Abuse Deterrent Research Articles

Abuse deterrence testing: A dose ratio escalation study examining naloxone coadministered with intravenous hydromorphone in non-treatment-seeking, opioid-dependent drug users.

To assess the reduction in intravenous (IV) abuse potential of hydromorphone from different dose ratio combinations with naloxone in opioid-dependent drug users. Randomized, blinded, dose ratio escalation study. Single center. Following conversion to a stable IV dose of hydromorphone, 12 non-treatment-seeking, opioid-dependent subjects were randomly assigned and received at least one dose of study drug; seven subjects received all five study treatments. Five subjects withdrew early from the treatment phase: adverse events (2) and participant decision (3). Participants underwent a dose-selection phase to stabilize on an individualized hydromorphone dose. Stable subjects were dosed intravenously on 5 consecutive days. The dose received was one of five hydromorphone/naloxone dose ratios that included the combination of hydromorphone and placebo naloxone. Hydromorphone/naloxone treatment always involved increasing dose ratios of naloxone (8:1, 6:1, 4:1, and 2:1) with the hydromorphone-placebo naloxone treatment randomly assigned within the sequence of dose ratios. Drug Liking visual analog scale (VAS), Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS). Hydromorphone/naloxone placebo produced subjective effects typical of opioid administration, while hydromorphone/naloxone dose ratios were associated with significant increases in SOWS and OOWS scores (p < 0.05). Compared with hydromoprophone/naloxone placebo, naloxone reduced the effects of hydromorphone on most measures, including Drug Liking VAS, the antagonism was greatest for the 4:1 and 2:1 ratios. This study was an ethical investigation of the abuse deterrence potential of four hydromorphone/naloxone dose ratios. The IV coadministration of commercially available IV solutions of hydromorphone and naloxone in 4:1 and 2:1 ratios had statistically greater reductions of abuse-related opioid effects and triggers of withdrawal symptoms and there was a convergence of subjective and objective pharmacodynamic results and safety findings. An oral modified-release product, developed with a 2:1 hydromorphone/naloxone ratio, may have important public health benefits by reducing high-risk, IV abuse of prescription opioids, while providing pain relief when ingested orally and used in accordance with the Product Monograph.

Pain Control in the Presence of Drug Addiction.

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.

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

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.

(430) Bioequivalence and food effect of a novel, abuse-deterrent (AD), extended-release (ER) morphine product candidate compared with a currently available non-AD, ER morphine product

Abuse-deterrent (AD) formulations of opioids have been deemed an important component of risk mitigation for opioid abuse. A novel morphine AD extended-release (ER), injection-molded tablet (ADER-IMT) product candidate has been developed using proprietary Guardian™ technology (Egalet Corporation, Wayne, PA) utilizing an injection molding manufacturing process that produces hard tablets that are resistant to rigorous physical and chemical manipulations. The bioequivalence of morphine ADER-IMT and a marketed non-AD morphine ER product were assessed in two phase 1, randomized, open-label, single-dose, crossover studies in healthy adults aged 18–55 years. In study 1 (n=66), fasted subjects received oral morphine ADER-IMT (30 mg), morphine ER (30 mg), or morphine ADER-IMT (2 × 15 mg) in 3 sequential periods. In study 2, one cohort (n=40) received morphine ADER-IMT (60 mg) or morphine ER (60 mg) under fasting conditions in 2 treatment periods; a second cohort (n=25) received morphine ADER-IMT (60 mg) under fed conditions in an additional treatment period. In both studies, all subjects received naltrexone 50 mg before and after each study drug administration. Pharmacokinetic parameters for morphine included area under the plasma concentration vs time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t), AUC from time 0 extrapolated to infinity (AUC0-inf), and maximum plasma concentration (Cmax). Bioequivalence criteria were from Food and Drug Administration guidelines. In study 1, (fasting conditions) bioequivalence was demonstrated among all 3 treatments (morphine ADER-IMT [30 mg], morphine ER [30 mg], and morphine ADER-IMT [2 × 15 mg]) for all 3 pharmacokinetic parameters. In study 2, bioequivalence (fasting conditions) was demonstrated between morphine ADER-IMT (60 mg) and morphine ER (60 mg); further, the fed/fasted analysis demonstrated no clinically relevant food effect for morphine ADER-IMT (60 mg). Morphine ADER-IMT was generally well tolerated with no unexpected adverse events. Funded by Egalet Corporation.

(444) Clinical results of an abuse potential study with REMOXY®, an abuse deterrent, extended release product

(444) Clinical results of an abuse potential study with REMOXY®, an abuse deterrent, extended release product

(425) Dissolution studies in the presence of alcohol with an abuse-deterrent, extended-release morphine product candidate

Some extended-release (ER) opioid formulations may be prone to rapid drug release (dose dumping) when co-ingested with alcohol, potentially causing toxicity, overdose, and even death. Dissolution testing in the presence of various concentrations of alcohol to assess the potential for dose dumping was conducted with a novel morphine abuse-deterrent (AD), ER, injection-molded tablet (morphine ADER-IMT) product candidate. Morphine ADER-IMT applies proprietary Guardian™ technology (Egalet Corporation, Wayne, PA) that uses a novel plastic injection molding process for manufacturing the tablets. Dissolution of morphine ADER-IMT (15-mg, 60-mg, and 100-mg dosages) was evaluated (n=12) at 37ºC±0.5ºC in 900 mL 0.1 N HCl (pH 1.2; reflecting gastric pH) or buffer (pH 6.8; reflecting intestinal pH) media containing 0, 5, 10, 20, and 40% ethanol, using a standard United States Pharmacopeia apparatus. Morphine release was measured by high-performance liquid chromatography with an ultraviolet detector (285 nm) at 15, 30, 45, 60, 75, 90, 105, and 120 minutes. All dissolution profiles for morphine ADER-IMT 15 mg and 60 mg complied with f2 profile comparison test criteria, indicating comparable dissolution profiles among aqueous (0% ethanol) and ethanol-containing media. The 100-mg dosage demonstrated a significantly slower dissolution in 40% ethanol and therefore did not pass the f2 test. Ethanol in concentrations of 5%–20% had no clear effect on dissolution rates in either pH 1.2 or pH 6.8. However, a trend showing a decrease in dissolution rates for all dosages was observed with increasing ethanol concentrations, and a significant decrease in dissolution rate was observed with 40% ethanol. No evidence of alcohol dose dumping was observed with morphine ADER-IMT, and slower dissolution rates occurred at higher alcohol concentrations. Funded by Egalet Corporation.

(145) Relative abuse of abuse deterrent formulations via alternative oral routes

(145) Relative abuse of abuse deterrent formulations via alternative oral routes

(263) A model to quantify potential medical events avoided and cost savings from abuse deterrent opioids

(263) A model to quantify potential medical events avoided and cost savings from abuse deterrent opioids

Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations

Prescription drug products abuse/misuse is epidemic in United States. Opioids drug forms major portion of prescription drug product abuse. Abuse deterrence formulation (ADF) is one of the many approaches taken by sponsors to tackle this problem. It involves formulating opioids into dosage forms that will be difficult to abuse/misuse. Current investigation focused on evaluating the abuse deterrent properties (ADP) of ADF manufactured by direct compression method. Effect of process and formulation variables on ADP was investigated by statistical design of experiment (fractional factorial design). Independent factors studied were molecular weight of polyethylene oxide (Polyox™), curing time, temperature and method, and antioxidant type. Sotalol hydrochloride was selected as a model drug. ADP investigated were hardness/crush resistance, syringeability and injectability, physical manipulation (reduction into powder) and drug extraction in water and alcohol. Hardness and syringeability are evaluated by newly developed quantitative procedure. Other properties were also investigated such as morphology, crystallinity, assay and dissolution. The hardness and drug extraction was significantly (p<0.05) affected by curing temperature. Formulations could be powdered in 3min irrespective of their hardness. Syringeability and injectability were intrinsic properties of the polymer used in the formulation, and were not affected by the investigated factors. Crystallinity of the polymer and drug changed, and was dependent upon curing temperature and time. The dissolution and assay were independent of formulation and process parameters studied. In conclusion, the study indicated some advantages of ADF product compared to non-ADF prepared by direct compression. However, the ADF should not be viewed as abuse proof product rather as incrementally improved product.

PC-FACS

PC-FACS

Will a Better Mousetrap Help when You Work in a Lion’s Den? What is the Role of Abuse Deterrent Pharmaceuticals in Hospice and Palliative Care? (FR460)

Will a Better Mousetrap Help when You Work in a Lion’s Den? What is the Role of Abuse Deterrent Pharmaceuticals in Hospice and Palliative Care? (FR460)

Risk based in vitro performance assessment of extended release abuse deterrent formulations

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.

Abuse Deterrent Opioid Formulations: A Review

Over last decade the number of prescriptions for opioid analgesics has been increased. Opioids are essential in the management of pain in many patients, but they are associated with the potential risks for abuse, overdose and mortality. There are number of efforts made in the development of abuse deterrent formulations of opioids to reduce these risks. These formulations deter or resist the abuse of opioid analgesics. Different types of abuse deterrent formulations of opioids have been or are currently being developed with the potential to reduce abuse and other risks associated with opioids. This article summarizes the potential for prescription opioid abuse, development of various abuse deterrent opioid formulations, patented abuse deterrent technologies and various abuse deterrent formulations currently in market.

A Reality Check: The Need for a Deeper Understanding of Opioid Abuse Treatment Options: A Policy Statement From the American College of Clinical Pharmacology.

Most clinical pharmacologists agree that prescription drug abuse is no longer just a trending topic; it has reached epidemic levels in the United States. Although the United States makes up less than 5% of the global population, 80% of the opioids and 99% of the hydrocodone used in the world are used by people in the United States.1 Members of the American College of Clinical Pharmacology (ACCP) are intimately involved with the development of novel drugs, many for the treatment of chronic pain. The ACCP is uniquely positioned to serve both its membership and the public by providing scientific knowledge to optimize research, development, and the utilization of medication for the benefit of all, which is the vision of the organization. This position paper asserts that increased physician, pharmacist, and scientific researcher education is the best way to create a better understanding of opioid abuse and dependence as well as its treatment. Understanding, acceptance, and the promotion of supervised treatment options such as combined psychotherapy with Suboxone treatment paradigms provide rapid and significant lifesaving options as compared to programs relying on complete abstinence. Additionally, the FDA's recent guidances2, 3 supporting the development of abuse deterrent formulations of opioids and the thorough evaluation of the potential of a new chemical entity (NCE) to be abused has been proposed to prevent the widespread tampering that currently occurs through both patient abuse and general diversion of the supply.

Impacts of drinking-age legislation on arrests for alcohol-impaired driving among young people in Canada, 2009–2012

Aims: Provide an overview of FDA’s evaluation of novel abuse deterrent (AD) opioid products. Methods: Abuse and misuse of opioid drug products is a public health concern. One approach for managing the problem is reformulation of the products tomake them safer and less euphorigenic. Current efforts focus primarily on making the products more difficult to “manipulate” for injection, insufflation and inhalation. The development, assessment, and regulation of AD formulations of opioid products that are less prone to abuse or misuse is a policy priority. The FDA Center for Drug Evaluation and Research developed guidance to evaluate and label ADopioid formulations (2013), and held public meetings. Results: Premarket assessment of AD products involves three categories of studies. The first category consists of in-vitro manipulation and extraction studies to evaluate whether the AD features of a new formulation can be compromised under experimental conditions. Pharmacokinetic (PK)/pharmacodynamic (PD) studies (second category) are designed tounderstand the in vivoproperties of the new formulation by comparing the PK profiles of the “manipulated” formulationwith the intact formulation and other drugs by one or more routes of administration, and to collect PD data such as adverse events due to administration of themanipulated formulation. In the third category, the relative abuse potential of the AD formulation (intact and manipulated) is studied in human abuse potential studies. Results of the premarket assessment are used for labeling. As FDA gains experience in the evaluation of AD products, questions arise regarding science-based approaches to appropriately characterize the deterrent properties and to support labeling of the products. Conclusions: Abuse-deterrent technologies and evaluation methodology are rapidly changing. FDA recognizes the need to identify the best approaches to characterize these products to support labeling. Financial support: N/A.

Regulatory challenges in evaluating the abuse deterrent properties of novel opioid products

Warmer and drier conditions over the past decade in California, in addition to court-mandated restrictions on the Sacramento River Delta water supply, have generally reduced the amount of water resources available to Southern California. These constraints on water supply led water agencies to implement a range of water conservation and watering restrictions programs, mostly targeted at outdoor use. The City of Los Angeles, the largest of 88 cities in the County of Los Angeles and the most populous in the United States, took several measures to attempt to reduce residential water consumption. Three phases of water restrictions were implemented during the 2008–2010 period: voluntary restrictions (FY2008), mandatory restrictions (FY2009), and yet more stringent mandatory restrictions combined with a price increase and a decrease in overall household allocations (FY2010). Our research aims at quantifying the impact of these increasing restrictions on single-family residential water use across the City. Ten years of monthly individual billing data (2000–2010) were obtained from the Los Angeles Department of Water and Power (LADWP), the municipal utility for the City. Monthly single-family customer water use records at the Public Use Microdata Area level from 2000 to 2007 were used to develop and validate a linear regression model that integrated unemployment and climate information during a period without restrictions. Predictions from the model were then compared to actual consumption to assess the impact of water restrictions during the 2008–2010 period. We also contrasted voluntary water restrictions counseled by LADWP with mandatory water use restrictions. Results show that more stringent mandatory outdoor watering restrictions combined with pricing measures were most effective and resulted in a 23% decrease in City average single-family water use during summer of FY2010. Voluntary restrictions in FY2008 were less effective in reducing water use.

Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety.

We read with great interest the article entitled ‘Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety’ by Simon and colleagues, published in the April 2015 Issue of Therapeutic Advances in Drug Safety [Simon et al. 2015]. We agree with the authors that Federal abuse-deterrent formulation (ADF) policy does not reflect the urgency of the prescription drug abuse epidemic and does not go far enough toward changing the status quo. We also agree with the authors that policies must also require federal prescription drug benefit plans to cover ADFs to ensure consumers have access to such medications. However, we disagree with the statement ‘ADFs have been proven to reduce prescription drug abuse and its consequences, and even an incremental reduction in abuse can have a significant impact on the nation by reducing the costly social, physical, mental, and public health problems resulting from abuse’. The study by Coplan and colleagues [Coplan et al. 2013] was quoted as the main reference to support the argument by Simon and colleagues that ‘ADF have been proven to reduce prescription drug abuse and its consequences…’. However, in the study by Coplan and colleagues, what was additionally reported was a 20% increase in abuse exposure for other single-entity oxycodone, and 42% increase in abuse exposure for heroin, concomitant with the 36% decrease in abuse exposure for reformulated extended-release (ER) oxycodone (ADF). Coplan and colleagues also acknowledged that reformulating one product’s tablets will not treat opioid addiction, and substitution of other available opioids is likely to consequently occur. Michna and colleagues examined the degree of adherence to the ER opioid, following its switching to a reformulated ER opioid (ADF), and found some patients changed to other ER opioids without abuse-deterrent technology or discontinued ER opioids [Michna et al. 2014]. The conclusion of their study was that abusers may seek more easily abusive alternatives. These include prescription opioids without abuse deterrent technology. Preliminary data suggest that the reformulation of opioids to resist tampering may influence media attention, recreational user preferences, and opioid availability in ways that may in turn alter their attractiveness to recreational users [Romach et al. 2013]. ER oxymorphone abuse has been mentioned in popular media only since recreational users began to recognize it as an alternative to the reformulation of ER oxycodone (ADF), which is designed to be tamper-resistant. Increased public awareness of higher potency with oxymorphone ER and the difficulties of tampering with reformulated ER oxycodone may have lessened abuse of ER oxycodone and made ER oxymorphone a preferred choice for some recreational users [Romach et al. 2013]. Indeed, total oxymorphone prescriptions increased sharply from 268,000 in 2007 to 1.22 million in 2012. In the first quarter of 2011, 325,000 oxymorphone prescriptions were dispensed by retail pharmacies [Drug Enforcement Administration, 2013]. According to the Drug Abuse Warning Network (DAWN ED), total estimated emergency department visits associated with oxymorphone increased from 4599 in 2010 to 12,122 in 2011. The American Association of Poison Control Centers reported 1041 total oxymorphone exposures in 2011, an increase from 169 in 2010 [Drug Enforcement Administration, 2013]. To examine the change in prevalence of prescription opioid abuse after introduction of an abuse-deterrent formulation oxycodone ER in August 2010, Cassidy and colleagues conducted a cross-sectional study, and found significantly greater abuse of oxymorphone ER and buprenorphine, coinciding with the introduction of ADF oxycodone ER [Cassidy et al. 2014]. Cassidy and colleagues conclude that replacement of a widely prescribed opioid with ADF formulation may have had little effect on overall prescription opioid abuse as a class. Another issue of great concern is escalating heroin abuse since the introduction of reformulated ER oxycodone (ADF) to the market. There were 119,000 total users in 2003, but 281,000 by 2011. In addition, first-time past-year use nearly doubled between 2005 and 2011. The death rate of heroin overdose from the 28 states (surveyed) doubled, from 2010 to 2012, from 1.0 to 2.1 per 100,000 [Rudd et al. 2014]. Heroin overdose death rates increased significantly for both sexes, all age groups, all census regions, and all racial/ethnic groups other than American Indians/Alaska Natives. In conclusion, at this point, the introduction of ADF opioids has resulted in significantly reduced abuse of those specific ADF opioids after they have fully replaced the original formulations. However, this has resulted in merely a shift away from the ADF opioids to other traditional non-ADF opioids or heroin, and unfortunately, no effect on the overall rates of opioid abuse.

Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate-release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax ) and effect occurring over 2 hours postdose (AUE0-2 h ). Crushed ALO-02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax , 60.5 vs 92.8; AUE0-2 h , 105.4 vs 160.0, respectively) and High (Emax , 25.2 vs 86.9; AUE0-2 h , 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO-02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO-02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.

Jurisdictional differences in opioid use, other licit and illicit drug use, and harms associated with substance use among people who tamper with pharmaceutical opioids.

The harms associated with non-medical use of pharmaceutical opioid analgesics are well established; however, less is known about the characteristics and drug-use patterns of the growing and hidden populations of people using pharmaceutical opioids illicitly, including the frequency of pharmaceutical opioid injection. This paper aimed to undertake a detailed examination of jurisdictional differences in patterns of opioid use among a cohort of people who regularly tamper with pharmaceutical opioids in Australia. Data were drawn from the National Opioid Medications Abuse Deterrence study. The cohort was recruited from New South Wales (NSW; n = 303), South Australia (SA; n = 150) and Tasmania (TAS; n = 153) to participate in face-to-face structured interviews collecting data on use of pharmaceutical opioids, benzodiazepines, other sedative drugs and illicit substances, as well as the harms associated with substance use. TAS participants reported greater use and injection of certain pharmaceutical opioids (particularly morphine and methadone tablets), and limited heroin use, with lower rates of engagement in opioid substitution treatment, compared with NSW participants. NSW participants were more socially disadvantaged and more likely to report risky injecting behaviours and injecting-related injuries and diseases compared with SA and TAS participants. SA participants reported greater rates of pain conditions, greater use of pain-based services, as well as broader use of pharmaceutical opioids in regards to forms and route of administration, compared with NSW participants. Distinct jurisdictional profiles were evident for people who tamper with pharmaceutical opioids, potentially reflecting jurisdictional differences in prescribing regulatory mechanisms and addiction treatment models.

(419) Analysis of adverse events of interest reported to the FDA before and after the introduction of abuse deterrent formulation of extended-release oxycodone (OxyContin)

(419) Analysis of adverse events of interest reported to the FDA before and after the introduction of abuse deterrent formulation of extended-release oxycodone (OxyContin)