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14 Articles in Volume 18, Issue #7
A 2018 Update: The Federal Pain Research Strategy
A Commentary on Medical Cannabis
Are Abuse-Deterrent Opioids Appropriate for Your Pain Patient?
Behind the AHRQ Report
Challenges Facing Abuse-Deterrent Formulations
Demystifying Opioid Abuse-Deterrent Technologies
Editorial: Our Clinical Pain Neighborhood
Independent Pain Practice: A Case Example
Inside Performing Arts Medicine
Letters to the Editor: ACT Therapy; Compounded Topicals
Nerve Growth Factor and Targeting Chronic Pain
Pain Control for Athletes: What Works?
Quality Training: One Center’s Experience with Pain Assessment
The Importance of Developing Professional Relationships in Pain Practice

Demystifying Opioid Abuse-Deterrent Technologies

A review of existing and emerging ADF products – and their potential implications on the opioid epidemic.

Continued struggles within the United States regarding the opioid epidemic has prompted the FDA and other government agencies to support change in the way opioid drugs are manufactured.1 A major effort in this regard is FDA’s support of the pharmaceutical industry’s development of new technologies and innovations that may allow for the safer prescribing of opioids. One such innovation is abuse-deterrent formulations (ADFs) of opioids, which began to enter the market in 2010 after the agency approved an ADF formulation of OxyContin; these formulations are geared toward deterring prescription opioid misuse and abuse by making the final substances difficult to crush, chew, gel, or dissolve.

Bumpy roadThe road ahead for integrating abuse-deterrent opioids into everyday pain practice may be bumpy. (Source: 123RF)

The purpose of this review is to outline the reasoning behind the emphasis on improving ADFs, the current FDA approval process for including ADF information in package inserts, and to highlight unique ADF technologies, including key differences that may impact prescribing and use.

Support for ADFs

In 2016, the CDC labeled prescription opioid misuse and abuse in the United States as an epidemic, citing that more than 3.8 million people in 2014, 12 years or older, reported illicit use of prescription opioid analgesics.2,3 In addition, the number of overdose deaths involving overall opioid analgesics (alone or combined with other substances, both legal and illicit) had increased by over 4.5-fold between 1999 and 2014.4 Not only did these trends result in significant morbidity and mortality, but they were also extremely cost-exhaustive. In 2009, it was estimated that the US dollar cost of prescription opioid abuse to society was around $55.7 billion; a number that has likely increased.5

The significant societal and economic impact caused by this crisis has led to serious rethinking of different formulation approaches. While the standard of care still supports the use of non-opioid pharmacologic and non-pharmacologic modalities as a first-line approach to manage pain, there are millions of patients who have significant and complex pathology that warrants long-term opioid analgesic use. Best practices also promote the use of extended-release opioids to help reduce baseline chronic pain, with the intermittent use of immediate-release (IR) opioids to help manage breakthrough pain as needed.

Notably, the 2016 CDC Guideline on Prescribing Opioids for Chronic Pain controversially suggested that extended-release (ER) opioids be used only after immediate-release products have been utilized.6 ER opioids are distributed into the bloodstream at a steady rate over a prolonged period of time and therefore contain, on average, 8 to 24 hours of opioid doses in a single oral formulation, or 3 to 7 days in transdermal patch formulations, when compared to their IR counterparts; IR formulations contain 3 to 6 hours, on average, of medication in a single unit. Thus, if ER dosage forms are manipulated in such a way that bypasses their ER mechanism, a higher payload of opioid may be immediately accessed, and thus, abused or misused. For this reason, ADFs are being emphasized as a potential means to help reduce prescription opioid abuse and misuse.

The definition of an ADF includes opioids that have one or more properties that work to increase the difficulty of abuse, making abuse less attractive, and/or less rewarding.1, 7 There are seven designated categories outlined by FDA for guidance on the development of ADFs, including:

  • physical/chemical barriers
  • agonist/antagonist combinations
  • aversion technologies
  • delivery system technologies
  • new molecular entities and prodrugs
  • different combinations of ADFs
  • novel approaches.1

See Tables I and II for details.1,7 Although the FDA’s regulation of ADF technology is still evolving, the agency has provided a framework for how a developer may pursue approval for product labeling indicating that their ADF opioid is likely to reduce abuse by specific routes of administration.1,7

Types of Abuse-Deterrent Properties(Table provided by author)

Table II has been corrected from its original printed version.

FDA-Approval of Abuse-Deterrent Labeling

To obtain FDA approval for abuse-deterrent labeling, sufficient evidence must be presented that indicates that the opioid’s abuse-deterrent properties are effective.1 In 2015, the agency released guidance for industry to describe how these new formulations are to be evaluated, including recommendations for how specific studies should be conducted and analyzed, and how labeling claims may be made given the results of these studies. The three premarket studies required include:

  • laboratory based in vitro manipulation and extraction studies (Category 1)
  • pharmacokinetic studies (Category 2)
  • clinical abuse potential studies (Category 3).1

The results of these premarket studies must then be confirmed by post-market trials (Category 4). The major difference between the three premarket categories and the post-market studies is that premarket studies focus on assessing the abuse-deterrent properties in a controlled setting.1 The major goal for the post-market studies is to determine whether the commercial availability of the product actually results in significant reductions in abuse, misuse, and adverse clinical outcomes in real-world scenarios.1 All post-market trial results have to be submitted to the FDA along with the results of Category 1-3 studies. To date, no pharmaceutical company or product has achieved Category 4 status.

Available Abuse-Deterrent Opioids with FDA-Approved Labeling

The following FDA-approved opioid products have product labeling that includes information regarding how their specific ADF technology may reduce abuse by specific routes of administration, including these branded medications:

  • Oxycodone products
    • OxyContin (Purdue Pharma)
    • Targiniq ER (Purdue Pharma)
    • Xtampza ER (Collegium Pharmaceutical)
    • RoxyBond IR (Inspirion Delivery Sciences and Daiichi Sankyo)
  • Morphine products
    • EMBEDA (Pfizer)
    • MorphaBond (Inspirion Delivery Sciences and Daiichi Sankyo)
    • ARYMO ER (Egalet)
  • Hydrocodone products
    • Hysingla ER (Purdue Pharma).

Note: Vantrela ER (Teva) and Troxyca ER (Pfizer) were removed by the manufacturers from FDA review in May 2018.

Table III outlines the major differences between these products in greater detail, however, they all incorporate specific information regarding abuse-deterrent studies in their package inserts. As shown in Table III, most of the formulations were designed with physical and chemical abuse-deterrent properties, including use of RESISTEC technology (Purdue Pharma) in OxyContin CR and Hysingla ER; SentryBond technology (Inspirion) in both MorphaBond and RoxyBond; Guardian technology (Egalet) in Arymo ER; and DETERx technology (Collegium Pharmaceutical) in Xtampza ER.

Opioids with FDA-Approved Labeling for Abuse-Deterrent Properties(Table provided by author)

Embeda ER has FDA-approved abuse-deterrent labeling that utilize the agonist/antagonist approach, and is co-formulated with naltrexone. While each has shown to be relatively effective in making it more difficult to abuse, it is extremely important to note that none of them absolutely prevent abuse, and every one still has potential for abuse through the ingestion of an amount greater than recommended.

Available Abuse-Deterrent Opioids without FDA-Approved Labeling

There are also a handful of opioids on the market that are formulated with abuse-deterrent properties, but do not have FDA-approved abuse-deterrent labeling. Manufacturers of these products have chosen to formulate their products with what they believe to be abuse-deterrent properties, however, have not provided sufficient evidence to FDA to gain approval for such labeling. Some of these products are listed in Tables I and II, as they are still categorized in the same manner as opioids with FDA-approved labeling: Zohydro ER (Pernix Therapeutics, Exalgo ER (Mallinckrodt Pharmaceuticals), Kadian ER (Allergan), Oxecta (Pfizer and Acura Pharmaceuticals), Xartemis XR (Mallinckrodt Pharmaceuticals), Oxaydo (Egalet), and Nucynta ER (Depomed).

Suboxone (Indivior), Zubsolv (Orexo), and Bunavail (BioDelivery Sciences) are all combination products that combine the partial opioid agonist/antagonist buprenorphine with the opioid antagonist naloxone.8 The function of naloxone is to bind and antagonize mu-opioid receptors, and because it has minimal oral absorption and low oral bioavailability, the only way it will act is if the above formulations are manipulated in such a way to allow for snorting, inhalation, or intravenous injection. Notwithstanding however, it remains puzzling that buprenorphine has a higher affinity toward the mu-opioid receptor compared to naloxone.9 Therefore, even if these formulations are abused in such a way that allows naloxone to be active, displacement of buprenorphine off of the mu-opioid receptor at high doses will likely fail to actually block and negate buprenorphine’s effects. At low doses, where overdose is not an issue, there will be some competitive binding for unoccupied receptors.10

The newest FDA-approved opioid with abuse-deterrent technology is Apadaz (KemPharm). The product combines benzhydrocodone and acetaminophen and uses Ligand Activated Therapy (LAT) technology, a novel prodrug platform in which one or more molecules or ligands are chemically attached to the parent drug (hydrocodone in this case).11 When the medication is administered orally, normal enzymatic processes in the gastrointestinal tract separate the ligand from the prodrug and release the parent drug (hydrocodone) to exert its therapeutic effect.11 An extended-release hydromorphone product (KP511/ER) which also uses LAT technology is still in clinical trials but, so far, has shown that serum hydromorphone levels increased more slowly and to a lesser extent after oral administration of excessively large doses of KP511/ER compared to oral doses of hydromorphone HCL in rats.12 Although this same principle should be true for Apadaz, per its package insert, results from oral and intranasal human abuse potential studies did not find an ability for Apadaz to deter abuse by either route.

Abuse-Deterrent Opioids in Development

There are a variety of opioid products still undergoing clinical trials or currently being developed with newer and advanced abuse-deterrent technologies (See Table IV). REL-1015 (Levocap ER, Relmada) is a levorphanol ER product in Phase 3 trials, and FT227 (Avadel Pharmaceuticals) is an ER hydromorphone product produced in Phase 2 trials. REL-1015 utilizes Relmada’s SECUREL technology that helps to prevent the product from being crushed through physical and chemical properties and also increases the difficulty for intravenous abusers to extract the active drug from the dosage form.14,15 FT227 utilizes Avadel’s Trigger Lock technology, which contains sustained-release Micropump-particles that are resistant to crushing, resistant from drug extraction through alcohol, water, and other mediums; the technology also prevents injection through viscosifying ingredients.14, 16

Abuse-Deterrent Opioids in Development(Table provided by author)

NKTR-181 (NEKTAR) is a novel chemical entity, long-acting, mu-opioid receptor agonist.17 Rapid entry through the blood-brain barrier by almost all mu-opioid receptor agonists is thought to be the reason for such fast and concentrated release of dopamine in the locus coeruleus, causing immediate euphoria – the primary mediator for addiction. This new mu-opioid agonist has a pegylated structure that allows for reduced permeability across the blood-brain barrier, so that its rate of entry into the brain is slowed.17 This would help attenuate dopamine release to minimize euphoria and possibly decrease the neuroplastic changes that ultimately lead to addiction.17 Preclinical data have shown that these properties do reduce the rate of entry into the brain compared to standard opioids, regardless of the route of administration.17 There are currently three Phase 3 trials underway that will help determine approval.

Practical Implications

When considering how to approach the design of an ADF, developers need to consider the ways in which opioids may be abused. For example, opioids may be manipulated and administered by different routes of administration for abuse including: oral, buccal (ie, chewing, sucking), inhalation, intranasal (ie, crushing, snorting), rectal, and intravenous. Often, an alternative route of administration is selected to achieve a shorter time (Tmax) to peak serum concentration (Cmax), which is associated with quicker penetration through the blood-brain barrier and increased likability of the drug. Route of administration ranked from fastest to slowest Tmax for most opioids is: inhalation, intravenous, intranasal, and oral.18

In a commentary, Budman and colleagues theorized that developing opioid ADFs could decrease the attractiveness for alternative routes of administration, thereby curbing the illegitimate use of opioids.18 A targeted approach in the development of opioid ADFs is to focus development efforts for the most commonly abused route of administration. Butler and colleagues surveyed more than 59,000 patients to determine the most common routes of administration for opioid abuse and discovered that hydrocodone was most often abused by being swallowed whole while morphine and hydromorphone were more commonly injected.19 In particular, morphine was more commonly injected than any other opioids. Oxycodone was most commonly abused intranasally and, when adjusting for the number of prescriptions, Oxycodone Controlled Release had the highest rate of abuse.19 In an earlier study by Butler, et al. that examined the history of opioid addiction, the authors determined that the likelihood of utilizing alternative routes of administration correlated with the length of time a user had been abusing prescription opioids.18,20 Through the development of strategically designed ADFs, it is therefore hoped that the progression of abuse by varying routes of administration may be avoided.

Conclusion

Given the extent of the recent opioid epidemic, abuse-deterrent opioid formulations offer a step in the right direction to increase difficulty for crushing or dissolving these products and thereby hasten the desire to abuse them. However, it should be noted that these products still have potential for being abused. Until recently, there was no opioid product on the market that deters one of the most common methods of abuse: simply swallowing multiple capsules or tablets. Benzhydrocodone (Apadaz) is one exception as of publication date that has shown decreased absorption when more than two tablets at a time are ingested. Ultimately, all opioid formulations must be able to deliver the opioid in some way to the patient, and therefore there may always be potential for subversion no matter the abuse-deterrent technology. Even in abuse-deterrent products that may successfully deter opioid abuse in the targeted route, the product may still be abused in a different way not previously considered in premarketing studies. For these reasons, prescribed opioids should always be closely monitored, and assessed and reassessed on a regular basis. While the expansion of commercially available ADFs is a move toward curbing the opioid epidemic, only time will tell whether these products successfully deter abuse and increase the safety of prescribed opioids.

See also, Nerve Growth Factor Targets Continue the Fight To Enter Market and PPM's Pain Scan literature review on this topic

Last updated on: October 24, 2018
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