle E; Chan, Stefanie; Fong, Stephanie; Phipps, Simon; Falke, Joseph J; Leinwand, Leslie A; Maier, Steven F; Yin, Hang; Rice, Kenner C; Watkins, Linda R

2010-01-01

Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll-like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically-employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling.

Initiation into Prescription Opioid Misuse among Young Injection Drug Users

PubMed Central

Lankenau, Stephen E.; Teti, Michelle; Silva, Karol; Bloom, Jennifer Jackson; Harocopos, Alex; Treese, Meghan

2011-01-01

Background Prescription opioids are the most frequently misused class of prescription drugs among young adults. Initiation into prescription opioid misuse is an important public health concern since opioids are increasingly associated with drug dependence and fatal overdose. Descriptive data about initiation into prescription opioid misuse among young injection drug users (IDUs) are scarce. Methods An exploratory qualitative study was undertaken to describe patterns of initiation into prescription opioid misuse among IDUs aged 16 to 25 years. Those young IDUs who had misused a prescription drug at least three times in the past three months were recruited during 2008 and 2009 in Los Angeles (n=25) and New York (n=25). Informed by an ethno-epidemiological approach, descriptive data from a semi-structured interview guide were analysed both quantitatively and qualitatively. Results Initiation into prescription opioid misuse was facilitated by easy access to opioids via participant’s own prescription, family, or friends, and occurred earlier than misuse of other illicit drugs, such as heroin. Nearly all transitioned into sniffing opioids, most injected opioids, and many initiated injection drug use with an opioid. Motives for transitions to sniffing and injecting opioids included obtaining a more potent high and/or substituting for heroin; access to multiple sources of opioids was common among those who progressed to sniffing and injecting opioids. Conclusion Prescription opioid misuse was a key feature of trajectories into injection drug use and/or heroin use among this sample of young IDUs. A new pattern of drug use may be emerging whereby IDUs initiate prescription opioid misuse before using heroin. PMID:21689917

Evidence that opioids may have toll like receptor 4 and MD-2 effects

PubMed Central

Hutchinson, Mark R.; Zhang, Yingning; Shridhar, Mitesh; Evans, John H.; Buchanan, Madison M.; Zhao, Tina X.; Slivka, Peter F.; Coats, Benjamen D.; Rezvani, Niloofar; Wieseler, Julie; Hughes, Travis S.; Landgraf, Kyle E.; Chan, Stefanie; Fong, Stephanie; Phipps, Simon; Falke, Joseph J.; Leinwand, Leslie A.; Maier, Steven F.; Yin, Hang; Rice, Kenner C.; Watkins, Linda R.

2009-01-01

Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling. PMID:19679181

Cell death sensitization of leukemia cells by opioid receptor activation

PubMed Central

Friesen, Claudia; Roscher, Mareike; Hormann, Inis; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf A.; Debatin, Klaus-Michael; Miltner, Erich

2013-01-01

Cyclic AMP (cAMP) regulates a number of cellular processes and modulates cell death induction. cAMP levels are altered upon stimulation of specific G-protein-coupled receptors inhibiting or activating adenylyl cyclases. Opioid receptor stimulation can activate inhibitory Gi-proteins which in turn block adenylyl cyclase activity reducing cAMP. Opioids such as D,L-methadone induce cell death in leukemia cells. However, the mechanism how opioids trigger apoptosis and activate caspases in leukemia cells is not understood. In this study, we demonstrate that downregulation of cAMP induced by opioid receptor activation using the opioid D,L-methadone kills and sensitizes leukemia cells for doxorubicin treatment. Enhancing cAMP levels by blocking opioid-receptor signaling strongly reduced D,L-methadone-induced apoptosis, caspase activation and doxorubicin-sensitivity. Induction of cell death in leukemia cells by activation of opioid receptors using the opioid D,L-methadone depends on critical levels of opioid receptor expression on the cell surface. Doxorubicin increased opioid receptor expression in leukemia cells. In addition, the opioid D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux in leukemia cells, suggesting that the opioid D,L-methadone as well as doxorubicin mutually increase their cytotoxic potential. Furthermore, we found that opioid receptor activation using D,L-methadone alone or in addition to doxorubicin inhibits tumor growth significantly in vivo. These results demonstrate that opioid receptor activation via triggering the downregulation of cAMP induces apoptosis, activates caspases and sensitizes leukemia cells for doxorubicin treatment. Hence, opioid receptor activation seems to be a promising strategy to improve anticancer therapies. PMID:23633472

Opioid Prescription, Morbidity, and Mortality in United States Dialysis Patients.

PubMed

Kimmel, Paul L; Fwu, Chyng-Wen; Abbott, Kevin C; Eggers, Anne W; Kline, Prudence P; Eggers, Paul W

2017-12-01

Aggressive pain treatment was advocated for ESRD patients, but new Centers for Disease Control and Prevention guidelines recommend cautious opioid prescription. Little is known regarding outcomes associated with ESRD opioid prescription. We assessed opioid prescriptions and associations between opioid prescription and dose and patient outcomes using 2006-2010 US Renal Data System information in patients on maintenance dialysis with Medicare Part A, B, and D coverage in each study year ( n =671,281, of whom 271,285 were unique patients). Opioid prescription was confirmed from Part D prescription claims. In the 2010 prevalent cohort ( n =153,758), we examined associations of opioid prescription with subsequent all-cause death, dialysis discontinuation, and hospitalization controlled for demographics, comorbidity, modality, and residence. Overall, >60% of dialysis patients had at least one opioid prescription every year. Approximately 20% of patients had a chronic (≥90-day supply) opioid prescription each year, in 2010 usually for hydrocodone, oxycodone, or tramadol. In the 2010 cohort, compared with patients without an opioid prescription, patients with short-term (1-89 days) and chronic opioid prescriptions had increased mortality, dialysis discontinuation, and hospitalization. All opioid drugs associated with mortality; most associated with worsened morbidity. Higher opioid doses correlated with death in a monotonically increasing fashion. We conclude that opioid drug prescription is associated with increased risk of death, dialysis discontinuation, and hospitalization in dialysis patients. Causal relationships cannot be inferred, and opioid prescription may be an illness marker. Efforts to treat pain effectively in patients on dialysis yet decrease opioid prescriptions and dose deserve consideration. Copyright © 2017 by the American Society of Nephrology.

Using Opioids Safely After Surgery

MedlinePlus

... Adult , Geriatric Using Opioids Safely After Surgery Using Opioids Safely After Surgery Stick to the lowest dose ... need opioid pain medicine. If your doctor says opioids aren’t necessary. If your doctor thinks you ...

Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Eenograft Model

PubMed Central

Chen, Yan; Zheng, Xue-Lian; Fang, Dai-Long; Yang, Yang; Zhang, Jin-Kun; Li, Hui-Li; Xu, Bei; Lei, Yi; Ren, Ke; Song, Xiang-Rong

2014-01-01

Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic. PMID:24552875

Solution formulation development and efficacy of MJC13 in a preclinical model of castration-resistant prostate cancer.

PubMed

Liang, Su; Bian, Xiaomei; Liang, Dong; Sivils, Jeffrey C; Neckers, Leonard M; Cox, Marc B; Xie, Huan

2016-01-01

MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castration-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), highly lipophilic (logP = 6.49), poorly soluble in water (0.28 µg/mL), and highly plasma protein bound (>98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for four consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls.

Solution Formulation Development and Efficacy of MJC13 in a Preclinical Model of Castrate-Resistant Prostate Cancer

PubMed Central

Liang, Su; Bian, Xiaomei; Liang, Dong; Sivils, Jeffrey C.; Neckers, Leonard M.; Cox, Marc B.; Xie, Huan

2015-01-01

MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castrate-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), very lipophilic (logP = 6.49), poorly soluble in water (0.28 μg/mL), and highly plasma protein bound (> 98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for 4 consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls. PMID:25380396

42 CFR 8.11 - Opioid treatment program certification.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Opioid treatment program certification. 8.11... PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Certification and Treatment Standards § 8.11 Opioid... Substances Act (21 U.S.C. 823(g)(1)) to dispense opioid drugs in the treatment of opioid addiction. An OTP...

42 CFR 8.11 - Opioid treatment program certification.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Opioid treatment program certification. 8.11... PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Certification and Treatment Standards § 8.11 Opioid... Substances Act (21 U.S.C. 823(g)(1)) to dispense opioid drugs in the treatment of opioid addiction. An OTP...

42 CFR 8.11 - Opioid treatment program certification.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Opioid treatment program certification. 8.11... PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Certification and Treatment Standards § 8.11 Opioid... Substances Act (21 U.S.C. 823(g)(1)) to dispense opioid drugs in the treatment of opioid addiction. An OTP...

42 CFR 8.11 - Opioid treatment program certification.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Opioid treatment program certification. 8.11... PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Certification and Treatment Standards § 8.11 Opioid... Substances Act (21 U.S.C. 823(g)(1)) to dispense opioid drugs in the treatment of opioid addiction. An OTP...

42 CFR 8.11 - Opioid treatment program certification.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Opioid treatment program certification. 8.11... PROVISIONS CERTIFICATION OF OPIOID TREATMENT PROGRAMS Certification and Treatment Standards § 8.11 Opioid... Substances Act (21 U.S.C. 823(g)(1)) to dispense opioid drugs in the treatment of opioid addiction. An OTP...

Opioid Analgesics.

PubMed

Jamison, Robert N; Mao, Jianren

2015-07-01

Chronic pain is an international health issue of immense importance that is influenced by both physical and psychological factors. Opioids are useful in treating chronic pain but have accompanying complications. It is important for clinicians to understand the basics of opioid pharmacology, the benefits and adverse effects of opioids, and related problematic issues of tolerance, dependence, and opioid-induced hyperalgesia. In this article, the role of psychiatric comorbidity and the use of validated assessment tools to identify individuals who are at the greatest risk for opioid misuse are discussed. Additionally, interventional treatment strategies for patients with chronic pain who are at risk for opioid misuse are presented. Specific behavioral interventions designed to improve adherence with prescription opioids among persons treated for chronic pain, such as frequent monitoring, periodic urine screens, opioid therapy agreements, opioid checklists, and motivational counseling, are also reviewed. Use of state-sponsored prescription drug monitoring programs is also encouraged. Areas requiring additional investigation are identified, and the future role of abuse-deterrent opioids and innovative technology in addressing issues of opioid therapy and pain are presented. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Physician Introduction to Opioids for Pain Among Patients with Opioid Dependence and Depressive Symptoms

PubMed Central

Tsui, Judith I.; Herman, Debra S.; Kettavong, Malyna; Alford, Daniel; Anderson, Bradley J.; Stein, Michael D.

2011-01-01

This study determined the frequency of reporting being introduced to opioids by a physician among opioid dependent patients. Cross-sectional analyses were performed using baseline data from a cohort of opioid addicts seeking treatment with buprenorphine. The primary outcome was response to the question: “Who introduced you to opiates?” Covariates included sociodemographics, depression, pain, current and prior substance use. Of 140 participants, 29% reported that they had been introduced to opioids by a physician. Of those who were introduced to opioids by a physician, all indicated that they had initially used opioids for pain, versus only 11% of those who did not report being introduced to opioids by a physician (p<0.01). There was no difference in current pain (78% vs. 85%, p=0.29), however participants who were introduced to opioids by a physician were more likely to have chronic pain (63% vs. 43%, p=0.04). A substantial proportion of individuals with opioid dependence seeking treatment may have been introduced to opioids by a physician. PMID:20727704

Long-Term Opioid Therapy Reconsidered

PubMed Central

Von Korff, Michael; Kolodny, Andrew; Deyo, Richard A.; Chou, Roger

2012-01-01

In the past 20 years, primary care physicians have greatly increased prescribing of long-term opioid therapy. However, the rise in opioid prescribing has outpaced the evidence regarding this practice. Increased opioid availability has been accompanied by an epidemic of opioid abuse and overdose. The rate of opioid addiction among patients receiving long-term opioid therapy remains unclear, but research suggests that opioid misuse is not rare. Recent studies report increased risks for serious adverse events, including fractures, cardiovascular events, and bowel obstruction, although further research on medical risks is needed. New data indicate that opioid-related risks may increase with dose. From a societal perspective, higher-dose regimens account for the majority of opioids dispensed, so cautious dosing may reduce both diversion potential and patient risks for adverse effects. Limiting long-term opioid therapy to patients for whom it provides decisive benefits could also reduce risks. Given the warning signs and knowledge gaps, greater caution and selectivity are needed in prescribing long-term opioid therapy. Until stronger evidence becomes available, clinicians should err on the side of caution when considering this treatment. PMID:21893626

Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: a single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers.

PubMed

Johnson, Franklin K; Stark, Jeffrey G; Bieberdorf, Frederick A; Stauffer, Joe

2010-06-01

Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extended-release morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphine-induced subjective effects, rendering the product less attractive for tampering. The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-beta-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for >or=2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-beta-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [In]-transformed C(max) and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study discharge and were monitored for adverse events (AEs) throughout the study. Of the 24 subjects enrolled in the study, 23 completed it. Most subjects were white (79%) and male (63%); the mean (SD) age was 39.3 (11.2) years and the mean weight was 77.6 (13.5) kg (range, 55.0102.5 kg). Plasma C(max) and AUC(0-t) of naltrexone after the administration of crushed pellets of MS-sNT (579 pg/mL and 1811 h . pg/mL, respectively) and naltrexone solution (584 pg/mL and 1954 h . pg/mL) were not significantly different; 90% CIs were 83.8% to 116% and 83.3% to 102%, meeting the regulatory requirements for assuming bioequivalence in this study population. Plasma naltrexone concentration was below the lower limit of quantitation (4.0 pg/mL) in 23 of 24 subjects (96%) after whole MS-sNT administration. Morphine AUC(0-t) was not significantly different whether MS-sNT was crushed (163 h . ng/mL) or administered whole (174 h . ng/mL), but C(max) was numerically higher (24.5 vs 7.7 ng/mL) and T(max) was numerically shorter (2.00 vs 7.03 hours) with MS-sNT crushed versus whole. The most commonly reported AEs were nausea (8/23 [35%], 10/24 [42%], and 3/23 [13%] subjects in the crushed, whole, and naltrexone groups, respectively) and emesis (6 [26%], 7 [29%], and 2 [9%]). In this single-dose study, when pellets from MS-sNT were crushed, naltrexone appeared to be completely released and available to mitigate morphine-induced effects. When MS-sNT was administered whole, morphine was released in an extended-release fashion while naltrexone remained sequestered.

The Speech multi features fusion perceptual hash algorithm based on tensor decomposition

NASA Astrophysics Data System (ADS)

Huang, Y. B.; Fan, M. H.; Zhang, Q. Y.

2018-03-01

With constant progress in modern speech communication technologies, the speech data is prone to be attacked by the noise or maliciously tampered. In order to make the speech perception hash algorithm has strong robustness and high efficiency, this paper put forward a speech perception hash algorithm based on the tensor decomposition and multi features is proposed. This algorithm analyses the speech perception feature acquires each speech component wavelet packet decomposition. LPCC, LSP and ISP feature of each speech component are extracted to constitute the speech feature tensor. Speech authentication is done by generating the hash values through feature matrix quantification which use mid-value. Experimental results showing that the proposed algorithm is robust for content to maintain operations compared with similar algorithms. It is able to resist the attack of the common background noise. Also, the algorithm is highly efficiency in terms of arithmetic, and is able to meet the real-time requirements of speech communication and complete the speech authentication quickly.

A Tamper-Resistant and Portable Healthcare Folder

PubMed Central

Anciaux, Nicolas; Berthelot, Morgane; Braconnier, Laurent; Bouganim, Luc; De la Blache, Martine; Gardarin, Georges; Kesmarszky, Philippe; Lartigue, Sophie; Navarre, Jean-François; Pucheral, Philippe; Vandewalle, Jean-Jacques; Zeitouni, Karine

2008-01-01

Electronic health record (EHR) projects have been launched in most developed countries to increase the quality of healthcare while decreasing its cost. The benefits provided by centralizing the healthcare information in database systems are unquestionable in terms of information quality, availability, and protection against failure. Yet, patients are reluctant to give to a distant server the control over highly sensitive data (e.g., data revealing a severe or shameful disease). This paper capitalizes on a new hardware portable device, associating the security of a smart card to the storage capacity of a USB key, to give back to the patient the control over his medical data. This paper shows how this device can complement a traditional EHR server to (1) protect and share highly sensitive data among trusted parties and (2) provide a seamless access to the data even in disconnected mode. The proposed architecture is experimented in the context of a medicosocial network providing medical care and social services at home for elderly people. PMID:18615200

Deficits in Autonomic Indices of Emotion Regulation and Reward Processing Associated with Prescription Opioid Use and Misuse

PubMed Central

Garland, Eric L.; Bryan, Craig J.; Nakamura, Yoshio; Froeliger, Brett; Howard, Matthew O.

2016-01-01

Rationale Prescription opioid misuse and high dose opioid use may result in allostatic dysregulation of hedonic brain circuitry, leading to reduced emotion regulation capacity. In particular, opioid misuse may blunt the ability to experience and upregulate positive affect from natural rewards. Objectives The purpose of this study was to examine associations between opioid use/misuse and autonomic indices of emotion regulation capability in a sample of chronic pain patients receiving prescription opioid pharmacotherapy. Methods Chronic pain patients taking long-term opioid analgesics (N = 40) completed an emotion regulation task while heart rate variability (HRV) was recorded, as well as self-report measures of opioid misuse, craving, pain severity, and emotional distress. Based on a validated cut-point on the Current Opioid Misuse Measure, participants were grouped as opioid misusers or non-misusers. Opioid misuse status and morphine equivalent daily dose (MEDD) were examined as predictors of HRV and self-reports of emotion regulation. Results Opioid misusers exhibited significantly less HRV during positive and negative emotion regulation, and significantly less positive affect, than non-misusers, after controlling for confounders including pain severity and emotional distress. MEDD was inversely associated with positive emotion regulation efficacy. Conclusion Findings implicate the presence of reward processing deficits among chronic pain patients with opioid-misusing behaviors, and opioid dosage was associated with deficient emotion regulation, suggesting the presence of compromised top-down cognitive control over bottom-up hedonic processes. Emotion regulation among opioid misusers may represent an important treatment target. PMID:27933366

The opioid epidemic and national guidelines for opioid therapy for chronic noncancer pain: a perspective from different continents.

PubMed

Häuser, Winfried; Schug, Stephan; Furlan, Andrea D

2017-05-01

A marked rise in opioid prescriptions for patients with chronic noncancer pain (CNCP) with a parallel increase in opioid abuse/misuse, and resulting deaths was noted in the Unites states in the past decade (opioid epidemic). In response, the US Center of Diseases Control (CDC) developed a guideline for prescribing of opioids for patients with CNCP. To assess (1) if there is an opioid epidemic in Australia, Canada, and Germany (2) to compare Australian, Canadian, German, and Center of Diseases Control guidelines recommendations for long-term opioid therapy for CNCP. National evidence-based guidelines and PubMed were searched for recommendations for opioid prescriptions for CNCP. There are signs of an opioid epidemic in Australia and Canada, but not in Germany. Guidelines in all 4 countries provide similar recommendations: opioids are not the first-line therapy for patients with CNCP; regular clinical assessments of benefits and harms are necessary; excessive doses should be avoided (recommended morphine equivalent daily doses range from 50 to 200 mg/d); stopping rules should be followed. All guidelines do not recommend the use of opioids in chronic pain conditions without an established nociceptive or neuropathic cause such as fibromyalgia and primary headache. Implementation of opioid prescribing guidelines should ensure that physicians prescribe opioids only for appropriate indications in limited doses for selected patients and advice patients on their safe use. These measures could contribute to reduce prescription opioid misuse/abuse and deaths.

Ceramic tamper-revealing seals

DOEpatents

Kupperman, David S.; Raptis, Apostolos C.; Sheen, Shuh-Haw

1992-01-01

A flexible metal or ceramic cable with composite ceramic ends, or a u-shaped ceramic connecting element attached to a binding element plate or block cast from alumina or zirconium, and connected to the connecting element by shrink fitting.

10 CFR 73.25 - Performance capabilities for physical protection of strategic special nuclear material in transit.

Code of Federal Regulations, 2012 CFR

2012-01-01

... tampering with transports and cargo containers; and (iii) Surveillance subsystems and procedures to detect... to establish activities for transferring cargo in emergency situations; and (iii) Removal controls...

10 CFR 73.25 - Performance capabilities for physical protection of strategic special nuclear material in transit.

Code of Federal Regulations, 2011 CFR

2011-01-01

... tampering with transports and cargo containers; and (iii) Surveillance subsystems and procedures to detect... to establish activities for transferring cargo in emergency situations; and (iii) Removal controls...

Computer Security Systems Enable Access.

ERIC Educational Resources Information Center

Riggen, Gary

1989-01-01

A good security system enables access and protects information from damage or tampering, but the most important aspects of a security system aren't technical. A security procedures manual addresses the human element of computer security. (MLW)

Prescription opioid misusing chronic pain patients exhibit dysregulated context-dependent associations: Investigating associative learning in addiction with the cue-primed reactivity task.

PubMed

Garland, Eric L; Bryan, Craig J; Kreighbaum, Lydia; Nakamura, Yoshio; Howard, Matthew O; Froeliger, Brett

2018-06-01

Associative learning undergirds the development of addiction, such that drug-related cues serve as conditioned stimuli to elicit drug-seeking responses. Plausibly, among opioid misusing chronic pain patients, pain-related information may serve as a conditioned stimulus to magnify opioid cue-elicited autonomic and craving responses through a process of second-order conditioning. We utilized a novel psychophysiological probe of pain-opioid conditioned associations, the Cue-Primed Reactivity (CPR) task. In this task, participants were presented with images as primes (200 ms) and cues (6000 ms) in pairs organized in four task blocks: "control-opioid," "pain-opioid," "control-pain," and "opioid-pain." Opioid-treated chronic pain patients (N = 30) recruited from an Army base in the Western United States were classified as opioid misusers (n = 17) or non-misusers (n = 13) via a validated cutpoint on the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 2008). Opioid misuse status was examined as a predictor of HRV, craving, and mood responses on the CPR task. HRV increased to a greater extent during the pain-opioid block compared to the control-opioid block for non-misusers compared to misusers (p = .003, η 2 partial  = 0.27). In contrast, craving increased to a greater extent from baseline to the pain-opioid block for misusers than for non-misusers (p = .03, η 2 partial  = .16). Findings suggest that opioid-treated chronic pain patients exhibit Pavlovian conditioned responses to opioid cues strengthened by an associative learning process of second-order conditioning when primed by pain-related images. This pain-opioid contingency appears to become disrupted among individuals who engage in opioid misuse, such that opioid-related stimuli elicit motivational responses irrespective of pain-related contextual stimuli. Copyright © 2018 Elsevier B.V. All rights reserved.

Impact of Preoperative Opioid Use After Emergency General Surgery.

PubMed

Kim, Young; Cortez, Alexander R; Wima, Koffi; Dhar, Vikrom K; Athota, Krishna P; Schrager, Jason J; Pritts, Timothy A; Edwards, Michael J; Shah, Shimul A

2018-01-16

Preoperative exposure to narcotics has recently been associated with poor outcomes after elective major surgery, but little is known as to how preoperative opioid use impacts outcomes after common, emergency general surgical procedures (EGS). A high-volume, single-center analysis was performed on patients who underwent EGS from 2012 to 2013. EGS was defined as the seven emergent operations that account for 80% of the national burden. Preoperative opioid use was defined as having an active opioid prescription within 7 days prior to surgery. Chronic opioid use was defined as having an opioid prescription concurrent with 90 days after discharge. A total of 377 patients underwent EGS during the study period. Preoperative opioid use was present in 84 patients (22.3%). Preoperative opioid users had longer hospital LOS (10.5 vs 6 days), higher costs of care ($25,331 vs $11,454), and higher 30-day readmission rates (22.6 vs 8.2%) compared with opioid-naïve patients (p < 0.001 each). After covariate adjustment, preoperative opioid use was predictive of LOS (RR 1.19 [1.01-1.41]) and 30-day hospital readmission (OR 2.69 [1.25-5.75]) (p < 0.05 each). Total direct cost was not different after modeling. Preoperative opioid users required more narcotic refills compared with opioid-naïve patients (5 vs 0 refills, p < 0.001). After discharge, 15.4% of opioid-naïve patients met criteria for chronic opioid use, vs 77.4% in preoperative opioid users (p < 0.001). Preoperative opioid use is associated with greater resource utilization after emergency general surgery, as well as vastly different postoperative opioid prescription patterns. These findings may help to inform the impact of preoperative opioid use on patient care, and its implications on hospital and societal cost.

Continuous opioid treatment for chronic noncancer pain: a time for moderation in prescribing.

PubMed

Colameco, Stephen; Coren, Joshua S; Ciervo, Carman A

2009-07-01

Physicians have embraced the concept of long-term opioid treatment for chronic noncancer pain (CNCP), as evidenced by increased prescribing. Many patients have benefited from more liberal opioid prescribing, but many have not, and prescription opioid abuse has risen significantly coincident with increased prescribing. Because of the potentially serious adverse effects of opioids, physicians must balance potential benefits against risks, especially in individuals at risk for opioid misuse, abuse, or dependence. This article reviews long-term, continuous opioid treatment of CNCP, current treatment guidelines, addiction risk stratification, opioid-induced hyperalgesia, and endocrine dysfunction.

Prescription practices involving opioid analgesics among Americans with Medicaid, 2010.

PubMed

Mack, Karin A; Zhang, Kun; Paulozzi, Leonard; Jones, Christopher

2015-02-01

Recent state-based studies have shown an increased risk of opioid overdose death in Medicaid populations. To explore one side of risk, this study examines indicators of potential opioid inappropriate use or prescribing among Medicaid enrollees. We examined claims from enrollees aged 18-64 years in the 2010 Truven Health MarketScan® Multi-State Medicaid database, which consisted of weighted and nationally representative data from 12 states. Pharmaceutical claims were used to identify enrollees (n=359,368) with opioid prescriptions. Indicators of potential inappropriate use or prescribing included overlapping opioid prescriptions, overlapping opioid and benzodiazepine prescriptions, long acting/extended release opioids for acute pain, and high daily doses. In 2010, Medicaid enrollees with opioid prescriptions obtained an average 6.3 opioid prescriptions, and 40% had at least one indicator of potential inappropriate use or prescribing. These indicators have been linked to opioid-related adverse health outcomes, and methods exist to detect and deter inappropriate use and prescribing of opioids.

The opioid manager: a point-of-care tool to facilitate the use of the Canadian Opioid Guideline.

PubMed

Furlan, Andrea D; Reardon, Rhoda; Salach, Lena

2012-01-01

The Opioid Manager is designed to be used as a point-of-care tool for providers prescribing opioids for chronic noncancer pain. It condenses the key elements from the Canadian Opioid Guideline and can be used as a chart insert. The Opioid Manager has been validated and is available for download from the Guideline's Web site http://nationalpaincentre.mcmaster.ca/opioidmanager/. The Opioid Manager is divided into the following four parts: A) before you write the first script, B) initiation trial, C) maintenance and monitoring, and D) when is it time to decrease the dose or stop the opioid completely? The Opioid Manager has been downloaded by 1,432 users: 47 percent family physicians, 18 percent pharmacists, 13 percent other physicians, and 22 percent miscellaneous. To show how to use the Opioid Manager, the authors created a 10-minute video that is available on the Internet. The Opioid Manager is being translated to French, Spanish, Portuguese, and Farsi.

PEG-PE/clay composite carriers for doxorubicin: Effect of composite structure on release, cell interaction and cytotoxicity.

PubMed

Kohay, Hagay; Sarisozen, Can; Sawant, Rupa; Jhaveri, Aditi; Torchilin, Vladimir P; Mishael, Yael G

2017-06-01

A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was developed. DOX was incorporated in micelles (M-DOX) of polyethylene glycol-phosphatidylethanolamine (PEG-PE) which in turn were adsorbed by the clay, montmorillonite (MMT). The nano-structures of the PEG-PE/MMT composites of LOW and HIGH polymer loadings were characterized by XRD, TGA, FTIR, size (DLS) and zeta measurements. These measurements suggest that for the LOW composite a single layer of polymer intercalates in the clay platelets and the polymer only partially covers the external surface, while for the HIGH composite two layers of polymer intercalate and a bilayer may form on the external surface. These nanostructures have a direct effect on formulation stability and on the rate of DOX release. The release rate was reversely correlated with the degree of DOX interaction with the clay and followed the sequence: M-DOX>HIGH formulation>LOW formulation>DOX/MMT. Despite the slower release from the HIGH formulation, its cytotoxicity effect on sensitive cells was as high as the "free" DOX. Surprisingly, the LOW formulation, with the slowest release, demonstrated the highest cytotoxicity in the case of Adriamycin (ADR) resistant cells. Confocal microscopy images and association tests provided an insight into the contribution of formulation-cell interactions vs. the contribution of DOX release rate. Internalization of the formulations was suggested as a mechanism that increases DOX efficiency, particularly in the ADR resistant cell line. The employment of organic-inorganic hybrid materials as drug delivery systems, has not reached its full potential, however, its functionality as an efficient tunable release system was demonstrated. DOX PEG-PE/clay formulations were design as an efficient drug delivery system. The main aim was to develop PEG-PE/clay formulations of different structures based on various PEG-PE/clay ratios in order to achieve tunable release rates, to control the external surface characteristics and formulation stability. The formulations showed significantly higher toxicity in comparison to "free" DOX, explained by formulation internalization. For each cell line tested, sensitive and ADR resistant, a different formulation structure was found most efficient. The potential of PEG-PE/clay-DOX formulations to improve DOX administration efficacy was demonstrated and should be further explored and implemented for other cancer drugs and cells. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

National addictions vigilance intervention and prevention program (NAVIPPRO): a real-time, product-specific, public health surveillance system for monitoring prescription drug abuse.

PubMed

Butler, Stephen F; Budman, Simon H; Licari, Andrea; Cassidy, Theresa A; Lioy, Katherine; Dickinson, James; Brownstein, John S; Benneyan, James C; Green, Traci Craig; Katz, Nathaniel

2008-12-01

The National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) is a scientific, comprehensive risk management program for scheduled therapeutics. NAVIPPRO provides post-marketing surveillance, signal detection, signal verification and prevention and intervention programs. Here we focus on one component of NAVIPPRO surveillance, the Addiction Severity Index-Multimedia Version (ASI-MV) Connect, a continuous, real-time, national data stream that assesses pharmaceutical abuse by patients entering substance abuse treatment by collecting product-specific, geographically-detailed information. We evaluate population characteristics for data collected through the ASI-MV Connect in 2007 and 2008 and assess the representativeness, geographic coverage, and timeliness of report of the data. Analyses based on 41,923 admissions to 265 treatment centers in 29 states were conducted on product-specific opioid abuse rates, source of drug, and route of administration. ASI-MV Connect data revealed that 11.5% of patients reported abuse of at least one opioid analgesic product in the 30 days prior to entering substance abuse treatment; differences were observed among sub-populations of prescription opioid abusers, among products, and also within various geographic locations. The ASI-MV Connect component of NAVIPPRO represents a potentially valuable data stream for post-marketing surveillance of prescription drugs. Analyses conducted with data obtained from the ASI-MV Connect allow for the characterization of product-specific and geospatial differences for drug abuse and can serve as a tool to monitor responses of the abuse population to newly developed "abuse deterrent" drug formulations. Additional data, evaluation, and comparison to other systems are important next steps in establishing NAVIPPRO as a comprehensive, post-marketing surveillance system for prescription drugs. Copyright (c) 2008 John Wiley & Sons, Ltd.

Increases in self-reported fentanyl use among a population entering drug treatment: The need for systematic surveillance of illicitly manufactured opioids.

PubMed

Cicero, Theodore J; Ellis, Matthew S; Kasper, Zachary A

2017-08-01

Recent reports indicate a sharp increase in fentanyl-related overdose deaths across the United States, much of which is likely related to the introduction of cheap, illicitly manufactured fentanyl derivatives. In this study, we sought to estimate the magnitude of illicit fentanyl use from 2012 to 2016 using a national opioid abuse surveillance system. The study program surveyed 10,900 individuals entering substance abuse treatment for opioid use disorder, with participants asked to endorse past month 'use to get high' of fentanyl drugs, stratified by identifiable (i.e., branded) fentanyl formulations or a 'type unknown' drug alleged to contain fentanyl. Total past-month fentanyl-use rose modestly from 2012 to 2016. While use of known fentanyl products remained relatively stable (mean=10.9%; P=0.25), endorsements of 'unknown' fentanyl products nearly doubled from 9% in 2013 to 15.1% by 2016 (P<0.001). Data show no discernable indication that this increase is diminishing or stabilizing. This first attempt to assess the prevalence of illicit fentanyl use shows that recent increases in fentanyl use seem to be due almost entirely to 'unknown' fentanyl presumed to be illicitly manufactured. Given that it is difficult to assess the extent to which fentanyl may have been substituted for another drug (i.e., oxycodone, alprazolam, etc.) or was used as a heroin admixture, our data likely represent an underestimation of the full magnitude of illicit fentanyl abuse. As such, this growing public health problem requires immediate attention and more systematic efforts to identify and track its abuse. Copyright © 2017. Published by Elsevier B.V.

Employment-based reinforcement of adherence to depot naltrexone in unemployed opioid-dependent adults: a randomized controlled trial.

PubMed

Everly, Jeffrey J; DeFulio, Anthony; Koffarnus, Mikhail N; Leoutsakos, Jeannie-Marie S; Donlin, Wendy D; Aklin, Will M; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E; Silverman, Kenneth

2011-07-01

Naltrexone can be used to treat opioid dependence, but patients refuse to take it. Extended-release depot formulations may improve adherence, but long-term adherence rates to depot naltrexone are not known. This study determined long-term rates of adherence to depot naltrexone and whether employment-based reinforcement can improve adherence. Participants who were inducted onto oral naltrexone were assigned randomly to contingency (n = 18) or prescription (n = 17) groups. Participants were offered six depot naltrexone injections and invited to work at the therapeutic workplace on week days for 26 weeks, where they earned stipends for participating in job skills training. Contingency participants were required to accept naltrexone injections to maintain workplace access and to maintain maximum pay. Prescription participants could work independently of whether they accepted injections. The therapeutic workplace, a model employment-based intervention for drug addiction and unemployment. Opioid-dependent unemployed adults. Depot naltrexone injections accepted and opiate-negative urine samples. Contingency participants accepted significantly more naltrexone injections than prescription participants (81% versus 42%), and were more likely to accept all injections (66% versus 35%). At monthly assessments (with missing urine samples imputed as positive), the groups provided similar percentages of samples negative for opiates (74% versus 62%) and for cocaine (56% versus 54%). Opiate-positive samples were more likely when samples were also positive for cocaine. Employment-based reinforcement can maintain adherence to depot naltrexone. Future research should determine whether persistent cocaine use compromises naltrexone's effect on opiate use. Workplaces may be useful for promoting sustained adherence to depot naltrexone. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

The Effect of DA-9701 in Opioid-induced Bowel Dysfunction of Guinea Pig.

PubMed

Hussain, Zahid; Rhee, Kwang Won; Lee, Young Ju; Park, Hyojin

2016-07-30

Opioid induced bowel dysfunction (OIBD) is associated with decreased gastrointestinal (GI) propulsive activity due to intake of opioid analgesics. DA-9701, a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber has promising effects on GI motor function. Therefore, we aim to evaluate the prokinetic effects of DA-9701 in an OIBD model of guinea pig. The ileal and distal colon muscle contraction in presence of different doses of DA-9701, morphine, and combination (morphine + DA-9701) was measured by tissue bath study. The prokinetic effect of DA-9701 was assessed by charcoal transit and fecal pellet output assay in an OIBD model of guinea pig. DA-9701 significantly increased the amplitude and area under the curve of ileal muscle contraction, while there was insignificant effect on the distal colon compared to the control. The maximal amplitude of ileal muscle contraction was acquired at a concentration of 10 μg/mL of DA-9701. In contrast, morphine significantly decreased the amplitude of ileal and distal colon muscle contraction compared to the control. Morphine delayed both upper (P < 0.01) and lower (P < 0.05) GI transit, and delayed GI transit was restored by the administration of DA-9701. Morphine induced reduction of contractility was significantly ameliorated by addition of DA-9701 in both ileal and distal colon muscles. DA-9701 significantly increased the amplitude of contraction of the ileal muscle, however the distal colon muscle contraction was insignificant. Additionally, it restored delayed upper and lower GI transit in an OIBD model of guinea pig, and it might prove to be a useful candidate drug in a clinical trial for OIBD.

Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors

PubMed Central

2013-01-01

Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators. PMID:24010861

Managing Opioid Addiction Risk in Plastic Surgery during the Perioperative Period.

PubMed

Demsey, Daniel; Carr, Nicholas J; Clarke, Hance; Vipler, Sharon

2017-10-01

Opioid addiction is a public health crisis that affects all areas of medicine. Large numbers of the population across all racial and economic demographics misuse prescription opioids and use illicit opioids. The current understanding is that opioid misuse is a disease that requires treatment, and is not an issue of choice or character. Use of opioid medication is a necessary part of postoperative analgesia, but many physicians are unsure of how to do this safely given the risk of patients developing an opioid misuse disorder. This review gives an update of the current state of the opioid crisis, explains how current surgeons' prescribing practices are contributing to it, and gives recommendations on how to use opioid medication safely in the perioperative period.

Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain.

PubMed

Bartoli, Adrian; Michna, Edward; He, Ellie; Wen, Warren

2015-01-01

Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (Hysingla™ ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post-hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23-31% of the study populations). Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0-10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double-blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD's safety and tolerability profiles were similar to other opioid analgesics.

Adverse events associated with single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews.

PubMed

Moore, R Andrew; Derry, Sheena; Aldington, Dominic; Wiffen, Philip J

2015-10-13

This is an update of a Cochrane overview published in Issue 9, 2011; that overview considered both efficacy and adverse events. This overview considers adverse events, with efficacy dealt with in a separate overview.Thirty-nine Cochrane reviews of randomised trials have examined the adverse events associated with individual drug interventions in acute postoperative pain. This overview brings together the results of those individual reviews. To provide an overview of adverse event rates associated with single-dose oral analgesics, compared with placebo, for acute postoperative pain in adults. We identified systematic reviews in The Cochrane Database of Systematic Reviews on The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group. We extracted information related to participants experiencing any adverse event, and reports of serious adverse events, and deaths from the individual reviews. Information was available from 39 Cochrane reviews for 41 different analgesics or analgesic combinations (51 drug/dose/formulations) tested in single oral doses in participants with moderate or severe postoperative pain. This involved around 350 unique studies involving about 35,000 participants. Most studies involved younger participants with pain following removal of molar teeth.For most nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and combinations not containing opioids, there were few examples where participants experienced significantly more or fewer adverse events than with placebo. For aspirin 1000 mg and diflunisal 1000 mg, opioids, or fixed-dose combination drugs containing opioids, participants typically experienced significantly more adverse events than with placebo. Studies of combinations of ibuprofen and paracetamol reported significantly fewer adverse events.Serious adverse events were rare, occurring a rate of about 1 in 3200 participants.Most reviews did not report specific adverse events. Despite ongoing problems with the measurement, recording, and reporting of adverse events in clinical trials and in systematic reviews, the large amount of information available for single oral doses of analgesics provides evidence that adverse events rates are generally similar with active drug and placebo in these circumstances, except at higher doses of some drugs, and in combinations including opioids.

Endogenous opiates and behavior: 2014.

PubMed

Bodnar, Richard J

2016-01-01

This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants). This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants). Copyright © 2015 Elsevier Inc. All rights reserved.