Expert Opinion on Drug Metabolism & Toxicology
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Safety and performance of current abusedeterrent formulations
Rand Ahmad, Samaneh Alaei & Hamid Omidian
To cite this article: Rand Ahmad, Samaneh Alaei & Hamid Omidian (2018) Safety and
performance of current abuse-deterrent formulations, Expert Opinion on Drug Metabolism &
Toxicology, 14:12, 1255-1271, DOI: 10.1080/17425255.2018.1546289
To link to this article: https://doi.org/10.1080/17425255.2018.1546289
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EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
2018, VOL. 14, NO. 12, 1255–1271
https://doi.org/10.1080/17425255.2018.1546289
REVIEW
Safety and performance of current abuse-deterrent formulations
Rand Ahmad, Samaneh Alaei and Hamid Omidian
College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
ARTICLE HISTORY
ABSTRACT
Introduction: Prescription opioid abuse is now an epidemic that has forced the government and
industries to take initiatives. These include developing abuse-deterrent formulations (ADFs), issuing
regulatory guidances and allocating massive budgets to ensure the safety and effectiveness of these
medications.
Areas covered: This review covers the regulatory guidance on evaluation and labeling of the branded
and generic ADFs. It also includes the relevant patents and technologies, the in-vitro, in-vivo, the postmarketing data, the FDA reviews, and the products’ labeling of the FDA-approved products with abusedeterrent features.
Expert opinion: Despite the development of a dozen products with abuse-deterrent features, most of
these technologies rely on the same deterrent agent, making it easier for abusers to focus their
manipulation efforts and share their experience to defeat the technology. Further advancement in
the field requires developing more robust, more diverse, safer, and affordable deterrent technologies
for the extended- and immediate-release opioid products. Moreover, advances in the reporting of the
post-market results, issuance of policies in support of the ADFs, and concurrent monitoring of the illicit
opioid market are other considerations that can further help in confronting the epidemic.
1. Introduction
Opioid painkillers are analgesics used to manage severe pain
such as lower back pain and pain experienced by cancer
patients or patients undergoing major surgeries [1]. Misuse,
abuse, overdose, subsequent health complications, and death
have been associated with the use of this class of prescription
analgesics, representing the prescription opioid epidemic.
The emergence rate of new nonmedical use of prescription
drugs estimated to be around 5,700 cases/day in 2013 [2]. In
2012 alone, 259 million prescriptions were filled [3], reflecting
the ease of obtaining prescription drugs as a result of overprescribing [4]. Despite the later awareness about the addiction potential associated with opioid analgesics, more than
half of the Americans in 2017 were prescribed opioids with
even an increased number of days per prescription, 18 days on
average [5]. The emergency rooms have also recorded a high
number of visits related to the prescription opioid abuse,
around 488,000 visits in 2011 [2]. According to the CDC, the
sales of prescription opioid drugs have quadrupled from 1999
to 2014, and this was paralleled by increased overdose deaths.
The deaths among young adults (18–25 years old) were
reported to be more than 1,700 in 2014, mainly due to prescription opioid overdosing [6]. In the US alone, the number of
deaths has increased over the years, exceeding 16,500 cases in
2016, again as a result of overdosing prescription opioids [7].
This number is reported to be five times higher than in 1999
[5]. In connection with the high number of deaths in 2016, the
cases of prescription opioids misuse were reported to reach
CONTACT Hamid Omidian
omidian@nova.edu
S University Drive, Fort Lauderdale, FL 33328, USA
© 2018 Informa UK Limited, trading as Taylor & Francis Group
Received 14 March 2018
Accepted 6 November 2018
KEYWORDS
Opioids; abuse-deterrent;
formulation; technology;
post-marketing; safety;
toxicity
11.5 million cases, out of which 2.1 million were the first time
misuse [8]. The problem of abusing prescription opioids also
affected the economy. In 2016, the White House proposed
$1.1 billion to treat opioid-use disorder as part of tackling
the epidemic of abusing illicit and prescription opioids [9].
In 2017, an overall cost of the prescription opioid abuse was
estimated around $78.5 billion [10]. Prescription drug abuse
continues to be a burden on the health care and the economy
at a significant national scale, driving Federal government,
pharmaceutical industries, academic institutions, and most
recently insurance companies to combat this crisis.
In response to the prescription opioid epidemic, a dozen of
abuse-deterrent formulations (ADFs) have been developed.
These formulations are equipped with technologies to resist
the drug products’ manipulation and abuse by alternate routes
(Figure 1) while maintaining the proper drug release when used
as intended. Methods of manipulating the opioid products
include crushing/chewing the tablets for oral administration, coingestion of the drug product with alcohol, oral administration of
multiple units of the drug product, crushing the drug product
into fine particles for intranasal (IN) administration, and crushing
and dissolving the drug product in a solvent suitable for intravenous (IV) administration [11]. These methods of manipulation
aim to achieve a faster drug release and rapid onset of euphoric
effect. Among all, the IV drug administration may be considered
the most dangerous route of abuse [12–14]. The drug is injected
directly into the bloodstream, increasing the risk of overdose and
death, as well as hepatitis C and HIV infections.
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, 3200
1256
R. AHMAD ET AL.
Article highlights
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The number of deaths due to prescription opioid abuse was over
16,500 in 2016 with an estimated cost of ~ $78.5 billion in 2017.
Prescription opioid abuse is a complicated problem, exposing abusers
to subsequent overdose health complications as well as toxicities
derived from the excipients, the impurities, and the degradants of
the manipulated drug and excipients; in particular when taken at
larger amounts than allowed and administered via a non-oral route.
The currently marketed ADFs, in general, have shown promise in
reducing prescription drug abuse based on various pre-market studies
and the available post-market surveillance.
Despite the promising outcomes, the two major challenges left to be
tackled are the liability to abuse by multiple oral administration of
intact dosage units and the limited availability of the post-market
data.
Safer, more robust, more diverse, and cheaper deterring technologies
need to be developed for both the extended- and immediate-release
dosage forms.
The unlimited number of ways that a prescription opioid can be
manipulated calls for the FDA to continuously revise its guidelines to
better evaluate the abuse-deterrent capability of the submitted ADFs.
Further success and promise with the ADFs can be reinforced by the
Government and State policies in support of their development, prescription, and insurance coverage.
This box summarizes key points contained in the article.
In addition to developing ADFs to combat the opioid drug
epidemic, the FDA has outlined guidelines for their in-vitro
and in-vivo evaluations. Products are evaluated based on the
anticipated routes of abuse along with the characteristics of
the deterrent technology utilized in each product. There are
currently 17 approved products (Table 1), some acquired the
FDA abuse-deterrent labeling, while others failed to fully comply with the FDA requirements despite exhibiting some abusedeterrent features.
This paper collectively reviews the FDA regulatory considerations in evaluating the ADFs and the status of the approved
products, their formulation, and manufacturing technologies,
Figure 1. Abuse-deterrent technologies used in the FDA-approved products.
in-vitro and in-vivo testing, safety, and post-marketing data,
where available. It is paramount to periodically review the
available data for these products. This allows for the early
detection of any flaws in their technologies and formulations
as well as the associated challenges in the field, which may
emerge over time (e.g., study design challenges, potential
toxicities).
2. FDA considerations for evaluating and labeling
ADFs
Two guidances have been issued by the FDA [18,19], one for the
branded products and another for the generics, both presenting
general recommendations to assess the ADF products.
2.1. The FDA guidance for the branded ADFs
The FDA guidance assessing the branded products was finalized
in April 2015. It describes the various categories of the ADFs
based on the tamper-resistant technologies that they utilize. In
principle, these categories are either dependent on the formulation or on the new discoveries as described in Figure 1. In
addition to the ADFs’ categories, the guidance describes the premarket and post-market studies required for their evaluations.
The pre-market studies involve three categories of testing; the invitro manipulation studies, the in-vivo pharmacokinetic studies,
and the in-vivo clinical abuse potential studies. The post-market
studies include a formal epidemiological surveillance as well as
supportive studies. Table 2 provides a full description of the preand post-market studies. The study design should take into
consideration the formulation, the abuse-deterrent technology,
all the anticipated routes of abuse, the appropriate positive
controls, comparators, placebos, and the results of the earlier
studies (e.g., the best extracting solvent determined from the
category 1 studies should be used in the category 2 pharmacokinetic studies).
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
1257
Table 1. Summary of the products with abuse-deterrent features.
Product
name
Arymo ER
Embeda
Exalgo
Hysingla ER
Nucynta ER
Morphabond
ER
Opana ER
Oxaydo
Deterring technology
Guardian™: A crush and extraction resistant, injection- molded
matrix
Agonist/Antagonist: A sequestered antagonist
OROS: A crush resistant semipermeable membrane and an
extraction resistant core
RESISTEC™: A crush and extraction resistant thermallycompressed tablet
INTAC®: A crush and extraction resistant melt-extruded matrix
SentryBond™: A crush and extraction resistant controlledrelease formulation
Roxybond
INTAC®: A crush and extraction resistant melt-extruded matrix
Acura’s Aversion®: Extraction resistant and nasal irritating
formulation
RESISTEC™: A crush and extraction resistant thermally
compressed tablet
SentryBond™: A crush and extraction resistant formulation
Suboxone
Targiniq ER
Troxyca ER
Agonist/Antagonist: Drug-antagonist matrix
Agonist/Antagonist: Drug-antagonist matrix
Agonist/Antagonist: A sequestered antagonist
Vantrela ER
OraGuard™: A crush and extraction resistant controlled-release
matrix
Xartemis XR
Depomed’s Acuform and Mallinckrodt’s Technology:
Extraction resistant formulation
DETERx®: A crush and extraction resistant controlled-release
matrix
OxyContin
Xtampza ER
Zohydro ER
BeadTek™: Extraction resistant matrix
Main deterring
agent(s)
PEO*
ADF
labeling
Yes
Naltrexone HCl
Yes
Cellulose acetate
PEO*
PEO*
PEO*
Acrylate
copolymer
Alginic acid
PEO*
PEO*
SLS
PEO*
Acrylate
copolymer
Alginic acid
Naloxone HCl
Naloxone HCl
Naltrexone HCl
FDA status (deterred route(s))
IV
Marketing
status
Available
Available
No
IV upon crushing, IN, and oral
upon crushing
_____
Yes
IV, IN, and oral upon chewing
Available
No
Yes
IV and IN
No
No
Available
_____
Available
Available
_____
_____
Withdrawn
Available
Yes
IV and IN
Available
Yes
IV and IN
No
Yes
Yes
_____
IV and IN
IV upon crushing, IN, and oral
upon crushing
IV, IN, and oral
Approved,
not
marketed
Available
Discontinued
Discontinued
Glyceryl
behenate■
HPMC
PEO*
Yes
Beeswax¤
Carnauba wax¥
Myristic acid§
PEO*
Yes
No
No
_____
IV and IN
Discontinued
Discontinued
Available
_____
Available
* Toxic to the endothelial cells by the IV route [108].
■Emits irritating fumes upon thermal decomposition by smoking [15]
¤ A natural excipient with toxicity concerns due to residual environmental and apicultural contaminants [95]
¥ Emits irritating fumes upon thermal decomposition by smoking [16]
§ Poisonous by the IV route and emits irritating fumes upon thermal decomposition by smoking [17]
There are different challenges and limitations associated
with each testing category. For instance, the design of category 1 studies should anticipate the various tampering methods and conditions that abusers may use. These methods
could be manual (e.g., crushing with a spoon or hammer) or
mechanical (e.g., coffee grinder). A major limitation with the
manual manipulation methods is the variances in the applied
force among different subjects, complicating the assessment
process, and questioning the credibility of the results.
Moreover, these studies should consider all the possible routes
of abuse that in turn increase the cost, time, and the volume
of the generated data.
The challenges relevant to the category 2 studies include
some specific circumstances where the test product cannot be
evaluated for a specific route of abuse. For instance, if the
presence of an excipient prohibits the IN administration of the
product, the study should exclude the assessment of the IN
route. Moreover, the manipulated products utilized in the
studies must be reproducible to minimize the variation in
the results. This requires skilled and knowledgeable personnel
capable of preparing consistent samples [20].
The category 3 studies are challenged by the sample reproducibility as well as the inability to use the crossover design in
certain instances. This design is recommended for the studies
that measure the subjective outcomes such as in the clinical
abuse potential studies. However, when blinding the test and
positive control products after manipulation is not possible,
another study design should be used. For example,
a manipulated crush-resistant ADF can have coarse particles,
while the non-ADF control can be crushed into fine powder. In
this case, since the subjects can distinguish the difference in
the physical appearance between the two products, a parallel
group study design should be considered.
The category 4 studies face more challenges as drug abuse
and the related outcomes are under-reported by the abusers.
Furthermore, the change in the population between the preand post-market study periods is another issue. For instance,
the centers that capture the cases of abuse, misuse, overdose,
etc. (e.g., poison center, treatment center), may relocate during
the study period, invalidating the reference baseline for comparison. The misclassification of the abused product and data
inaccuracy (e.g., the number of the abused drugs, single or
multiple routes of abuse) can further confound these studies.
Moreover, controlling for the concurrent interventions that
impact the outcomes is another important consideration. For
example, overlooking the policies addressing the prescription
opioid epidemic leads to underestimated or overestimated
outcomes. Lastly, the post-market studies should involve the
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R. AHMAD ET AL.
Table 2. The required studies for the evaluation of the branded ADFs.
Study
Pre-market studies
Category 1
(Laboratory
manipulation
and extraction
studies)
Objective
Study conditions and requirements
Evaluate the deterring characteristics and capacity - In-vitro study
- Employing various manipulation conditions expected to
alter the drug release or enable drug administration by
an alternate route (e.g., heating, cooling, agitation,
grinding, solvent addition, etc.)
- Use of a manipulated comparator product
- Testing the dissolution of intact and manipulated
products
- For extraction studies: Use of intact comparator and test
products
- For smoking studies: Use of pure active ingredient
comparator, in salt and base forms
Category 2
Determine the PK parameters of the manipulated - In-vivo study
(Pharmacokinetic
formulation
- Employing the manipulation method(s) that resulted in
studies)
the maximum drug release in Category 1 studies
- Use of intact test product and intact and manipulated
comparators
- Studying the food and alcohol effects
- Evaluating one or more routes of administration
relevant to the test product
- Sampling at different points to cover the onset, peak,
and offset of the effects
- For the oral route: The participants are healthy
volunteers who are under naltrexone blockage
- For the nasal route: The participants are subjects with
history of nasal abuse
Category 3 (Clinical Evaluate the clinical impact
- In-vivo study
abuse potential
- Applying a randomized, double-blind, crossover,
studies)
placebo- and positive-controlled study design is
preferred
- Employing the manipulation method(s) that resulted in
the maximum drug release and plasma concentrations
in Category 1 and Category 2 studies
- Application of a prequalification phase; to exclude
participants who cannot distinguish the placebo effect
from the drug effect
- Pre-qualification dose ≥lowest test dose; to exclude
participants who cannot tolerate the dose of the test
drug, especially for multi-dosing studies
- Applying a test dose which is known to produce a high
level of drug liking in recreational users
- Evaluating the route of administration relevant to the
test product
- The participants are recreational drug users experienced
with the route of abuse under evaluation
- For agonist/antagonist combination products: The
participants may include physically dependent
population to evaluate the antagonist effect in
precipitating withdrawal symptoms
- Use of Visual Analogue Scales (VAS) for the assessment,
bipolar or unipolar
Post-market studies
Category 4 Formal Determine if meaningful reductions in abuse,
- Existence of a study hypothesis
studies
misuse, addiction, overdosing, and death have - Conduction of multiple studies by referring to different
been achieved in real-world post-approval
data sources to encompass the interrelated behavioral,
settings
clinical, and societal factors contributing to drug abuse
- Full understanding of the data sources
- Use of multiple branded and generic comparators
- The participants are the general population with at least
one study involving high-risk population while not
being restricted to this specific population only
- Running the study for sufficient duration
- Compliance with good epidemiological practice
- Validation of self-reported assessments
- Considering both population and drug utilization bases
to estimate the outcomes
- Considering the variables (e.g., demographic and
geographic) that may affect the results
Category 4
Provide additional data on abuse and abuse- Use of data sources that capture diversion, tampering
Supportive
deterrence to help in the interpretation of the
practices, prescribing trends, and street prices of
information
formal studies
prescription drugs
- Inclusion of specific populations of interest is highly
recommended
Outcomes
- Quantity of the opioid
extracted upon
manipulation
- Ease of drawing the drug
solution into a syringe
- For agonist/antagonist
products: Quantity of the
opioid antagonist
released upon
manipulation
- Maximum concentration
(Cmax)
- Time to Cmax (tmax)
- Area under the curve
(AUC0-t, AUC0-∞)
- Relevant partial AUC
(AUC0–30, AUC0–2)
- Terminal elimination halflife (t1/2)
- Rate of rise of drug
concentration
Primary endpoint:
- Immediate drug liking
Secondary endpoints:
- Retrospective overall drug
liking
- Retaking the drug
- High
- Alertness
- Drowsiness
- Nausea
- For the nasal route;
Intranasal irritation,
runny nose, facial pain,
nasal congestion
Profile of subjective effects:
- Onset of effect
- Rate of rise to reach onset
- Peak duration
- Offset of effect
- Abuse (frequency and
prevalence)
- Misuse (frequency and
prevalence)
- Addiction
- Overdose
- Death
-
Abuse
Misuse
Addiction
Overdose
Death
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
Table 3. Principles for the comparative evaluation of the generic products to
their referenced ADFs.
Principle
Tier-based
approach
Requirement
Gradual increase in the
complexity of the
manipulation conditions
with the subsequent tiers
PerformanceComprehensive knowledge
based
of the route of abuse
assessment
under evaluation and its
appropriate measures
Comprehensive knowledge
of the abuse deterrence of
the referenced ADF for the
route under evaluation
Most effective
Tampering with the product
manipulation
under different thermal,
mechanical, physical, and
chemical conditions, and
identifying all the
parameters of
manipulation
Sample selection As a minimum, the intact
drug product and the
most effectively
manipulated one
Comparative
Validation of the reference
extractability
point;
studies
<50% of the drug can be
extracted from the most
effectively manipulated
referenced ADF within
30 minutes in any tested
solvent and thermal
condition
Studies with
Oral: Bioavailability
respect to all
assessment upon
probable routes
ingesting chewed or
of abuse
physically manipulated
products
Parenteral: Extractability and
syringeability studies for
both intact and
manipulated products
Nasal: Bioavailability and
pharmacodynamic studies
of sniffed manipulated
products
Inhalation: Sublimation
potential studies on intact
and manipulated products
Rational
Ascertain testing
efficiency
Avoid unnecessary steps
Compare products with
different formulation
designs
1259
products in the oral PK studies. These studies are conducted to
ensure a proper sequestration and minimal absorption of the
antagonist. Another category of products with special recommendations is those incorporating aversive agents other than
the ones in the referenced ADFs. In this case, neither in-vitro
testing nor PK studies are feasible options. The pharmacodynamic studies that determine the clinical abuse potential (e.g.,
desire to retake the drug) could alternatively be used.
3. FDA-approved ADFs
Maximize the extraction
of the abusable agent
Assess the two extreme
forms
Evaluate the abuse
deterrence equivalency
between the tested
generic product and
the referenced
branded ADF
Assess the ruggedness of
the products toward
all possibilities of
abuse
surveillance of multiple comparators, and the results should
be adjusted for the population and prescription variables [21].
This requires an increased workload and time for collecting
and analyzing the data.
2.2. The FDA guidance for the generic ADFs
Generic opioids need to be safe and effective and display
comparable abuse deterrence to the branded ADFs. The guidance, issued in 2016, and finalized in November 2017, is
pertinent to solid oral opioid generics. It describes the general
basics for demonstrating a deterrence equivalency between
the generic products and their referenced ADFs (Table 3).
The guidance provides some specific recommendations
with regards to particular types of ADFs. For instance, in
agonist/antagonist combinations, both ingredients must be
quantified in the oral and nasal PK studies using manipulated
products. Such ADFs also require an evaluation of the intact
3.1. Agonist/antagonist combination
3.1.1. Embeda
In 2009, the FDA approved an ADF that could interfere with
the pharmacological effect of morphine sulfate if the product
is manipulated. Embeda extended-release capsules (Pfizer Inc.)
is composed of multilayer pellets, where each pellet contains
morphine sulfate and sequestered naltrexone HCl at a ratio of
25:1. The drug release profile in Embeda is controlled by
hydrophobic polymers (ethyl cellulose and methacrylic acid
copolymer) that coat the morphine sulfate layer. The sodium
chloride underneath the drug layer also contributes to the
drug release due to its osmotic activity [22].
Crushing the pellets is associated with an immediate release
of morphine and naltrexone from the dosage form. The antagonist would, in turn, block the μ-opioid receptors upon an IN or IV
administration. On the other hand, the oral administration of
the intact capsules results in an adequate morphine release and
low plasma concentrations of the sequestered naltrexone (if
any). This assures the absence of the antagonistic effect when
the medication is used as intended [23–25].
The integrity of the naltrexone sequestering coat after
administering the crushed and intact Embeda capsules was
evaluated in-vivo. The plasma levels of 6-β-naltrexol (naltrexone metabolite) were measured because the metabolite is
more bioavailable. The results assured the rigidity of the polymeric coat upon the regular use of the product [26]. The study
also revealed that the oral administration of the intact and
crushed Embeda, in comparison with morphine sulfate solution, were associated with significantly lower mean scores for
drug liking and drug high effects. These outcomes were attributed to the controlled-release delivery system of morphine
and the release of naltrexone, respectively [26]. In another
study, the oral abuse potential of morphine was compared
between crushed Embeda and crushed ER morphine. The
crushed Embeda, due to naltrexone release, showed statistically significant lower mean and median scores for the abuse
potential responses [27].
A study by Setnik et al. [28], examined the IN abuse potential
of crushed Embeda versus crushed non-ADF ER morphine.
Despite having lower abuse potential measures with the crushed
Embeda, 22–30% of the subjects in this study showed no reduction in the drug liking and drug high. In another study examining
the IV abuse potential, the results indicated significantly lower
drug high, drug liking, and euphoria for morphine/naltrexone
combination or placebo than morphine alone [29].
It was reported that morphine dose dumping (up to 5 fold Cmax)
is probable if co-ingested with 40% alcohol, while the naltrexone
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R. AHMAD ET AL.
core remains intact [30]. Furthermore, the FDA determined that the
oral abuse of the crushed beads is possible due to the fact that it
was accompanied by euphorigenic effects [30]. The safety review
of Embeda during its first year of marketing revealed that the most
frequent adverse events were headache, nausea, pruritis, drug
ineffectiveness, and drug withdrawal syndrome [31]. While the
first three are the expected adverse effects of morphine, the drug
ineffectiveness and withdrawal syndrome could be due to either
the lower high experienced by the abusers with these formulations
or an inferior performance of the sequestering coat and the subsequent release of naltrexone [32].
The published post-marketing data of Embeda included
a case report by Ruan et al. [33], where a 50-year-old man
suffering from severe opioid withdrawal symptoms was
brought to the hospital. It was shown that the man crushed
the product for oral abuse. Another case of withdrawal symptoms associated with the oral abuse of Embeda was reported
by Jang et al. [34].
3.1.2. Targiniq ER
In September 2013, Purdue Pharma, L.P. submitted an NDA for
oxycodone HCl/naloxone HCl extended-release tablets. The
product was approved by the FDA in July 2014. Unlike
Embeda, the antagonist in Targiniq is not sequestered and
the abuse-deterrent property of the product relies on the
physical and chemical difficulty of tampering with the formulation to separate the two drug molecules from each other
[35]. Thus, abusing Targiniq by the IN or IV route is associated
with an antagonistic effect exerted by naloxone.
Characterized by its low oral bioavailability (≤2%), naloxone
does not interfere with the legitimate oral drug use [36]. The
product itself has no claims on oral drug abuse due to the fact
that the systemic naloxone concentration is clinically insignificant to block the agonist’s effect if a chewed or crushed tablet
is ingested [37].
Targiniq was available in three strengths, 5 mg/10 mg,
10 mg/20 mg, and 20 mg/40 mg (naloxone/oxycodone). Due
to an intolerance to higher doses of naloxone especially in the
fed state where the opioid withdrawal symptoms may appear
[37], the product was never marketed at higher strengths.
Targiniq ER is currently discontinued.
3.1.3. Troxyca ER
Developed by Pfizer, Troxyca is an extended-release capsule
consisting of oxycodone HCl and naltrexone HCl pellets. The
product has been discontinued despite the fact it was
approved by the FDA in 2016. The deterrence mechanism
utilizes an agonist/antagonist approach [38] where naltrexone
is sequestered in the pellet core. However, the sequestering
coat can be disrupted if the pellets are crushed or dissolved in
the selected organic solvents. This results in naltrexone release
at concentrations sufficient to limit the euphoric effect of
oxycodone [39]. On the other hand, the abuse-deterrent
antagonist remains sequestered and preserves the therapeutic
effectiveness of oxycodone if the product is used as intended.
A study by Setnik et al. [40] reported lower high and drug
liking scores upon an oral abuse of crushed Troxyca compared
to crushed oxycodone IR formulation at similar doses
(P < 0.0001). Since the bioavailability of Troxyca and the
referenced non-ADF product was comparable, it was proposed
that the lower scores are due to the antagonist effect of
naltrexone released after the pellets were crushed [39]. In
another study [41], Setnik et al. investigated the IN abuse
potential of the crushed Troxyca pellets, and they observed
lower scores with the ADF compared to oxycodone IR and
placebo (P < 0.0001).
The relative IV abuse potential of oxycodone HCl combined
with naltrexone HCl (mimicking the IV administration of Troxyca
ER) was evaluated by Backonja et al. [42]. The results suggested
that Troxyca ER can deter the IV drug abuse if the capsule
contents are crushed. In assessing the alcohol-induced dose
dumping, the study showed no change in the Cmax value when
the drug was administered with 20% ethanol. However, coingestion with 40% ethanol was associated with a 37% increase
in the Cmax, suggesting a potentially fatal overdose if Troxyca ER
is co-administered with high concentrations of alcohol [43].
3.2. Physical/chemical barriers
3.2.1. OxyContin
Oxycodone HCl tablets of Purdue Pharma L.P. was formulated
as a controlled-release dosage form and approved by the FDA
in 1995 [44]. The product, designed to gradually release the
active agent over time with a slower onset and lower Cmax,
was thought to reduce addiction. However, abusers could
effectively tamper with the controlled-release formulation. In
an attempt to reduce the drug abuse, Purdue reformulated
the extended-release tablets late in 2007.
The new formulation contained thermally cured high molecular weight poly(ethylene oxide) (PEO) [45], and the FDA
approved the product in 2010. The first FDA-approved ADF
resists crushing/chewing using standard methods of manipulation. Further, the product impedes syringing/injecting using
aqueous solvents and resists dose dumping upon co-ingestion
with alcohol [46]. Despite all the improvements, the reformulated product was still vulnerable to crushing and extraction
using unconventional tampering methods.
A placebo-controlled study evaluated the pharmacokinetics
and pharmacodynamics of crushed reformulated tablets administered intranasally. The original OxyContin and oxycodone
active ingredient were used as comparators. The results
revealed lower Cmax, longer tmax and reduced overall drug
liking with the reformulated OxyContin [47]. The reformulated
OxyContin was found to be more effective in decreasing the
drug abuse via the non-oral routes [48].
Several post-marketing data that assess the rates of abuse,
overdose, and death indicated reductions in all the outcomes
with the reformulated OxyContin in comparison with different
extended-release (ER) and immediate-release (IR) comparators
(ER morphine, ER oxymorphone, IR oxycodone, and IR hydromorphone) [48–50]. A study by Coplan et al. [51], utilizing The
National Poison Data System covering all US poison centers,
revealed that the abuse, therapeutic errors, and accidental exposures to reformulated OxyContin have been decreased, while
increased with the other oxycodone products and heroin.
Other post-marketing data confirmed that the abusers shifted
to heroin and other prescription drugs, and switched to the oral
abuse [52]. On the other hand, a study by Severtson et al. [53]
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
showed a decline of abuse via both oral and non-oral routes.
Different studies reported that the reformulated product was
associated with reduced sales and lower street prices [54,55].
Several studies conducted in Australia indicated a decline
in dispensing OxyContin, especially the higher strengths [56].
Although this significantly reduced the IV abuse of the
OxyContin product, it happened at the expense of greater
abuse for morphine and fentanyl [56–58]. Despite the reduction in these outcomes, the drug product could still be
abused by various manipulating methods. Three cases of
OxyContin abuse were reported in Australia; one involved
a 29-year-old female who tampered with the new formulation by breaking the tablets with kitchen shears and soaking
the small parts in water and heating them. The person was
admitted to the hospital several times for thrombotic microangiopathy (TMA), visual disturbances, as well as kidney function deterioration [59]. The TMA associated with the IV abuse
of the product has also been reported in other studies
[60,61]. It was suggested that the PEO incorporated in the
new formulation has caused toxicity on the endothelial cells,
resulting in TMA [59].
Different patterns of abuse for the reformulated
OxyContin product have been determined by Vosburg
et al. [62]. The posts on the social media and blogs reveal
that the abusers have either switched to non-ADF IR products, continued the abuse of OxyContin (with microwaving,
freezing before crushing, or heating in the oven), or chewed
or sucked tablets orally. The post-marketing data indicated
several cases of suffocation with the tablets due to the
formation of a gooey mass in the abuser’s throat as well
as rare incidences of intestinal obstruction that forced medical intervention [63].
3.2.2. Hysingla ER
Hysingla ER is an extended-release oral formulation of hydrocodone bitartrate that utilizes the ResistecTM Technology. The
FDA approved the product in 2014 with oral, IN, and IV
abuse-deterrent labeling [64]. Due to the hydrogelation of
PEO, the product resists extraction in water and cannot be
injected for abuse. Moreover, the in-vitro studies showed that
crushing and grinding the Hysingla ER was more difficult
than OxyContin [45].
On the other hand, it was found that the crushed Hysingla ER
significantly loses its controlled-release feature if shaken vigorously in various heated solvents [64]. Moreover, the drug could
be extracted from its formulation as a free base using organic
solvents in which the deterring agent (PEO) is not soluble.
Studies conducted to evaluate the abuse potential of the
product showed lower Cmax and higher tmax values with the
milled, chewed, and intact Hysingla ER compared to
a hydrocodone oral solution [65]. Significantly lower drug
liking and take drug again scores were also reported [64,66].
In another IN pharmacokinetics and abuse potential studies,
the Hysingla ER product was manipulated manually and
mechanically. The manipulated test product was then compared to hydrocodone powder, and the results were in favor
of the ADF [67]. The safety studies reported several cases of
choking and esophageal obstruction as appeared to be
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caused by the glue-like mass attached to the esophagus
[64,68]. These studies have also shown that Hysingla ER is
generally well-tolerated and can provide a 24 h. pain relief if
administered as intended [69,70].
3.2.3. Morphabond ER
The extended-release product is the first morphine singleentity ADF marketed in the US [71]. It was approved in 2015
with IN and IV abuse-deterrent labeling [72]. Unlike Embeda
that relies on the pharmacological effect to deter drug abuse,
the SentryBondTM Technology utilized in this product offers
deterrence to physical and chemical manipulations [73].
The tablet is composed of an outermost layer (diffusion
layer) consisting of a homogeneously distributed morphine
within ethyl acrylate and methyl methacrylate copolymer dispersion. The diffusion layer in its matrix form provides
a controlled drug release even if the tablet is manipulated.
This outer layer is bound to an inner acrylic copolymer barrier
layer. The barrier layer improves the mechanical strength of
the dosage form, providing crush resistance. The two layers
are inseparable during physical manipulation of the product.
This prevents any extra drug release from the inner side of the
diffusion layer even after the product is crushed. An optional
expansion layer is described in the US Patent 7,955,619 [74].
This third layer is covered by the insoluble barrier layer and
composed of polymers (e.g., alginic acid) that expand in contact with solvents.
If Morphabond ER is taken intact as prescribed, the insoluble barrier layer protects the expansion layer. Therefore, the
drug release is only controlled by the diffusion layer. However,
when physically compromised for subsequent IV abuse or coingestion with alcohol, the expanding polymer of the product
is mixed with the diffusion-barrier layer fragments and swells
in contact with solvents. This prevents drug abuse by slowing
down the rate of the drug release [74].
The in-vitro syringeability and extraction volume studies confirmed the deterrence capacity of the product to an IV abuse. The
interference of alcohol co-ingestion with the drug release was
also excluded. The IN pharmacokinetic and dynamic assessments
of crushed Morphabond ER demonstrated approximately 50%
lower Cmax compared to MS Contin (morphine sulfate ER tablet)
as well as lower scores of drug retaking, liking, and high [75,76].
In comparison with the oral intact Morphabond ER, similar scores
and bioavailability results were obtained, indicating that the
extended-release characteristics were maintained even after
the dosage form was crushed [77]. The safety of the product
upon its chronic use is still uncertain; the FDA has requested
more post-marketing data to identify the risk of cancer, focal
myocarditis, hepatotoxicity, and teratogenicity as potential outcomes of the chronic exposure to new excipients used in
Morphabond ER [78].
3.2.4. Arymo ER
Arymo ER, an extended-release tablet of morphine sulfate manufactured by Egalet, was approved by the FDA in 2017.
Therefore, this product is among the most recent products
acquiring the ADF labeling for the IV route of abuse. The abuse
deterrence by the IN route was not granted due to three years
exclusivity of Morphabond that expires in October 2018 [71].
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R. AHMAD ET AL.
Arymo ER utilizes the Egalet’s GuardianTM Technology,
where the matrix of morphine sulfate and PEO is injectionmolded under heat and high pressure [71,79,80]. This technology provided the tablets with a hardness ≥400 N, compared to
63 N for MS Contin. Furthermore, the GuardianTM Technology
could maintain some of the controlled-release properties of
the drug even after it was physically tampered [80].
The in-vitro manipulation by various crushing tools excluding knife and electric grinders resulted in particles larger than
500 µm. The chemical manipulation in aqueous solvents for
drug extraction resulted in the formation of a viscous mass
that could hardly be syringed. The studies revealed no alcohol
dose dumping effect with the intact tablets. The in-vitro tests
also showed that the product could not be abused by vaporization followed by smoking [81].
An oral pharmacokinetic randomized crossover study
showed that the Cmax of a crushed Arymo ER is higher than
that of the intact tablet and lower than that of a crushed nonADF morphine sulfate ER tablet. The oral abuse potential studies, despite showing a statistical difference in the drug liking
scores between the manipulated Arymo ER and the regular
extended-release morphine sulfate tablets, failed to demonstrate a statistically significant difference in the take drug
again scores. Thus, the Arymo ER can still be abused orally [82].
Due to the formation of a sticky mass, choking or spitting
may occur upon licking the tablet before oral administration.
Additionally, swelling of the dosage form may cause intestinal
obstruction, especially in patients with small gastrointestinal
lumen [82]. According to the FDA, Arymo ER was found to be
bioequivalent to MS Contin and it was exempted from conducting the efficacy and safety studies [83]. Egalet is still
required to fully characterize the toxicity of PEO as a postmarketing requirement [81].
3.2.5. Roxybond
Roxybond, an oxycodone HCl tablet product, was approved by
the FDA in 2017. It is the first immediate-release formulation
labeled with abuse-deterrent properties, compliant with the
FDA’s 2015 guidance for the ADFs’ evaluation and labeling
[18]. Roxybond is manufactured using a similar technology
employed in the other Inspiron’s ADF product, Morphabond.
It consists of three functional layers; expansion, barrier, and
diffusion layers as previously described with Morphabond. The
SentryBond™ technology offers abuse-deterrent characteristics
via the physical and chemical barriers without using antagonists or aversive agents [84].
The pre-marketing in-vitro studies conducted by Inspiron
Delivery Sciences show that Roxybond resists cutting, crushing,
grinding, and breaking. Roxybond can resist physical manipulation by selected household and laboratory tools, and the
crushed particles are not suitable for nasal insufflation. It was
concluded that Roxybond can impede drug abuse by routes
that require size reduction [85]. Furthermore, both intact and
manipulated forms of the drug are claimed to be resistant to
solvent extraction. The formulation forms a viscous gel, resisting the passage through a needle and making the solution
preparation for the IV administration more difficult [84].
The pre-marketing IN pharmacokinetics studies of the product
showed lower Cmax and longer tmax when Roxybond was crushed
and insufflated compared to crushed and insufflated oxycodone
IR tablets, as well as intact oral Roxybond [84]. Using a bipolar
Visual Analog Scale, lower overall drug liking scores of 63.84, 80.78,
and 78.16 were obtained for the crushed IN Roxybond, crushed IN
IR oxycodone, and intact oral Roxybond, respectively. The take
drug again also followed a similar trend with 61.83, 82.07, and
76.72 scores, respectively [84,86].
3.3. Delivery system
3.3.1. Xtampza ER
Given sufficient IN and IV abuse-deterrent evidences, the
extended-release oxycodone capsule product of Collegium
Pharmaceutical Inc. was granted an ADF labeling in 2016.
The pharmacokinetic studies showed that the crushed or
chewed product could resist oral dose dumping. However,
Xtampza ER score for take drug again was found to be inadequate for deterring abuse via an oral route [87]. Co-ingesting
the product with different concentrations of hydroalcoholic
solutions, up to 40%, as well as concomitant administration
of food, showed an unlikely dose dumping effect in in-vitro
and in-vivo dose dumping studies [88].
In their IN abuse potential studies, Webster et al. [89]
showed that the crushed Xtampza ER is associated with lower
Cmax, comparable tmax, and lower drug liking compared to the
orally administered intact product. In an in-vitro study, the IV
abuse potential of the product was evaluated against an
extended- and immediate-release oxycodone under different
conditions of abuse. Different outcomes including the percent
of drug extraction, syringeability, and injectability were measured. The results showed that less than 15% of the drug
could be extracted with Xtampza ER under the most challenging conditions of abuse used in the study [90]. Gudin et al.
[91] compared Xtampza ER to the reformulated OxyContin.
When manipulated for oral abuse, the Xtampza ER showed
a greater deterrence based on its pharmacokinetic data.
The Xtampza ER capsules are filled with microspheres containing waxy excipients [88], which constitute a lipid-based
matrix of beeswax, carnauba wax, and myristic acid. Oxycodone
in its base form is mixed with the hydrophobic matrix [92,93].
Increasing the lipophilicity of the drug substance along with the
hydrophobic nature of the matrix limits the drug solubility in
aqueous media. Furthermore, the waxy materials in the formulation tend to speckle rather than breaking into smaller particles
upon crushing, limiting the particles’ comminution to a smaller
size when the product is crushed [94].
The FDA has requested a thorough analysis of the beeswax
as a natural excipient with potential residues of environmental
and apicultural contaminants, along with validated test methods for detecting and quantifying such residuals [95].
Moreover, despite that the maximum permitted daily intake
of oxycodone is 1.5 g, if the daily intakes of oxycodone from
Xtampza ER are higher than 288 mg, the novel excipients in
the drug product are required to be tested for their general
toxicity, teratogenicity, effect on fertility, and carcinogenicity
[95,96].
The efficacy and safety of Xtampza ER, as well as the
patients’ compliance, were confirmed in patients with chronic
low back pain [97]. Xtampza ER microspheres have shown to
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
be convenient for patients with swallowing difficulties; the
drug substance maintains its extended-release mode from
the microspheres upon mixing with soft foods, administration
by nasogastric or gastrostomy feeding tubes, or chewing
[88,98,99]. On the other hand, despite the efforts to overcome
the food-effect on Xtampza ER, the drug bioavailability was
shown to be dependent on the food intake [100]. The drug
plasma levels fluctuated with the type, amount, and timing of
the food intake. Moreover, with high-fat meal intake, overdosing remains to be a safety concern [95].
3.3.2. Vantrela ER
The hydrocodone bitartrate product manufactured by Teva
Pharmaceuticals was approved by the FDA in 2017 after it
was agreed that the product, at the minimum, showed
a moderate abuse reduction via the oral, IN, and IV routes.
The product is an extended-release tablet of hydrocodone
granules coated with a controlled-release polymer and mixed
with a gel-forming excipient [101]. The hydrophobic glyceryl
behenate in the coating provides a sustained drug release.
Further, it confers crush and aqueous extraction resistance
properties [102]. Ethyl cellulose (EC) is also expected to provide some mechanical strength to the coating [102].
The matrix of Vantrela ER is capable of partially maintaining
the extended-release pattern of hydrocodone if the drug product is crushed or dissolved in various solvents. Furthermore,
due to its hydroxypropyl methylcellulose (HPMC) content, the
formulation becomes too viscous in small extraction volumes,
deterring the IV abuse.
The in-vitro and in-vivo testing of the product in different
concentrations of alcohol showed no dose-dumping [101,103].
On the other hand, pre-heating the tablet resulted in a faster
drug release in some cases [101]. The product was not marketed and has recently been discontinued just one year after it
was approved.
4. Drug products with abuse-deterrent features
4.1. Opana ER
The oral extended-release oxymorphone tablet by Endo
Pharmaceuticals approved in 2006 was first designed without
abuse-deterrent features. In 2010, Endo Pharmaceuticals partnered with Grünenthal GmbH and reformulated Opana ER
using a thermally extruded drug-PEO matrix. Specific extruder
and processing parameters were used in the development of
the product [104–106]. The new formulation intended to provide hardness and gelling properties to the tablet, making the
tablet crush and extraction resistant, respectively [107]. The
reformulated tablets were approved by the FDA in
December 2011. However, the product was not granted the
abuse-deterrent labeling due to insufficient supporting data.
In early 2012, the reformulated Opana ER started replacing
the original formulation in the market. In the following year,
Endo submitted a supplemental application with preliminary
post-marketing data, requested the FDA to approve the reformulated product as an ADF. But the FDA dismissed the request
due to indecisive post-marketing data available at that time.
Moreover, some data suggested the easiness of abuse via
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injection; 79% of the API was extractable in 5 mL solvent from
thermally treated reformulated tablets [108]. Three years later,
the manufacturer resubmitted the supplemental application
with epidemiological data. The FDA review and discussion of
the supplement was canceled following its withdrawal by Endo.
Nevertheless, the preliminary review before the withdrawal
revealed remarkable shifting from the IN to the IV route of
abuse after the product was reformulated [109,110].
Since its launch, several cases of acute kidney injury and
TMA have been reported in individuals abusing the reformulated Opana ER by injection [108, 111–113]. The Center for
Biologic Evaluation and Research concluded from a study that
the cause of TMA is the high molecular weight PEO
(~7000,000 Da) [108]. Moreover, a study by Hunt et al. [114]
showed the blockade of a dialysis catheter and tubing with
a gelatinous material presented in a patient’s plasma who
abused the Opana ER intravenously. The post-marketing data
have also indicated an HIV outbreak in Indiana as
a consequence of injecting the melted Opana ER tablets
[114]. The reformulated tablets were also associated with several cases of hepatitis infection [108].
The FDA review highlighted the fact that there were limitations for the accurate interpretation of these post-marketing
results. The original Opana ER was reported to be abused
years after it was removed from the market, indicating the
misidentification of the abused drug product. The underreporting of the overdose cases and abuse is another factor
affected the accuracy of the post-marketing data. Lastly, the
choice of the geographic regions covered in the studies is an
additional limitation evidenced by the higher prescribing and
abuse rates of Opana ER in Tennessee versus other regions.
Overall, and based on the low benefit to risk ratio suggested
by the post-marketing data, the FDA requested Endo
Pharmaceuticals to withdraw the reformulated Opana ER
from the market, and Endo voluntarily recalled the product
in July 2017 [109].
4.2. Suboxone
Reckitt Benckiser Pharmaceuticals has developed sublingual
tablets of buprenorphine and naloxone that was approved
by the FDA in 2002 [115]. The applicant reformulated the
product as sublingual films, which was later approved by the
FDA in 2010. The sublingual films are less vulnerable to
damage during shipping and storage and more difficult to
counterfeit compared to tablets.
The primary active ingredient in Suboxone is buprenorphine; a μ-opioid receptor partial agonist and a kappa receptor antagonist. This drug substance is a schedule III-controlled
substance, which is prone to abuse like the other opioids.
However, the approach employed in Suboxone to minimize
its abuse relies on the pharmacodynamic properties of buprenorphine. As a partial agonist, the drug is associated with less
euphoria and subsequently lower drug dependence potential.
Additionally, the formulation incorporates an antagonist
(naloxone), which in turn opposes the agonist’s effect if the
product is abused by injection. The 4:1 ratio of buprenorphine
to naloxone was shown to provide the maximum antagonism
effect [116].
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R. AHMAD ET AL.
The product is intended for sublingual and buccal use,
where naloxone is not absorbed at a clinically significant
level [117]. The suboxone sublingual films are composed of
a buffered polymeric matrix. The buffer system maintains an
optimum pH of 2–4 at which the absorption of buprenorphine
is maximized, while that of naloxone is minimized.
It was found that the intramuscular injection of buprenorphine/naloxone was associated with the antagonistic effect,
while the sublingual administration was devoid of such effect.
This suggests that the product can deter abuse by injection.
However, the product’s labeling indicates that Suboxone’s
abuse by the IV or IN routes is possible by those having
a low level of dependence to full μ-opioids or those who are
dependent on partial agonists (e.g., buprenorphine) [116].
The post-marketing reports have shown hepatic abnormalities with the use of buprenorphine in general. The reports
also included several cases of death as a result of overdosing
by opioid-naive individuals. With regards to Suboxone, in
particular, the most commonly reported post-marketing
adverse events include stomatitis, glossitis, and ulceration of
the mouth or tongue [116].
4.3. Exalgo
Mallinckrodt Pharmaceuticals received the FDA approval for
its extended-release hydromorphone HCl product in 2010.
The OROS technology (Osmotic Release Oral System, ALZA
Corporation) used in the manufacturing of Exalgo exhibits
some abuse-deterrent properties. Originally, the technology
was developed to provide a controlled drug release over 24
h utilizing the osmosis concept. The system is composed of
a semi-permeable membrane (permeable to water but not
to the drug) of cellulose acetate surrounding the tablet and
an inner matrix. The inner core has two layers; a drug layer
containing hydromorphone HCl and a push layer containing
an expandable osmopolymer (e.g., poly(ethylene oxide)) as
well as an osmotic compound (e.g., sodium chloride). As
water enters the inner matrix through the semipermeable
membrane, the osmopolymer expands and subsequently
pushes the dissolved or suspended drug out through
a laser-drilled orifice at one side of the tablet’s outer membrane [118,119]. The abuse-deterrent features were suggested to be due to the rigidity of the outer cellulose
acetate membrane that provides resistance to breaking
and grinding, resulting in large particles that are unfit for
snorting. Moreover, the fragments generate viscosity in aqueous media, making the extraction, and syringing processes
harder.
Sathyan et al. studied the effect of alcohol on the pharmacokinetics of Exalgo [119]. The study showed that the controlled-release properties of Exalgo tablets were maintained
when co-ingested with alcohol. The bioavailability of the
OROS formulation in the elderly was also reported to be marginally affected by alcohol [120]. In another study by Pande
et al. [121], the product withstood physicochemical manipulations and it was to some degree difficult to abuse in comparison
with a controlled-release oxycodone comparator.
The post-marketing surveys of NAVIPPRO® (The National
Addictions Vigilance Intervention and Prevention Program),
ASI-MV substance abuse treatment center data and NPDS
(The National Poison Data System) suggest a lower abuse
liability via alternative routes of administration. Online posts
and drug discussion forums using WIS® (Web Informed
Services Internet monitoring program) also show a lower
abuse desirability for the Exalgo product [122].
4.4. Oxaydo
Oxaydo is an immediate-release product of oxycodone HCl. It
was developed by Acura Pharmaceuticals and received the
FDA approval in 2011 with no abuse-deterrent labeling.
There is no evidence to show that the Acura’s Aversion®
technology incorporated in Oxaydo could actually reduce the
abuse liability compared to an immediate-release oxycodone.
However, the manufacturer claims that the product partially
deters the physical and chemical manipulations that may discourage the IN abuse [123,124].
The history of the drug product dates to 2010 when the
FDA rejected the drug application under the name Acurox.
The Acurox formulation was originally developed using niacin
as an aversive agent, which was determined by the FDA to
offer insufficient abuse-deterrent properties [38]. It was proposed that the flushing aversive effect of niacin can easily be
overcome by taking the drug with food or NSAIDs.
Additionally, the undesirable effect can emerge at therapeutic doses as well, making the product unpleasant even if
taken as prescribed [11]. The currently approved formulation
utilizes gel-forming polymers (e.g., PEO) to deter drug extraction and syringing. Furthermore, it contains sodium lauryl
sulfate (SLS), a skin and mucosal irritant that deters the
nasal insufflation [38].
4.5. Nucynta ER
The FDA approved Janssen Pharmaceuticals’s extendedrelease Tapentadol HCl tablets in 2011. Nucynta ER was developed using the INTAC® technology (Grünenthal Group), where
the drug is dispersed in a PEO matrix using a hot melt extrusion process [125].
The abuse-deterrent features of Nucynta ER are derived
from tapentadol molecule itself as well as the INTAC® technology. Based on the NAVIPPRO ASI-MV surveillance system,
tapentadol drug substance was found to have less abuse
potential [126]. Similar findings were reported by DailyGovoni et al. [127], indicating a lower desirability for the nonmedical use of tapentadol in comparison with other opioids
among recreational drug abusers. Another study by Vosburg
et al. [128] also showed a lower rate of abuse with tapentadol
versus other opioids.
In terms of resistance against physical manipulation, syringing, and smoking, Nucynta ER abuse-deterrent properties were
comparable to those of Oxycontin ER [129]. In comparison
with Nucynta IR formulation, the extended-release version of
the product was found to be less attractive to abuse [127]. The
Nucynta ER is known to be abused mostly by swallowing the
whole intact tablet, similar to what is reported for the ER
opioids with abuse-deterrent labeling (62.5% versus 53.4% of
abusers, respectively). Nucynta ER has lower abuse potential
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
by the IV route (< 15% of abusers), whereas other ER opioid
products without abuse-deterrent labeling or any abusedeterrent features were shown to be abused via injection by
the majority of the abusers (57.6% and 49.4%, respectively)
[130]. Co-ingestion of the product with 40% alcohol was associated with an increase in the Cmax and the AUC, while the tmax
was not affected [131].
4.6. Xartemis XR
A combination of oxycodone and acetaminophen (7.5 mg/
325 mg) extended-release tablet product was approved by
the FDA in 2014 with some abuse-deterrent features. The
product manufactured by Mallinckrodt Pharmaceuticals is currently not available in the market. The dosage form was
designed using Depomed’s Acuform technology that is not
an abuse-deterrent technology in the first place. Acuform is
a gastroretentive drug delivery system, relying on swellable
polymers, which allow the tablet to reside longer in the stomach. Xartemis further utilizes PEO in a bilayer design; an
immediate-release and an extended-release layers, both containing oxycodone and acetaminophen [132]. The fact that
a smaller amount of oxycodone is contained in Xartemis compared to single entity extended-release formulations, makes
Xartemis less attractive to abuse via multiple administrations.
The acetaminophen’s hepatotoxicity at high doses also makes
the product less desirable to abuse [133,134].
Eisenhauer et al. [135] reported that Xartemis ER, compared
to an oxycodone/acetaminophen immediate-release formulation, better resists size reduction using different crushing and
grinding tools except when a mortar and pestle is used.
Preconditioning by heating, freezing or microwaving did not
decrease the resistance of the product to size reduction. It was
also observed that the crushed tablets resist extraction and
form a pasty mixture in water. This mixture is difficult to draw
in a syringe presumably due to the presence of PEO in the
composition and the higher weight of the tablets [135]. It was
also suggested that Xartemis XR is less prone to abuse by
insufflation and injection [135,136]. Nevertheless, there are
currently no long-term studies available to ascertain the true
impact of such formulations on the opioid abuse [137].
4.7. Zohydro ER
Hydrocodone bitartrate extended-release capsules developed
by Zogenix was first approved in 2014. Its approval created
controversies among the health care providers regarding the
impact of adding a potent opioid in a high dose formulation
without any abuse-deterrent features. In response to the rising
criticism [138], the company introduced a new formulation of
Zohydro ER using BeadTek™ (Alkermes PLC [139]) technology
in January 2017. The reformulated product failed to acquire
the ADF labeling, and it is only considered to exhibit abusedeterrent features.
The reformulated Zohydro ER capsules contain three different indistinguishable multi-particulate coated carrier beads;
immediate-release beads, sustained-release beads, and inert
beads. The immediate-release beads are sugar spheres coated
with the drug and other excipients. The sustained-release
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beads are manufactured by coating the immediate-release
beads with amino methacrylate copolymers. The combination
of the immediate- and extended-release beads provide an
extended release profile that was already present in the original formulation. However, in the reformulated capsules, the
inert beads containing PEO can generate a viscous gel upon
crushing and the addition of solvents that hinders drug extraction and syringing [139].
The pharmacokinetic studies evaluating the effect of food
have shown no significant changes on AUC0-t and Cmax.
Additionally, no substantial evidence was found for alcoholinduced dose-dumping when Zohydro ER was co-ingested
with 20% alcohol (1.1-fold increase in Cmax compared to no
alcohol ingestion). However, following co-administration with
40% alcohol, an increase in the absorption of hydrocodone
(2.3-fold increase in Cmax) was reported. Also, there was an
associated decrease in the tmax, suggesting that the Zohydro
ER should not be taken with alcohol [140,141].
5. Conclusion
The health complications and the associated costs due to the
use, misuse, and abuse of prescription opioids have increased
over the past decade and resulted in the emergence of the
opioid crisis. In response, ADFs have been developed, and invitro and in-vivo methods have been proposed by the FDA to
evaluate the ADF products. Since 2009, several drug products
exhibiting abuse-deterrent features have been introduced to
the market, and some were granted the ADF labeling. While
a few of these products utilize the drug delivery approach or
the agonist/antagonist combination, most of these products
utilize the physical/chemical barriers to deter the drug abuse.
Interestingly, most of the approved ADFs are extended-release
products and use the same deterring agent, i.e., PEO.
Moreover, there is currently no generic prescription opioid
product with an FDA-approved ADF labeling.
Although most of the ADFs have been in the market for
some years now, the available published post-marketing and
safety data are not enough to draw final conclusions about
their clinical impact in reducing the drug abuse. However,
some safety concerns have been raised regarding the high
molecular weight PEO. Moreover, one of the approved products (Opana ER) has been removed from the market after it
was found that the abusers could abuse the drug by injection.
6. Expert opinion
Safety and efficacy are prime FDA requirements and safeguard for
achieving maximum but safe therapeutic effects. Manipulating
prescription drugs including opioids can disrupt this safeguard
and result in an unsafe access to opioid medications.
As opposed to non-abusable dosage forms that are only
used by patients, the ADFs are used by both patients and nonpatients (abusers). This requires the ADFs to be equipped with
special but safe and powerful technologies. It is expected that
the deterrent technologies employed in manufacturing of the
ADFs work very effectively when the medication is manipulated for purposes other than therapy.
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R. AHMAD ET AL.
Given the fact that the realm of drug abuse is vast, and
abusers can always find more effective ways to abuse medications, the safety, and performance of the ADF products should
be continuously monitored and evaluated.
The FDA has so far helped with the epidemic by issuing
two major guidance to deal with the branded and the generic
ADFs. Although the guidance evaluates the ADFs under variety of manipulating conditions, the ADFs differ in their deterrent technologies and each can potentially be best abused by
very different techniques and procedures. This requires the
FDA to continuously revise its guidance to build a more comprehensive guideline to evaluate all ADFs under all routes of
administrations.
Given the complexity of abuse, variety of deterrent technologies, and multiple routes of drug administrations, the
industry may end up with more and more ADFs with abusedeterrent features than with abuse-deterrent labeling. So far,
the FDA granted the abuse-deterrent labeling to 10 out of 17
ADF products and 6 products have been denied the abusedeterrent labeling, and one has been withdrawn from the
market.
The ADF products that acquired the abuse-deterrent labeling have shown promising results in the pre-market in-vitro and
in-vivo assessments. Regardless of the deterrent technology, all
the products have shown a reduced abuse liability. Although it
would take some years to better evaluate the impact of the
ADFs in the real world, the post-marketing data on OxyContin
confirms the potential of these formulations in resisting the
drug abuse. The epidemiological results have in general indicated a decline in the different abuse outcomes, reduction in
the product’s desirability, and shifting from the IN and IV routes
of abuse to the less dangerous oral routes.
Recognizing the shortcomings of the abuse-deterrent technologies, the deterring agents used in their formulations, and
the regulatory guidelines are part of the evaluation process as
well. This is critical for further development of safer and more
robust formulations. As covered in this review, 11 out of 17
ADF products are based on the physical and chemical barrier
approaches, mostly utilizing PEO as a deterring agent. The
facts that most of the products are based on the same technology and even rely on the same deterring agent, would
make it a lot easier for abusers to share their knowledge and
experience and focus their efforts to maximize abuse.
The most robust deterring mechanism so far seems to be
the agonist/antagonist combination, whether the antagonist is
blended with the drug matrix or sequestered. However, this
deterring approach is still susceptible to abuse by the oral
route. The formulations containing naloxone in a matrix form
can be abused by chewing a single unit of the product. The
formulations sequestering the antagonist are susceptible to
abuse by orally administering multiple intact dosage units. The
abuse via multiple administrations also applies to the other
technologies and remains a major challenge. Another concern
with the agonist/antagonist combination products is the food
effect. Foods rich in fat enhance the solubility of the hydrophobic coating that sequesters the antagonist, forcing the
release of the antagonist. The antagonist will then interfere
with the agonist effect when the drug is used as intended.
The majority of the approved ADFs and products with abusedeterrent features are extended-release dosage forms. This may
shift the abuse efforts towards the immediate-release formulations that are available in the market without abuse-deterrent
features. Therefore, it is worth considering monitoring the prescribing patterns and to equip the immediate-release formulations with abuse-deterrent technologies.
The safety of the deterring agents incorporated in the ADF
products is another source of concern. It is known that the
maximum amount of an excipient that can safely be used in
an oral dosage form can significantly be higher than when it is
used via a non-oral route. Moreover, depending on how
severe an ADF is manipulated, an excipient may lose its original identity to a more toxic side-product that may carry
a lower lethal dose (LD50). Nevertheless, many relevant warnings are reported in the labels of different drug products and
the FDA has issued two guidelines in this regard [142,143].
Besides the toxicities caused by the excipients, the impurities
(e.g., organic impurities, inorganic impurities, and residual solvents) contained within these excipients pose another risk.
The case is even worsened by taking these excipients at larger
amounts and by routes other than those allowed in the FDA
Inactive Ingredients Database [144].
The relative assessment of the deterrence efficacy of the
different ADFs is another challenging aspect. The use of the invitro pre-market results as a base for the initial comparison is
not feasible where the products utilize different deterring technologies requiring different outcomes. Moreover, the assessment involves multiple quantitative and qualitative measures
(e.g., drug amount extracted, manipulation time, exerted effort,
etc.), which complicate the evaluation process. For instance,
a manipulated product showing a higher drug extraction may
have undergone a longer tampering time and required multiple
manipulation steps, rendering it less attractive to abusers in the
real-world scenarios. The same applies for comparisons based
on the pharmacokinetic and clinical abuse potential outcomes;
abusers may spend a longer time and greater efforts to defeat
a product’s deterring technology, rendering the product less
desirable to abuse.
Regardless of the deterrent technology and formulation, the
post-marketing studies measure the same outcomes (e.g., abuse,
misuse, and overdosing). These outcomes also reflect the products’ desirability among the abusers in the real-world settings.
The comparisons based on the post-marketing studies seem to
be the most reliable despite the associated challenges as shown
in this review. The post-marketing studies are still ongoing for
many ADF products, and it may take years before they can
provide meaningful outcomes. The data is still lacking for most
of the approved products, especially for those marketed recently.
Moreover, some products including those with low prescription
volume or low market supply may require longer post-marketing
study.
The development and evaluation of the ADFs are costly
and may result in a higher price tag. Moreover, the market
share of the new ADF products can also be affected by the
position of the insurance companies whether they are willing
to cover the new costly ADF products, as well as the readiness
of the prescribers to adopt these products. To date, the
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
prescription of ADFs is still limited in comparison with the
conventional non-ADF products [145]. Therefore, the future
of the ADF products may be more promising if alternative
cheaper but effective technologies are utilized in the manufacturing of the ADF products and Government or State policies are set in place to support such new products.
Due to the fact that difficult manipulation of the ADFs may
force the abusers to use illicit drugs, the post-marketing surveillance studies should consider the most frequently abused
street drugs as additional comparators. Despite the ADFs’
potential in impeding the drug abuse, cheap non-tamper
resistant street drugs are still readily available. Shifting to illicit
drugs impose a serious risk and may magnify the opioid
epidemic and its associated costs.
The prescription opioid epidemic is a multifaceted issue
and requires multifaceted solutions. Developing ADFs is only
part of the solution, and a meaningful positive impact on the
epidemic requires other initiatives including educational and
awareness programs about the safe prescribing, dispensing,
and administering of the ADFs. These programs should target
physicians, pharmacists, patients, and their guardians.
Moreover, naloxone availability, as well as laws and policies
that enforce monitoring the doctor shopping and prescribing
patterns, can also be influential.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One reviewer is an employee of the RADARS System, which provides
postmarketing surveillance data to pharma and to US FDA. One of the
peer reviewers who engaged in our double-blind peer review process is
affiliated to the same institution as the authors. The other peer reviewer
has no relevant affiliations to declare.
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