Impact of Abuse Deterrent Formulations of Opioids in Patients With Chronic Pain in the United States: A Cost-Effectiveness Model.

OBJECTIVE: Opioid abuse is a significant public health problem in the United States. We evaluate the clinical effectiveness and economic impact of abuse-deterrent formulations (ADF) of opioids relative to non-ADF opioids in preventing abuse. METHODS: We developed a cost-effectiveness model simulating 2 cohorts of 100 000 noncancer, chronic-pain patients newly prescribed either ADF or non-ADF extended-release (ER) opioids and followed them over 5 years, tracking new events of opioid abuse and opioid-related overdose deaths in addition to tracking 5-year cumulative costs of therapeutic use and abuse of ADF and non-ADF opioids. Patients in each cohort entered the model for therapeutic opioid use from where they could continue in that pathway, discontinue opioid use, or abuse opioids or die of opioid overdose-related or unrelated causes. In addition, one-way sensitivity and scenario analysis were conducted. RESULTS: Over a 5-year time period, using ADF opioids prevented an additional 2300 new cases of opioid abuse at an additional cost of approximately $535 million to the healthcare sector. Threshold analyses showed that a 40% decrease in ADF opioid costs was required to attain cost neutrality between the 2 cohorts, whereas a 100% effectiveness in abuse reduction still did not result in cost neutrality. A 43% decrease in diversion with ADFs relative to non-ADFs was required to attain cost neutrality. Including a societal perspective produced results directionally similar to the base-case analysis findings. CONCLUSION: ADF opioids have the potential to prevent new cases of opioid abuse, but at substantially higher costs to the health system.

Application of hot-melt extrusion technology in immediate-release abuse-deterrent formulations.

OBJECTIVE: Hot-melt extrusion (HME) technology has been used for manufacturing extended-release abuse-deterrent formulations (ADFs) of opioid-type analgesics with improved tamper-resistant properties. Our objective was to describe application of this technology to immediate-release (IR) ADFs. DESIGN: For development of a sample IR ADF (hydrocodone 10 mg/acetaminophen 325 mg) based on HME, feasibility studies were performed using different excipients. The formulation selected for further development was evaluated via in vitro test battery. Moreover, in vivo performance of IR ADF technologies was investigated in an open-label, randomized, cross-over, phase 1, relative oral bioavailability study with another opioid (model compound). SETTING: Single-center bioavailability trial. PARTICIPANTS: Twenty-four healthy white male subjects. INTERVENTIONS: ADF IR formulation of an opioid and marketed IR formulation. MAIN OUTCOME MEASURE(S): For feasibility and in vitro studies, dissolution profiles, syringeability, particle size distribution after physical manipulation, and extractability were evaluated. For the phase 1 study, pharmacokinetic parameters were evaluated and compared for ADF IR and a marketed IR formulation. RESULTS: After manipulation, the majority of particles from the ADF IR formulation were >500µm and, thus, not considered suitable for intranasal abuse, while the majority of particles for the reference marketed IR formulation were <500µm. The ADF IR formulation was resistant to syringing and preparation for potential intravenous injection. In healthy subjects, pharmacokinetics of an ADF and marketed IR formulation of an opioid were nearly identical. CONCLUSIONS: Application of HME to IR formulations led to development of products with improved mechanical resistance to manipulation for intranasal or intravenous preparation, but similar bioavailability.

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

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.

Abuse-deterrent features of an extended-release morphine drug product developed using a novel injection-molding technology for oral drug delivery.

OBJECTIVE: A novel technology platform (Guardian™ Technology, Egalet Corporation, Wayne, PA) was used to manufacture morphine abuse-deterrent (AD), extended-release (ER), injection-molded tablets (morphine-ADER-IMT; ARYMO® ER [morphine sulfate] ER tablets; Egalet Corporation), a recently approved morphine product with AD labeling. The aim of this article is to highlight how the features of Guardian™ Technology are linked to the ER profile and AD characteristics of morphine-ADER-IMT. RESULTS: The ER profile of morphine-ADER-IMT is attributed to the precise release of morphine from the polymer matrix. The approved dosage strengths of morphine-ADER-IMT are bioequivalent to corresponding dosage strengths of morphine ER (MS Contin®; Purdue Pharma LP, Stamford, CT). Morphine-ADER-IMT was very resistant to physical manipulations intended to reduce particle size, with <10 percent of particles being reduced to <500µm, regarded by the US Food and Drug Administration as a relevant cutoff for potential insufflation in their generic solid oral AD opioid guidance. Furthermore, morphine was not readily extracted from the polymer matrix of morphine-ADER-IMT in small- or large-volume solvent extraction studies that evaluated the potential for intravenous and oral abuse. CONCLUSIONS: The ER profile and AD characteristics of morphine-ADER-IMT are a result of Guardian™ Technology. The combination of the polyethylene oxide matrix and the use of injection molding differentiate morphine-ADER-IMT from other approved AD opioids that deter abuse using physical and chemical barriers. The high degree of flexibility of the Guardian™ Technology enables the development of products that can be tailored to almost any desired release profile; as such, it is a technology platform that may be useful for the development of a wide range of pharmaceutical products.

Intranasal abuse potential of an abuse-deterrent oxycodone formulation compared to oxycodone immediate release and placebo in nondependent, recreational opioid users.

OBJECTIVE: To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone. DESIGN: 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. SETTING: Single site in Canada (INC Research Toronto). PARTICIPANTS: Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test. INTERVENTION: 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). MAIN OUTCOME MEASURE: Peak effect (Emax) for bipolar Drug Liking (0-100 point visual analog scale). RESULTS: Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p<0.001) median Drug Liking Emax relative to placebo. Significant reductions (p<0.001) in median Drug Liking [Emax] 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 Emax for IN ELI-200 (p<0.001) compared to IN oxycodone IR. CONCLUSIONS: 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.

Projecting the cost, utilization, and patient care impact of prescribing extended release non-abuse-deterrent opioids to chronic pain patients.

OBJECTIVES: To estimate healthcare resource utilization, associated costs, and number needed to harm (NNH) from a physician's decision to prescribe extended-release (ER) non-abuse-deterrent opioids (non-ADO) as compared to ER ADOs in a chronic pain population. DESIGN: A 12-month probabilistic simulation model was developed to estimate the reduction of misuse and/or abuse from a physician's prescribing decisions for 10,000 patients. Model inputs included probabilities for opioid misuse and/or abuse-related events, opioid discontinuation, and switching from ADO to non-ADO. Estimated reductions in abuse associated with ADOs were obtained from positive subjective measures using human abuse liability studies. The model was run separately for commercial, Medicare, Medicaid, and Veterans Administration (VA) populations. The difference in healthcare resource utilization and associated costs (2015 USD) between the ADO and non-ADO simulations was calculated. NNH for non-ADO was also calculated. RESULTS: Misuse and/or abuse-related events for patients prescribed ER non-ADOs ranged from 223-1,410 and associated costs ranged from $20-$98 per patient for commercial and Medicare populations, respectively. Prescribing ER ADOs were associated with 87, 289, 264, and 417 fewer misuse and/or abuse-related events, saving $8, $35, $21, and $29 per patient in commercial, VA, Medicaid, and Medicare populations, respectively. NNH ranged from 185 in the commercial population to 40 in the Medicare population. Results were sensitive to decreases in the probability of misuse and/or abuse events but showed reductions. CONCLUSIONS: A physician's decision to prescribe ER ADOs could lead to large reductions in misuse and/or abuse-related events and associated costs across many patient populations.