The ALERRT^® instrument: a quantitative measure of the effort required to compromise prescription opioid abuse-deterrent tablets

Abstract

Background: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT ® instrument (PinneyAssociates; Bethesda, MD) uses visual analog scales to assess the labor, effort, and resources necessary to physically compromise AD product candidates in standardized settings. Objective: Use the ALERRT ® instrument for testing morphine abuse-deterrent, extended-release, injection-molded tablets (ADER-IMT) 60 and 100 mg and the comparators immediate-release (IR) morphine sulfate 30 mg and extended-release (ER) morphine sulfate 60 mg. Methods: Four technicians tested the products using 10 household tools. The ALERRT instrument quantified effort (all tools) and time (3 preselected tools) required for manipulation. Results: Morphine-ADER-IMT 60 and 100 mg were difficult to manipulate, as demonstrated by high scores (mean range, 71.0−99.0 and 77.0−99.5, respectively). IR and ER morphine sulfate were easy to manipulate (low scores; mean range, 2.0−14.8 and 2.3−17.5, respectively). Statistically significant mean differences between morphine-ADER-IMT and comparators' ALERRT scores were observed. Manipulations of morphine-ADER-IMT 60 and 100 mg for 300 seconds failed to produce substantial powdering. Manipulations of IR morphine sulfate (mean range, 65.5−175.8 seconds) and ER morphine sulfate (49.3−163.0 seconds) produced substantial to complete powdering in 92% of tablets. Conclusions: Morphine-ADER-IMT was extremely difficult to manipulate versus non-AD formulations of morphine. The ALERRT system differentiated the degree of effort for manipulation of morphine-ADER-IMT and non-AD morphine formulations, indicating sensitivity of this instrument as part of Category 1 testing. By measuring the degree of effort required for manipulation, the ALERRT instrument provides an empirical assessment into the relative difficulty of manipulating opioid analgesics for abuse.

Mitigation of IV Abuse Through the Use of Abuse‐Deterrent Opioid Formulations: An Overview of Current Technologies

“…Syringeability and injectability studies that involved exposing untreated and heat‐pretreated morphine‐ADER‐IMT tablets to a variety of solvents produced a viscous mass with low syringeability (syringe content <10% of starting content), compared with 30% to 60% of non‐ADF ER morphine that was syringeable in volumes suitable for injection . In addition, an evaluation of the degree of effort required to manipulate morphine formulations with different household tools reported that morphine‐ADER‐IMT was extremely difficult to manipulate and required considerably more effort and time to manipulate than non‐ADFs of IR and ER morphine, which may reduce the attractiveness of morphine‐ADER‐IMT for misuse and abuse since it cannot be readily prepared for injection . None of the extraction tools enabled complete or substantial powdering of morphine‐ADER‐IMT, whereas using the same tools for manipulation resulted in complete or substantial powdering for 97.2% of IR morphine sulfate tablets and 77.1% of ER morphine sulfate tablets …”

“…In addition, an evaluation of the degree of effort required to manipulate morphine formulations with different household tools reported that morphine‐ADER‐IMT was extremely difficult to manipulate and required considerably more effort and time to manipulate than non‐ADFs of IR and ER morphine, which may reduce the attractiveness of morphine‐ADER‐IMT for misuse and abuse since it cannot be readily prepared for injection . None of the extraction tools enabled complete or substantial powdering of morphine‐ADER‐IMT, whereas using the same tools for manipulation resulted in complete or substantial powdering for 97.2% of IR morphine sulfate tablets and 77.1% of ER morphine sulfate tablets …”

Standardization of In Vitro Testing During Development of Abuse‐Deterrent Opioids: Highlights From the Second and Third Category 1 Focus Group Meetings

“…ADFs are specifically designed to deter the use of opioids via unintended routes of administration, including intranasal and intravenous routes, which have been reported to double the risk for life‐threatening events and death . During this period of technological progress, new methods to assess potential abuse‐deterrent (AD) characteristics of ADFs have also been developed . Although guidance documents have been published regarding the development and labeling of new ADFs, until 2016, none of these initiatives addressed the requirements for generic ADFs .…”

“…3 During this period of technological progress, new methods to assess potential abuse-deterrent (AD) characteristics of ADFs have also been developed. 4 Although guidance documents have been published regarding the development and labeling of new ADFs, until 2016, none of these initiatives addressed the requirements for generic ADFs. 5 In March 2016, the U.S. Food and Drug Administration (FDA) released a draft guidance titled "General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products" (referred to as the opioid generic drug [OGD] guidance in this commentary) to address generic ADFs, which was subsequently finalized in November 2017.…”

Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) vs Extended-Release Morphine Administered Intranasally in Nondependent Recreational Opioid Users

“…Morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) are a unique AD, ER morphine product candidate incorporating a proprietary technology (Guardian, Egalet Corporation, Wayne, PA, USA) that is a polymer matrix tablet with a novel manufacturing process, plastic injection molding. This technology results in ER tablets with physical and chemical features that resist both common and more rigorous methods of manipulation, which limits particle size reduction and extraction of the active pharmaceutical ingredient (API) [ 13 ]. Using a recently developed instrument, Assessing Labor, Effort and Resources Required for Tampering (ALERRT; Pinney Associates, Bethesda, MD, USA), morphine-ADER-IMT was shown to be extremely difficult to manipulate [ 14 ].…”