Abuse-Deterrent Opioids: A Primer for Pharmacists


The FDA is encouraging the development of new abuse-deterrent technologies to combat opioid abuse.

The use of prescription drugs for nonmedical purposes is a growing public health epidemic in the United States. Although the majority of patients take their medications appropriately, an estimated 52 million people have used prescription medications for illicit purposes at least once in their lifetimes.1

In the last 2 decades, there has been a significant increase in opioid prescriptions, from 76 million in 1991 to 207 million in 2013.2 This increase is likely due to a US campaign against inadequate pain management that led to changes in prescribing behavior and an increase in opioid prescriptions.3

In the wake of this initiative, prescription opioid abuse has become a significant problem in this country, with approximately 1.9 million Americans engaging in opioid abuse or experiencing dependence.4

In 2013, drug overdose was the leading cause of injury death, surpassing deaths caused by motor vehicle crashes. That year, the US Centers of Disease Control and Prevention (CDC) reported 43,982 drug overdose fatalities, 16,235 of which were linked to prescription opioids.5

A 2014 study published in JAMA Internal Medicine revealed that prescription opioids were involved in 67.8% of emergency department (ED) visits in 2010. The largest proportion of these opioid overdoses occurred in the South.6

Increasing drug overdose has played a significant role in the rising medical costs associated with opioid abuse. In 2007, prescription opioid abuse costs were about $55.7 billion in the United States.5

The most commonly prescribed opioids in the United States are hydrocodone and oxycodone. A CDC analysis of prescription trends found that Alabama, Tennessee, and West Virginia lead the nation in narcotic prescriptions.6

Hydrocodone and oxycodone have a street value of $0.81 per mg and $0.97 per mg, respectively.7 As a result, diversion of prescription opioids has increased substantially.

According the 2013 National Survey on Drug Use and Health, 67.6% of those who used prescription opioids for nonmedical reasons obtained them from a friend or relative by either stealing them, buying them, or receiving them as a gift.9

Opioids may be manipulated for abuse through methods such as swallowing whole, snorting, smoking, or injecting into the bloodstream. According to the National Institute on Drug Abuse, hydrocodone and oxycodone are most often abused by swallowing, snorting, or injection, while morphine is commonly abused by injection, swallowing, or smoking.10

To combat opioid abuse, the FDA is encouraging the development of new abuse-deterrent technologies. In 2015, the FDA released a draft guidance document entitled “Abuse-Deterrent Opioids: Evaluation and Labeling,” which was the first step towards discussing how abuse-deterrent technologies should be studied for FDA approval.

The FDA requires 3 types of pre-market studies: laboratory-based in-vitro manipulation and extraction, pharmacokinetic trials, and clinical abuse studies on recreational drug users. It also requires phase 4 post-market studies to assess meaningful clinical endpoints such as reductions in abuse, misuse, and other untoward outcomes.11

With the new industry guidance, the FDA hopes to see more medications with abuse-deterrent properties approved, potentially decreasing opioid abuse rates.

None of the most recently approved abuse-deterrent products are actually new drugs; rather, they are redeveloped formulations or delivery systems designed to minimize or eliminate unauthorized drug use and abuse while still providing efficacious treatment options for the millions of patients seeking genuine pain management.

While pharmacists are already familiar with the drugs themselves, the new formulations and technologies may not be as well-known.


RESISTEC Technology

RESISTEC is a proprietary technology that uses a combination of polymer and processing, leading to physiochemical barriers to prevent crushing, dissolving, and breaking. These properties decrease the risk of abuse potential from intravenous and intranasal routes.

The polymer responsible for RESISTEC physiochemical barriers is an excipient known as polyethylene oxide.12 This ingredient works by using 2 different mechanisms.

The first mechanism is an increased hardness of the tablet, which hinders the ability to break or crush it for intranasal administration. The second mechanism is the formation of hydrogel.

The medication is entrapped in the polyethylene oxide polymer and slowly released from the polymer. After water interacts with the polymer and diffuses inside it, the outer layer swells due to hydration reaction between water and polyethylene oxide.13

RESISTEC technology is used in the new extended-release (ER) hydrocodone (Hysingla ER).

Guardian Technology

This technology is similar to RESISTEC in that it provides physicochemical barriers to prevent crushing, dissolving and breaking. It also forms a gel when dissolved in water.

The main components of Guardian Technology are the coat and matrix, which create the zero-order release for the tablets, causing them to maintain a consistent release rate for the drug when taken.14

The main purpose of the coat is to decrease the diffusion rate of water into the dosage form. When water eventually reaches the matrix, however, it is eroded and the medication is released.

The drug concentration and rate of erosion are the variables that determine the rate of drug release. This leads to a more constant concentration of the drug in the body, with lower peak concentration compared to immediate-release formulations.

There are several opioid products currently under development that are using this technology. Due to these products undergoing development, no additional information on their exact mechanisms of abuse deterrence have been released at this time.15

OROS Technology

Despite its tablet appearance, the Osmotic Controlled-Release Oral Delivery System (OROS) is actually a semipermeable capsule with a laser-drilled hole in it. It has been used for years for a variety of extended- and delayed-release medications, and it is now being used for oral ER hydromorphone.

The drug is placed inside the hollow casing, and as the “tablet” moves through the body, water passes through the case and is absorbed by an expandable chamber, which slowly pushes the drug out through the hole over several hours for an extended effect. The hardened case functions as a barrier to drug abusers, making it extremely difficult to crush.16

Opioid Antagonists

The most common opioid antagonists used in the United States today are naloxone and naltrexone. These drugs are traditionally used to treat opioid overdoses or dependence; however, they are now being incorporated into a dosage form to decrease abuse potential.

There are 2 main layers: the opioid outer layer and the sequestered naloxone layer at the core of the dosage pellet. When taken appropriately, the opioid is released while the naloxone is contained inside the core membrane.

However, if the dosage form is broken or crushed, then the core membrane is shattered, leading to the release of naloxone, which will block the effect of the opioid.17

AVERSION Technology

This technology offers 2 abuse-deterrent mechanisms as a result of the unique use of common inactive pharmaceutical ingredients.

The first mechanism uses sodium lauryl sulfate, which induces nasal passage irritation and discomfort if the tablets are crushed and snorted.

Sodium lauryl sulfate is a surfactant commonly in household products such as detergents, soaps, and shampoos. When inhaled, it may cause irritation of the respiratory tract more specifically burning pain in the nose and throat.18

The second mechanism uses polyethylene oxide in efforts to impede the extraction of the active ingredient with the use of solvents suitable for intravenous injection such as water, alcohol, and saline. When the tablets are dissolved in a solvent, the polyethylene oxide forms a viscous gel mixture that entraps the active ingredient.19

The combination of these mechanisms limits the ability of common opioid abuse methods through intravenous injection and nasal ingestion. Oxaydo is an example of a medication formulated with abuse-deterrent properties of AVERSION Technology.

INTAC Technology

Similar to RESISTEC, this technology employs physiochemical barriers to impede non-oral methods of abuse such as chewing, snorting, and injecting.

It uses polyethylene oxide and a unique hot-melt extrusion process that combines both heat and pressure.20 The result of this combination is a tablet of immense strength with high resistance to crushing.

In-vitro tamper-resistant testing compared the percent release of the drug over time among crushed conventional ER tablets, crushed tablets with INTAC Technology, and unaltered tablets for intended use. Results showed that crushed INTAC tablets and the unaltered tablets for intended use gradually released the active drug over approximately 14 hours.

However, the crushed conventional ER formulation released approximately 98% of the active drug immediately, confirming the abuse-deterrent properties of INTAC Technology.21

In addition to crush resistance, INTAC also uses the excipient polyethylene oxide, which forms a viscous gelling matrix that traps the active ingredient when the tablets are dissolved in solvents such as water, alcohol, and saline. The viscous gel makes extraction extremely difficult, leading to low extraction rates for IV injection.22

There are currently 2 FDA-approved products using INTAC Technology: Oxycontin and Opana ER.20


Hysingla ER

Hysingla ER was approved as an abuse-deterrent opioid on November 20, 2014.23 It is used to alleviate pain throughout the day with once-daily dosing.

When prescribed to a patient who is not currently taking any opioid, initiate 20 mg by mouth daily without regard to meals. Only opioid-tolerant patients are recommended doses of 80 mg/day or more.24

Hysingla ER and immediate-release (IR) hydrocodone have different pharmacokinetic properties. The IR hydrocodone concentration curve contains multiple peaks and troughs, while Hysingla ER peaks in relatively a delayed manner. Hysingla ER peaks at approximately 14 to 16 hours, while IR hydrocodone peaks after approximately 1 hour and falls to trough after approximately 6 hours.

In addition, Hysingla ER has a lower peak concentration than IR hydrocodone.25 The higher, more frequent peaks may be the reason IR hydrocodone has more abuse potential than Hysingla ER.

A randomized, double-blind, active comparator study compared the abuse potential of intranasal Hysingla ER with powdered IR hydrocodone. Patients who intranasally administered Hysingla ER were found to have significantly lower mean drug liking scores of 65.4 versus 90.4 with powdered IR hydrocodone. In addition, the mean take drug again scores were 36.4 and 85.2 for Hysingla ER and IR hydrocodone, respectively.

Another study compared the abuse potential of intact Hysingla ER and IR hydrocodone solution. The mean drug liking scores for Hysingla ER and hydrocodone solution were 34.3 and 89.7, respectively, which was found to be statistically significant.26

The lower scores with Hysingla ER supports a lower addiction potential.

Embeda ER

Given every 12 to 24 hours, Embeda ER is indicated for severe chronic pain requiring daily, around-the-clock treatment.27 In opioid-naïve patients, the recommended dose is 20 mg given every 24 hours without regard to food.

On October 17, 2014, Embeda ER became the third FDA-approved opioid with abuse-deterrent labeling.28

In a randomized, double-blind, active control clinical trial comparing the abuse potential of Embeda ER with intranasal morphine ER, Embeda ER had a significantly lower abuse potential based on the 100-point visual analog scale (VAS). The results showed mean drug like VAS scores of 65.2 and 80.2 for Embeda and morphine ER, respectively.

A second randomized, double-blind, active control clinical trial compared the mean drug like VAS scores of crushed Embeda and crushed morphine ER dissolved in solution. The drug like VAS scores were found to be 65.2 and 80.6 for Embeda ER and morphine ER, respectively.

This study also showed a statistically significant reduction in drug like VAS scores with Embeda compared with crushed morphine ER dissolved in solution.27 Embeda ER has also been shown to have a lower risk of pruritus than IR morphine.27

The pharmacokinetic properties of Embeda ER and morphine sulfate ER are similar. The median time to peak is slightly shorter with Embeda ER at 7.5 hours, compared with morphine sulfate ER’s at 10 hours. In addition, Embeda ER and morphine sulfate ER both have a similar degree of bioavailability.

Reformulated OxyContin

Reformulated OxyContin was approved in 2010 with abuse-deterrent labeling updated on April 16, 2013.29

While the 2 previously described FDA-approved abuse-deterrent opioids are dosed once a day, reformulated OxyContin is initiated at 10 mg every 12 hours in opioid-intolerant individuals without regards to food.

The pharmacokinetic profile of the reformulated product is similar to the formulation that it replaced. Because the pharmacokinetic parameters are similar, the potential for oral abuse has not changed significantly.30 The key difference is that the reformulated product was redesigned to prevent crushing and ingestion through non-oral routes.

A randomized, double-blind, 5-period pharmacodynamic study compared the abuse potential of intranasally administered reformulated OxyContin with original OxyContin.

The results showed significant reduction of abuse potential in the reformulated OxyContin group compared with the original OxyContin group, with mean drug liking scores of 80.4 and 94.0, respectively. In addition, the mean take drug back scores were 64.0 and 89.6 for reformulated OxyContin and original OxyContin, respectively.30


Originally marketed as Oxecta, Oxaydo is an IR formulation of oxycodone indicated for the management of acute and chronic moderate to severe pain. Oxaydo is the first and only IR oxycodone that discourages intranasal abuse.

A double-blind, active comparator, cross-over study in 40 non-dependent opioid users compared the drug liking and single-dose safety of crushed Oxaydo tablets and crushed IR oxycodone administered intranasally.

The results demonstrated that 30% of non-dependent recreational users would not take Oxaydo again compared with 5% in the oxycodone IR group. Despite these results, the clinical significance of the difference in drug liking and response to taking drug again has not been established.31

Oxaydo is available in 5 mg and 7.5 mg tablets and has not shown any comparable difference to other IR oxycodone formulations in terms of absorption and blood concentrations. Initial starting dose ranges from 5 to 15 mg every 4 to 6 hours.

In the study, patients in the Oxaydo group reported decreased ability to completely inhale the tablet and higher incidence of nasopharyngeal and facial adverse effects.

The aforementioned properties may be beneficial in determining the role of Oxaydo compared with other IR opioid formulations. For example, Oxaydo may be more useful in patients who require lower doses of opioids with suspected histories of substance abuse.31


First approved by the FDA on March 1, 2010,32 Exalgo is an ER formulation of hydromorphone made with OROS technology.33 It is available in 8 mg, 12 mg, 16 mg, and 32 mg tablets, and it can be given at 24-hour intervals for chronic pain management.

There are already several generic equivalents of Exalgo available on the market.34

When compared to IR hydromorphone at varying doses, Exalgo showed lower concentrations in the blood initially, but actually produced higher levels in patients after multiple dosing periods. This was also beneficial considering that IR formulations were given 4 to 6 times a day, while Exalgo was only given once, which greatly reduces the pill burden for the patient.34

Furthermore, IR hydromorphone tablets showed an increased absorption as high as 35% when given with meals, while the ER tablets were minimally affected by food.34

Another benefit seen with Exalgo is its lack of “dose dumping” exhibited by earlier ER hydromorphone formulations. When these older tablets were mixed with alcohol, they would rapidly release hydromorphone, leading to several deaths.33

Exalgo’s stable drug release could be seen as a crucial safety feature to the patient by reducing the risk of opioid toxicity with long-term treatment of chronic pain.

Due to its potency and duration of action, Exalgo is only approved for chronic pain management in opioid-tolerant patients defined as those who have been taking 60 mg of oral morphine for at least a week, or an opiate dosing equivalent to this. Examples of this include anyone who has been using transdermal fentanyl 25 mcg/hr, 30 mg/day of oral oxycodone, 8 mg/day of oral hydromorphone, and 25 mg/day of oral oxymorphone, all for at least a week.33

Targiniq ER

Targiniq ER was approved on July 23, 2014, though it has not yet been released. The tablet is a 2:1 mixture of oxycodone with naloxone (10 mg-5 mg, 20 mg-10 mg, and 40 mg-20 mg, respectively) covered by a film coating.

The tablets are designed to be given orally on a 12-hour basis and have a similar starting dose as other ER tablets at 10 mg oxycodone every 12 hours. Targiniq exhibits the same kinetics as ER oxycodone does alone, but with the benefit of an added abuse-deterrent property.35


Opioid abuse is a growing concern in the United States. Following massive increases in opioid prescriptions over the past several decades, drug manufacturers and the FDA have joined forces to create new technologies with the goal of abuse deterrence.

In the last few years, drug companies have developed multiple mechanisms to reduce opioid abuse potential. Despite these efforts, it is important for pharmacists to remember that the newer formulations will not deter all forms of abuse.

Nevertheless, the abuse-deterrent formulations may become cornerstone opioid treatments in the years to come.

This article was collaboratively written with Brittany Willis, Aaron Garrett, and Robert Guice, who are all 2016 PharmD Candidates at Auburn University’s Harrison School of Pharmacy.


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