Abuse Deterrent Research Articles

Oxymorphone and Oxycodone Pharmacy Purchases in US Counties: Prelude to the Largest Rural Human Immunodeficiency Virus Outbreak in US History.

The largest rural outbreak of human immunodeficiency virus (HIV) in the US was centered in Scott County, Indiana, and linked to injection practices involving the opioid Opana ER (oxymorphone extended release [ER] reformulated). We examined supply trends using pharmacy transactions of Opana ER in Scott and all US counties from January 2007 to December 2019. We calculated the monthly morphine milligram equivalents (MME) of Opana ER (and its competitor OxyContin) in pharmacies using the Automation of Reports and Consolidated Orders System (ARCOS) database from the Washington Post. We modeled the MME rate per capita in Scott County and five geographic comparators in seven distinct time periods including the market introduction of abuse deterrent formulations of both drugs and the HIV outbreak period (circa 2014). After Opana ER introduction, transaction rates surged in Scott County, where annual OxyContin MMEs were already seven-fold higher than Indiana overall (CY2009: 46.8 vs. 6.8 MME/pop., respectively). Immediately after OxyContin's reformulation, the Opana ER growth rate in Scott County surpassed all geographic comparators modeled (~27 times faster than the US, 1.28 vs. 0.047 MME/pop/month, respectively). By 2012, prior to the outbreak, MMEs from Opana ER almost perfectly replaced the diminishing OxyContin supply. When Opana ER with INTAC was subsequently introduced, pharmacy transactions declined precipitously by nearly 50%, persisting through the HIV outbreak period and market withdrawal. Opana ER rapidly supplanted OxyContin in a vulnerable population that was at heightened risk for HIV who subsequently faced an immediate supply shock after its reformulation. Pharmacy transactions are critical for suspicious order monitoring and pharmacovigilance by US and international agencies especially during deleterious supply shocks in legal and illicit drug markets.

Abuse Deterrent Dosage Forms: Approaches, Advantages and Limitations

Background: Abuse-deterrent formulations (ADFs) are dosage forms designed to prevent or discourage the misuse of prescription drugs, particularly opioids. They achieve this aim by either minimizing the benefit of tampering with the dosage form or making it challenging to change this dosage form. Therefore, one of the priorities for public health is to develop dosage forms that have abuse-deterrent formulations. The escalation in the prescription of opioids has led to a surge in their abuse or misuse, resulting in a high mortality rate. Objectives: This review article explores drug abuse methods among addicted individuals and lists the most frequently abused drug classes. Furthermore, this review concentrates on understanding the most prevalent technologies used to deter abuse of prescribed opioid drugs. Methods: The search included online published databases from PubMed, Google Scholar, Research Gate, Science Direct, Elsevier, and others. The objective was to collect as much information as possible from articles using the keywords “abuse deterrent formulations and abuse deterrent technology." Conclusions: Physical-chemical barriers and agonist-antagonist formulations are available as marketed drugs as well as aversive agents’ formulations. Each of these types can inhibit or reduce specific cases of opioid misuse. Although the success of these products mostly relies on robust formulation strategies, it also requires a thorough understanding of their benefits and broad adoption in the market.

Multidimensional opioid abuse deterrence using a nanoparticle-polymer hybrid formulation

Misuse of prescription opioid drugs is the leading cause of the opioid crisis and overdose-related death. Abuse deterrent formulations (ADFs) have been developed to discourage attempts to tamper with the formulation and alter the ingestion methods. However, abusers develop complex extraction strategies to circumvent the ADF technologies. For comprehensive deterrence of drug abuse, we develop tannic acid nanoparticles (NPs) that protect encapsulated opioids from solvent extraction and thermal challenge (crisping), complementing the existing formulation strategy to deter injection abuse. Here, we develop a hybrid ADF tablet (NP-Tab), consisting of iron-crosslinked tannic acid NPs encapsulating thebaine (model opioid compound), xanthan gum, and chitosan (gel-forming polymers), and evaluate its performance in common abuse conditions. NP-Tab tampered by crushing and suspended in aqueous solvents forms an instantaneous gel, which is difficult to pull or push through a 21-gauge needle. NPs insulate the drug from organic solvents, deterring solvent extraction. NPs also promote thermal destruction of the drug to make crisping less rewarding. However, NP-Tab releases thebaine in the simulated gastric fluid without delay, suggesting that its analgesic effect may be unaffected if consumed orally as prescribed. These results demonstrate that NP-Tab can provide comprehensive drug abuse deterrence, resisting aqueous/organic solvent extraction, injection, and crisping, while retaining its therapeutic effect upon regular usage.

Comparing the effects of decreasing prescription opioid shipments and the release of an abuse deterrent OxyContin formulation on opioid overdose fatalities in WV: an interrupted time series study

IntroductionThe 2010 release of an abuse deterrent formulation (ADF) of OxyContin, a brand name prescription opioid, has been cited as a major driver for the reduction in prescription drug misuse and the associated increasing illicit opioid use and overdose rates. However, studies of this topic often do not account for changes in supplies of other prescription opioids that were widely prescribed before and after the ADF OxyContin release, including generic oxycodone formulations and hydrocodone. We therefore sought to compare the impact of the ADF OxyContin release to that of decreasing prescription opioid supplies in West Virginia (WV).MethodsOpioid tablet shipment and overdose data were extracted from The Washington Post ARCOS (2006–2014) and the WV Forensic Drug Database (2005–2020), respectively. Locally estimated scatterplot smoothing (LOESS) was used to estimate the point when shipments of prescription opioids to WV began decreasing, measured via dosage units and morphine milligram equivalents (MMEs). Interrupted time series analysis (ITSA) was used to compare the impact LOESS-identified prescription supply changes and the ADF OxyContin release had on prescription (oxycodone and hydrocodone) and illicit (heroin, fentanyl, and fentanyl analogues) opioid overdose deaths in WV. Model fit was compared using Akaike Information Criteria (AIC).ResultsThe majority of opioid tablets shipped to WV from 2006 to 2014 were generic oxycodone or hydrocodone, not OxyContin. After accounting for a 6-month lag from ITSA models using the LOESS-identified change in prescription opioid shipments measured via dosage units (2011 Q3) resulted in the lowest AIC for both prescription (AIC = -188.6) and illicit opioid-involved overdoses (AIC = -189.4), indicating this intervention start date resulted in the preferred model. The second lowest AIC was for models using the ADF OxyContin release as an intervention start date.DiscussionWe found that illicit opioid overdoses in WV began increasing closer to when prescription opioid shipments to the state began decreasing, not when the ADF OxyContin release occurred. Similarly, the majority of opioid tablets shipped to the state for 2006–2014 were generic oxycodone or hydrocodone. This may indicate that diminishing prescription supplies had a larger impact on opioid overdose patterns than the ADF OxyContin release in WV.

Public health strategies to combat opioid crisis in the United States

Abstract Background: The opioid epidemic in the United States is a national public health crisis. Driven by an increase in availability of pharmaceutical opioids and by an increase in their consumption, specifically, for pain treatment, more so in the past twenty years, it has led to an economic cost of prescription opioid abuse, overdose, and dependence in the United States estimated to be 78.5 billion USD. Methods: A thorough evaluation of the relevant extracted literature has been used to answer the question of the most effective ways to regulate health markets to decrease the opioid crisis in the United States, using keywords and phrases such as opioid epidemic in the US, prescription drug abuse, prescription medication abuse in US, medication misuse, cost-effective ways to health market regulation, drug monitoring programs, prescriber continuing education, provider continuing education, and pain management optimization. Results: Overcoming this epidemic nationwide requires improvement in patient utilization of and access to safe and effective treatment options for opioid abuse and overdose, addressing the stigma correlated with opioid use, considering appropriate use of abuse deterrent formulations (ADF) along with patient education, and improving prescribing practices via utilization of drug monitoring programs, CDC opioid prescribing guidelines and provider continuing education. Conclusion: Utilizing and implementing the aforementioned steps has shown to be a challenge. Further and repeated attempts are needed, while at the same time considering possible new steps that could help reinforce their utilization further.

A Cross-Sectional Study of Tampering in Xtampza ER, an Abuse-Deterrent Formulation of an Extended-Release Opioid, in a Treatment Center Population.

While the current landscape of opioid use disorder (OUD) is complicated by the increase in use of non-prescription opioids, prescription opioids continue to be frequently used in non-medical ways. In response to this abuse, pharmaceutical companies have developed abuse deterrent formulations (ADFs) for extended-release (ER) opioids. To test the effectiveness of Xtampza ER ADF (oxycodone myristate) at reducing tampering, its rate of tampering in a treatment-center population was compared to immediate release (IR) single entity (SE) oxycodone, other ER oxycodone opioids, and ER oxymorphone. Data were collected between the third quarter of 2018 and the third quarter of 2021 from individuals entering nationally distributed opioid treatment programs. To determine odds of tampering with Xtampza ER compared to each comparator, a logistic model was fit with a random intercept allowing for multiple drugs in each subject. Within-subject correlation was assumed to have a compound symmetric relationship. Overlap among the categories of drug tampering was high. Logistic regression analyses found that oxycodone myristate had lower odds of tampering when compared to both IR SE oxycodone (OR = 0.23 [95% CI0.11, 0.50], p = 0.0002) and ER oxymorphone (OR = 0.30 [95% CI0.14, 0.67], p = 0.0038). Oxycodone myristate was not significantly different from other ER oxycodone opioids (OR = 0.5 [95% CI0.24, 1.03], p = 0.0612). These findings did not change when the estimates were adjusted for age and sex. Drugs employing ADF technology may reduce the likelihood of tampering when compared to non-ADF formulations in a treatment-center population, which represents an opportunity for intervention in OUD among those still requiring pain management.

Stability of Abuse-deterrent properties of PEO-based Abuse-deterrent formulation

Abuse of opioid drug products is a national health crisis in the US. To deter abuse, a number of drug products with abuse-deterrent (AD) properties have been approved by the US Food and Drug Administration (FDA). For abuse deterrence, it is critical to maintain the AD properties during the product shelf life. However, no information on the stability of AD properties during product shelf life is publicly available. In this study, stability of AD properties of surrogate AD formulation (ADF) of opioid active pharmaceutical ingredients (APIs) were studied. Surrogate extended release (ER) AD tablets were prepared by direct compression using Diltiazem HCl (model drug), polyethylene oxide (PEO WSR 301) polymer and magnesium stearate followed by curing at 70 °C for 30 mins. The stability studies were conducted at 25 °C/60 % RH and 40 °C/75 % RH storage conditions for 12 months (M) and 6 months (M), respectively. In vitro characterization and evaluation of AD properties of tablets were performed. As anticipated, the curing process increased the crushing strength of the tablets. However, the tablets could still be manipulated and compromised leading to an enhancement in the amount of drug extracted in solvents (e.g., water, alcohol), regardless of extraction temperature as well as tablet storage condition and time. Furthermore, the granule particle size as well as viscosity in water of manipulated samples were found to be lower for tablets stored at 25 °C/60 % RH or 40 °C/75 % RH for 12 M or 3 M/6M, respectively. The changes in AD properties eased the syringeability of hydrated samples and ultimately led to the withdrawal of higher amounts of drug into the syringe, thereby, impacting the abuse deterrence potential of the formulation by an IV route. These data demonstrated that the stability of AD properties (i.e., granule particle size, viscosity and syringeability-injectability) of PEO-based tablets was dependent on the storage condition. In conclusion, the design of AD formulation and setting of product quality profile should take into consideration the stability of AD properties during the product shelf life.

Emerging Trends in Abuse-Deterrent Formulations: Technological Insights and Regulatory Considerations.

Opioid medications are an integral part of the management of acute and chronic severe pain. However, non-medical practice of these prescription drug products is emerging as a serious public health problem. To control this opioid epidemic, USFDA is encouraging pharmaceutical companies to develop Abuse Deterrent Formulations (ADFs). ADF's are much more difficult to manipulate and abuse when compared to their conventional formulations. This feature of ADFs is due to their ability to incumber extraction of active ingredients, to prevent administration through alternative routes, making abuse of altered product less rewarding. The main objective of this review is to abridge different ADFs and various laboratory- based in vitro manipulation and extraction studies, demonstrating that these approved ADFs have the capabilities to deter abuse. The method includes the collection of data from different search engines like PubMed, FDA guidance documents, ScienceDirect, Google Patents to get coverage of literature in order to get appropriate information regarding ADFs. Various in vitro studies demonstrate that ADFs are effective in minimizing opioid drug abuse, including opioid overdose. However, real impact of these ADFs on reducing the drug abuse can be concluded only after receiving the post marketing data. ADFs are embracing fundamentally different paradigms in the management of severe pain. We believe that the development of abuse deterrent technologies would shift the architype, deterring multipill abuse and can prove as a breakthrough strategy in controlling this opioid epidemic menace.

PLA-PCL microsphere formulation to deter abuse of prescription opioids by smoking

Opioids are commonly prescribed across the United States (US) for pain relief, despite their highly addictive nature that often leads to abuse and overdose deaths. Abuse deterrent formulations (ADFs) for prescription opioids make the non-therapeutic use of these drugs more difficult and less satisfying. Although approximately one-third of surveyed abusers in the US reported smoking opioids, to our knowledge, no commercialized ADF effectively prevents opioid smoking. Here, we report a novel approach to deter smoking of a model prescription opioid drug, thebaine (THB), by using polymer blend microspheres (MS) comprising polylactic acid (PLA) and polycaprolactone (PCL). We utilized high-performance liquid chromatography (HPLC) and thermogravimetric analysis (TGA) to test the ability of PLA-PCL MS to limit the escape of vaporized THB. Additionally, we compared the abuse-deterrent potential of PLA-PCL MS to that of activated carbon (AC) and mesoporous silica (MPS), two materials with excellent drug-adsorbing properties. Our MS formulation was effective in reducing the amount of both active drug and thermal degradation products in the vapor generated upon heating of THB. These results support that PLA-PCL microspheres can be co-formulated in a tablet with common prescription opioids to deter their abuse via the smoking route.

A novel long-acting formulation of oral buprenorphine/naloxone produces prolonged decreases in fentanyl self-administration by rhesus monkeys

BackgroundDue to the poor oral bioavailability of buprenorphine, an oral formulation has not been thought possible. Lyndra Therapeutics is developing a once-weekly long-acting oral product containing buprenorphine. We evaluated the efficacy of this formulation in reducing intravenous (i.v.) fentanyl self-administration by three male and three female rhesus monkeys. MethodsBuprenorphine HCl and naloxone HCl were co-formulated using an 11:1 ratio of buprenorphine:naloxone in a controlled-release gastric residence formulation administered in an oral capsule (LYN-013). Naloxone was included to determine the feasibility of combining naloxone with buprenorphine in the formulation as an abuse deterrent. Complete fentanyl dose-response functions were determined during each session. The efficacy of single doses of 56/5, 112/10 and 168/15 mg buprenorphine/naloxone in reducing fentanyl self-administration was examined over 13 days. Results: LYN-013 significantly decreased the rate of responding for fentanyl for 3 days and significantly reduced total intake of fentanyl for 8 days. Time to maximal buprenorphine levels (Tmax) ranged between 56 and 68 h for all 3 doses. The maximal buprenorphine level (Cmax) following 168 mg was 2.3 ng/ml which was significantly greater that those observed for 56 mg (1.22 ng/ml) and 112 mg (1.35 ng/ml). Finally, the area-under-curves (AUCtau) were buprenorphine dose-dependently increased from 88 to 127–265 h*ng/ml. There were no signs of non-specific changes in behavior. ConclusionsA once-weekly oral buprenorphine/naloxone formulation produced sustained suppression of fentanyl self-administration in monkeys suggesting that oral delivery of buprenorphine with this formulation could provide a new opportunity to treat opioid use disorders (OUD).

Kentucky pharmacists’ experiences in dispensing abuse-deterrent opioid analgesics

BackgroundDespite pharmaceutical industry promise and enthusiasm, abuse-deterrent formulation (ADF) opioid use is relatively low. While some barriers to use have been addressed through state laws and policy, pharmacists’ experiences with and opinions of ADF opioids are unclear. ObjectivesThe objective of this study was to evaluate pharmacists’ perceptions of dispensing ADFs. MethodsThis was a cross-sectional survey of community pharmacists licensed and practicing in Kentucky conducted in late 2019. The survey asked about perception, experience dispensing, and insurance coverage of 5 ADF opioids available at the time. ResultsMost respondents (421/629, 67.9%) were familiar or very familiar with ADFs, and 63.1% agreed that all opioids should meet U.S. Food and Drug Administration standards for abuse deterrence. Aside from OxyContin, most ADF opioid formations were not stocked (range: 46.7%–73.6%). Third-party payer claims were occasionally or almost always rejected for most ADFs (range: 56.3%–75.4%). Contrary to intended mechanism of deterrence, ADFs were rated as the least effective strategy to reduce opioid misuse/abuse, with over half (51.2%) of respondents believing ADFs were not effective or somewhat effective. ADFs were rated as effective or very effective at reducing opioid abuse by swallowing intact by 37.4% of respondents. ConclusionPharmacists are familiar with ADFs but do not dispense them frequently. Pharmacists appear skeptical about the effectiveness of ADFs but support policies that could increase ADF uptake.

The effects of opioid policy changes on transitions from prescription opioids to heroin, fentanyl and injection drug use: a qualitative analysis

BackgroundBeginning in the 1990s, nonmedical use of prescription opioids (POs) became a major public health crisis. In response to rising rates of opioid dependence and fatal poisonings, measures were instituted to decrease the prescription, diversion, and nonmedical use of POs including prescription drug monitoring programs (PDMPs), pain clinic laws, prescription duration limits, disciplining doctors who prescribed an excessive number of POs, and the advent of abuse deterrent formulations of POs. This paper explores the unintended effects of these policies in the descriptions of why people who use opioids transitioned from PO to injection or heroin/fentanyl use.MethodsWe conducted 148 in-depth-interviews with people who use prescription opioids nonmedically, fentanyl or heroin from a rural, urban and suburban area in three states, Connecticut, Kentucky and Wisconsin. Interviews with people who use opioids (PWUO) focused on how they initiated their opioid use and any transitions they made from PO use to heroin, fentanyl or injection drug use.ResultsThe majority of participants reported initiating use with POs, which they used for medical or nonmedical purposes. They described needing to take more POs or switched to heroin or fentanyl as their tolerance increased. As more policies were passed to limit opioid prescribing, participants noticed that doctors were less likely to prescribe or refill POs. This led to scarcity of POs on the street which accelerated the switch to heroin or fentanyl. These transitions likely increased risk of overdose and HIV/HCV infection.ConclusionsA careful analysis of how and why people say they transitioned from PO to heroin or fentanyl reveals many unintended harms of policy changes to prevent overprescribing and diversion. Results highlight the importance of mitigating harms that resulted from policy changes.

Aversion liquid-filled drug releasing capsule (3D-RECAL): A novel technology for the development of immediate release abuse deterrent formulations using a fused deposition modelling (FDM) 3D printer

COVID19 has caused a significant socioeconomic burden worldwide. Opioid crisis was further intensified with the increasing number of opioid overdose/misuse related deaths in last two years. Abusers have adopted newer/efficient methods for manipulating and abusing commercial opioid formulations. Food and Drug Administration (FDA) has been strategizing tirelessly to prevent misuse/abuse of prescription opioids. One of the strategies is to develop an abuse deterrent formulation (ADF). The current study aims to develop a novel 3D printed drug-releasing capsule shell filled with an aversion liquid (3D-RECAL). Primarily, metformin hydrochloride (MT, model drug) loaded printable filaments of polyvinyl alcohol was prepared using hot melt extrusion. Following extrusion, a 3D printed capsule shell was designed and fabricated using a single nozzle fuse deposition modelling 3D printer. An aversion liquid to be filled in 3D-RECAL capsules was prepared by combining sudan black and sodium polyacrylamide starch in oil base. Mechanical analysis of extruded filaments suggested that the filaments with 20%w/w MT had a higher mechanical strength compared to other drug loadings. Instantaneous gelling and large black non-snortable particles were formed during solvent extraction and physical manipulation studies, respectively. Due to the drug being embedded in the capsule shell, MT release was immediately started with >85% of MT release within 45 mins in 0.1 N HCl. Due to the everlasting need for the newer efficient ADF technologies, 3D-RECAL can be a step in the right direction towards saving lives, providing safe and effective measures to deterring abusers.

Impact assessment of the variables affecting the drug release and extraction of polyethylene oxide based tablets

The overall objective of this research is to investigate the impacts of the polymer's molecular weight and source on the abuse deterrent properties of the PEO-based promethazine hydrochloride (PMZ HCl) tablets. Formulations were manufactured by hot-melt extrusion and direct compression, followed by curing. Thermal and mechanical manipulation techniques were applied and compared to the intact tablets. The prime mechanism of the drug release was found to be represented by the diffusion-controlled mechanism and the first-order model for the direct compressed and the hot-melt extruded whole tablets, respectively. A robust Artificial Neural Network (ANN) model was built, and a significance testing analysis was performed to identify the criticality and the impact of the investigated variables on the % release of the active pharmaceutical ingredient (API). The results showed that the use of the polymer from different suppliers had the lowest impact on the % release per time point. Furthermore, we observed that the tablets produced by hot-melt extrusion had faster release rates than tablets produced by direct compression. Moreover, the extraction studies showed that the % API recovered from the hot-melt extruded tablets was significantly higher than the direct compressed tablets regardless of the polymer molecular weight. The findings were attributed to the polymer's thermal degradation during the hot-melt extrusion process, which caused a reduction in solution viscosity and crystallinity of the polymer. The syringeability studies showed that it was relatively harder to withdraw the solution from the DOW samples; however, the % recovered API was higher than samples containing the polymer from Sumitomo Seika.

Degradation Products of the Abuse Deterrent Agent Poly(Ethylene) Oxide Under Thermal Manipulation Conditions

Degradation Products of the Abuse Deterrent Agent Poly(Ethylene) Oxide Under Thermal Manipulation Conditions

Impact Assessment of the Variables Affecting the Drug Release and Extraction of Polyethylene Oxide Based Abuse Deterrent Tablets

Impact Assessment of the Variables Affecting the Drug Release and Extraction of Polyethylene Oxide Based Abuse Deterrent Tablets

Differential Effects of Cannabidiol and a Novel Cannabidiol Analog on Oxycodone Place Preference and Analgesia in Mice: an Opioid Abuse Deterrent with Analgesic Properties.

Background and Purpose: This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects. Experimental Approach: To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials. To determine if the doses of CBD or CBD-val-HS that blocked opioid reward would affect nociceptive processes, animals were enrolled in the hot plate and abdominal writhing assays when administered alone or in combination with a subanalgesic (1.0 mg/kg) or analgesic (3.0 mg/kg) dose of oxycodone. Key Results: Results from condition place preference demonstrated CBD was not able attenuate oxycodone place preference while CBD-val-HS attenuated these rewarding effects at 8.0 mg/kg and was void of rewarding or aversive properties. In contrast to CBD, CBD-val-HS alone produced analgesic effects in both nociceptive assays but was most effective compared with oxycodone against thermal nociception. Of interest, there was a differential interaction of CBD and CBD-val-HS×oxycodone across the two nociceptive assays producing subadditive responses on the hot plate assay, whereas additive responses were observed in the abdominal writhing assay. Conclusion: These findings suggest CBD-val-HS alone, a nonrewarding analgesic compound, could be useful in pain management and addiction treatment settings.

Public health strategies to combat opioid epidemic in the United States: A systematic review

Abstract Background The opioid epidemic in the United States is a national public health crisis. Driven by an increase in availability of pharmaceutical opioids and by an increase in their consumption, specifically, for pain treatment, more so in the past twenty years, it has led to an economic cost of prescription opioid abuse, overdose, and dependence in the United States estimated to be 78.5 billion USD. The purpose of this systematic review was to identify and evaluate public health strategies that contribute towards combatting the opioid crisis. Methods Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, a search was conducted of the PubMed database for articles in English language that analyzed the most effective ways to regulate health markets to decrease the opioid crisis in the United States. Results The initial search yielded 2397 titles, of which 15 full-text articles were ultimately selected for inclusion in this systematic review. The review identified four categories in overcoming this epidemic nationwide, including required improvement in patient utilization of and access to safe and effective treatment options for opioid abuse and overdose, addressing the stigma correlated with opioid use, considering appropriate use of abuse deterrent formulations (ADF) along with patient education, and improving prescribing practices via utilization of drug monitoring programs, CDC opioid prescribing guidelines and provider continuing education. Conclusions Attempts to combat the opioid epidemic have been made, and the state and federal governments have only recently started to understand the magnitude of the seriousness of this public health crisis. While the methods with promising improvement of the situation have been identified, implementing them has shown to be a challenge. Continued application is needed, while considering possible new steps that could help reinforce their utilization further. Key messages Attempts to combat the opioid epidemic have been made, and the state and federal governments have only recently started to understand the magnitude of the seriousness of this public health crisis. The methods with promising improvement of the opioid crisis situation have been identified, however utilizing and implementing the existing public health strategies has shown to be a challenge.

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance.

BackgroundOver the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of “drug liking,” “take drug again”), which are referred to as ‘pharmacodynamic (PD)’ responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs.MethodsExtensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11th, 2010 until March 25th, 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data.FindingsFollowing oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65.InterpretationOur assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs.FundingThe study was partially funded by Fiscal Year 2017 Critical Path of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

Evaluating the stability of opioid efficacy over 12 months in patients with chronic noncancer pain who initially demonstrate benefit from extended release oxycodone or hydrocodone: harmonization of Food and Drug Administration patient-level drug safety study data.

Opioids relieve acute pain, but there is little evidence to support the stability of the benefit over long-term treatment of chronic noncancer pain. Previous systematic reviews consider only group level published data which did not provide adequate detail. Our goal was to use patient-level data to explore the stability of pain, opioid dose, and either physical function or pain interference in patients treated for 12 months with abuse deterrent formulations of oxycodone and hydrocodone. All available studies in the Food and Drug Administration Document Archiving, Reporting, and Regulatory Tracking System were included. Patient-level demographics, baseline data, exposure, and outcomes were harmonized. Individual patient slopes were calculated from a linear model of pain, physical function, and pain interference to determine response over time. Opioid dose was summarized by change between baseline and the final month of observation. Patients with stable or less pain, stable or lower opioid dose, and stable or better physical function (where available) met our prespecified criteria for maintaining long-term benefit from chronic opioids. Of the complete data set of 3192 patients, 1422 (44.5%) maintained their pain level and opioid dose. In a secondary analysis of 985 patients with a measured physical function, 338 (34.3%) maintained their physical function in addition to pain and opioid dose. Of 2040 patients with pain interference measured, 788 (38.6%) met criteria in addition. In a carefully controlled environment, about one-third of patients successfully titrated on opioids to treat chronic noncancer pain demonstrated continued benefit for up to 12 months.