Introduction:  Oxycodone is an opioid analgesic medication with a high risk for abuse.  This systematic review examined and compared the effect of various opioid-deterrent formulations of oxycodone on their ability to reduce opioid abuse.  Three types of abuse deterrent formulations (ADF) were studied: Technology-Based ADF’s, Opioid Antagonist ADF’s, and Aversive Excipient ADF’s. 

Methods:  Twelve randomized controlled trials that were published in English, conducted in North America within the past 5 years, and studied abuse deterrent formulations of oxycodone were included. Search methods for identification of studies were conducted through Pubmed and Cochrane Central Register of Controlled Trials (CENTRAL). The primary outcome was the effect of ADFs on oxycodone formulation manipulation and opioid abuse trends in  patients prescribed ADFs. The secondary outcomes were adverse events, quality of life, adherence (primarily being used as prescribed), and patient experience of euphoria. All reviewers performed all data abstraction and quality assessment individually. 

Results: Technology- based formulations were shown to be both effective in preventing opioid abuse and had a much lower incidence of adverse effects. 

Conclusion:  Although educating patients remains the most important step in reducing the epidemic of opioid abuse and overdose, studying additional ways to deter and reduce abuse can be extremely helpful in furthering the abuse potential.

  

Abuse of opioid analgesics is a major problem that has increased substantially in the United States throughout the past decade. In 2015, the total opiate-related overdose deaths was 33,091, which is nearly four-times the death rate in 1999.¹ Opioid abuse is contributed to a reduced quality of life and an increased risk of death from overdose. Opioids are primarily prescribed for pain management.  However, they are easily accessible without a prescription. 
 

Patient experience, resources, education, access, and drug properties are among the factors that influence substance abuse.¹ Opioid analgesics are a treatment option for moderate to severe pain that are prescribed to millions of patients annually. Although opioids can be abused through oral ingestion, the frequency of abuse by injection or inhalation increases as the duration and severity of abuse increases.²  Figure 1 illustrates the contributing factors to opioid abuse.

There is a critical need to reduce the abuse potential of opioid medications. Studies indicate that abuse with prescription opioids is a strong risk factor for heroin use.^3,4 The incidence of heroin users is 19 times higher among those who use opioids for nonmedical reasons than those who report medical use.³ Another study found that 50% of persons ages 18 to 33 years who had recently began using heroin reported having abused opioids in the past.⁴

The primary outcome was the effect of ADFs on oxycodone formulation manipulation and opioid abuse trends in patients prescribed ADFs. The secondary outcomes were adverse events, quality of life, adherence (primarily being used as prescribed), and patient experience of euphoria. Search methods for identification of studies were conducted through Pubmed and Cochrane Central Register of Controlled Trials (CENTRAL). All reviewers performed all data abstraction and quality assessment individually.

The inclusion criteria for the systematic review was inclusion of the terms “oxycodone,” “abuse deterrent,” “opioid,” “abuse resistant,” and “randomized.” The studies were all published in English and conducted in North America. Exclusion criteria were studies not published in English, conducted outside of North America, not relevant to the safety and efficacy of abuse deterrent formulations, and not evaluating oxycodone.

Data Collection
Three review authors independently assessed all the titles and abstracts identified as a result of the search strategy. Twenty-seven articles were collected on the search, 12 fit inclusion/exclusion criteria. Thirteen articles were not relevant to the study subject, as they were found to later fit the exclusion criteria and 2 publications were found to be published presentations. Three types of ADFs were evaluated in the data collected: opioid antagonist formulations, technology-based formulations, and aversive excipient-based formulations.

The three abuse deterrent formulation categories were ranked on an efficacy scale of 1-to-3, with 1 meaning highly effective and 3 meaning least effective. The efficacy was evaluated based on patient reported feeling, adverse events, and potential adherence. Of the studies included, nine were categorized as technology-based formulations, two as opioid antagonist formulations, and one as aversive excipient-based formulations. The previous drug effects were compared with adverse events to indicate how effective treatments were. In the rare occasions that the researchers disagreed on the ranking of the articles, they discussed the discrepancies until a consensus was reached.

Results
The following three tables describe the articles that were included in the systematic review. All three categories had similar efficacy results and were shown to prevent abuse. However, their safety profiles and types of abuse they prevented differed slightly.

Technology-based formulations such as DETERx (Table 1) are both safe and effective. These formulations have been found to statistically significantly prevent opioid abuse. When these medications are crushed, they have been found to maintain similar pharmacokinetics as when intact, thus lowering the likelihood of illicit use by crushing. This formulation also allows these medications to be available for patients who have trouble swallowing or require a G-tube for medication administration. These medications were also not found to have significantly different adverse effects than immediate release or extended release oxycodone.

Medications formulated with opioid antagonists such as naloxone or naltrexone (Table 2) have been found to be relatively effective in preventing abuse, particularly by non-oral routes such as intravenous injection and insufflation. These formulations have similar safety effects as current FDA-approved opioid analgesics.  However, adverse effects are common when they are crushed or chewed. This limits the use of these medications in patients who have trouble swallowing or require the use of a feeding tube for medication administration.