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.

The recent Draft FDA Guidance for Industry (Abuse-Deterrent Opioids Evaluation and Labeling) recognizes the need for safer opioids designed to deter abuse through their chemical structure. Current experience in the field has been with re-formulations of the drugs that are highly abused, hence the draft guidance does not provide specific consideration of new molecules with reduced abuse potential specifically engineered into the chemical structure. Since physical manipulation is not relevant in this setting, a new molecule with reduced abuse potential that is not subject to degradation or transformation of the chemical bonds to yield an abusable opioid may warrant an additional tier in the draft FDA guidance.

Background:

In an effort to address the continuing problem of prescription opioid abuse, manufacturers are incorporating new technologies into formulations that are designed to deter product tampering and misuse. Standards for laboratory assessment of tamper deterrent properties of new formulations have not previously been developed.

Methods:

Experimental designs were developed for the in vitro laboratory assessment of the tamper deterrent properties of reformulated oxycodone. Given that an exhaustive study of all potential tampering methods was impractical; this model was developed to evaluate the product in an incremental fashion with iterative changes that were amenable to objective and replicable laboratory testing.

Results:

A description of the model is provided along with pertinent examples involving assessment of reformulated oxycodone with comparisons to the original formulation. Physical and chemical procedures were developed that relate to “real-world” scenarios that may be applied to opioid formulations. Test results were interpreted in relation to the relative ease or difficulty of the manipulation as compared to control materials and the amount and purity of active drug that could be accessed. Results from some of the tests were designed to be useful in predicting whether specific tampering methods would facilitate or deter drug administration by different routes of administration.

Conclusions:

This model, developed to assess the tamper deterrent properties of reformulated oxycodone, should have application in the assessment of other drug formulations designed to exhibit tamper deterrence properties.

Objective:

Prescription monitoring programs (PMPs) are statewide databases containing prescriber and patient-level prescription data on select drugs of abuse. These databases are used by medical professionals or law enforcement officials to identify patients with prescription drug use patterns indicative of abuse or providers engaging in illegal activities. Most states have implemented PMPs in an attempt to curb prescription drug abuse and diversion. However, assessment of their impact on drug abuse is only beginning. This study aimed to evaluate the relationship between PMPs and opioid misuse over time in two drug abuse surveillance data sources.

Methods:

Data from the RADARS® System Poison Center and Opioid Treatment surveillance databases were used to obtain measures of abuse and misuse of opioids. Repeated measures negative binomial regression was applied to quarterly surveillance data (from 2003 to mid-2009) to estimate and compare opioid abuse and misuse trends. PMP presence was modeled as a time varying covariate for each state.

Results:

Results support an association between PMPs and mitigated opioid abuse and misuse trends. Without a PMP in place, Poison Center intentional exposures increased, on average, 1.9% per quarter, whereas opioid intentional exposures increase 0.2% (P = 0.036) per quarter with a PMP in place. Opioid treatment admissions increase, on average, 4.9% per quarter in states without a PMP vs 2.6% (P = 0.058) in states with a PMP. In addition to the time trend, population and a measure of drug availability were also significant predictors. A secondary analysis that classified PMP based upon ideal characteristic showed consistent though not significant results.

Conclusions:

Two observational data sources offer preliminary support that PMPs are effective. Future efforts should evaluate what PMP characteristics are most effective and which opioids are most impacted.

Stimulants are a diverse array of drugs that range from everyday caffeine to prescription medications and illicitly manufactured street drugs. The surveillance of misuse and abuse of stimulants many times confounds prescription and illicit street drugs such that the data are not specific enough to guide mitigation efforts or assess their impact. This review highlights the surveillance efforts that are conducted in the United States (US) for stimulant misuse and abuse. These surveillance efforts include national level surveys as well as reporting systems such as Poison Centers and emergency departments. This epidemiologic analysis has implications for interpreting the current known neuropharmacology of stimulants and possibly informing future neuropharmacology research that may contribute to a better understanding of potential neuropharmacologic factors influencing differing patterns of use, abuse, and adverse consequences associated with various stimulants. This article is part of the Special Issue entitled ‘CNS Stimulants’.

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.

The goal of this study was to measure the amount of “work” (ie, combination of time, effort, and resources) required to physically compromise the AD technology of EG-001 tablets compared with marketed formulations of immediate-release and extended release morphine using standardized manipulation techniques and a newly developed instrument, the Assessing Labor, Effort and Resources Required for Tampering scales (ALERRT tm; PinneyAssociates, Bethesda, MD), visual analog scales or VASs.

Multidrug use is well documented among nonmedical users of prescription stimulants. We sought to provide insight into the drug use patterns of those reporting nonmedical use of prescription attention-deficit hyperactivity disorder (ADHD) stimulants in an attempt to discern whether such use is a first step in a pattern of drug-abusing behavior or, conversely, is a later development accompanied or preceded by a history of drug abuse. A cross-sectional, population-based survey of the U.S. civilian, non-institutionalized population aged 12 years and older was analyzed for lifetime nonmedical use of prescription ADHD stimulants, lifetime nonmedical use of another prescription drug, illicit drug use, and drug use initiation patterns. This included 443,041 respondents from the 2002-2009 National Survey on Drug Use and Health. Lifetime nonmedical use of prescription ADHD stimulants was reported by 3.4% of those aged 12 years and older. Of these, 95.3% also reported use of an illicit drug (i.e., marijuana, cocaine/crack, heroin, hallucinogens, inhalants) or nonmedical use of another prescription drug (i.e., tranquilizers, pain relievers, or sedatives), and such use preceded nonmedical use of prescription ADHD stimulants in 77.6% of cases. On average, 2.40 drugs were used prior to the first nonmedical use of prescription ADHD stimulants. These data suggest that nonmedical use of prescription ADHD stimulants is not commonly an initiating factor leading to the nonmedical use of other prescription medications or abuse of illicit drugs. Rather, nonmedical use of prescription ADHD stimulants appears to be adopted by individuals already engaged in broader patterns of drug abuse and misuse.

The problem of prescription drug abuse in the United States began more than 100 years ago and became
epidemic in the last decade producing many tragic consequences with incredible societal costs. Drug overdoses have doubled over the last 10 years and now surpass deaths from motor vehicle accidents (DHHS, 2013). Congress reacted to this ongoing tragedy in 2012 by mandating the Food and Drug Administration (FDA) promulgate guidelines for the development of abuse-deterrent formulations (ADFs) for prescription opioid medications as one of the approaches to reducing this problem.The FDA responded in 2013 by issuing a draft guidance to industry for assessment of ADFs (FDA, 2013). The 2013 guidance expanded initial guidance proposed in 2010 (FDA, 2010).FDA is expected to issue final guidance for industry in the latter part of 2014.