Download The Abuse Potential of Remoxy, an

Pain Medicine 2011; 12: 618–631
Wiley Periodicals, Inc.
OPIOIDS, SUBSTANCE ABUSE &
ADDICTIONS SECTION
pme_1093
Beatrice Setnik, PhD,* Carl L. Roland, PharmD,*
Jody M. Cleveland, MS,* and Lynn Webster, MD†
*Research and Development, King Pharmaceuticals,
Inc., Cary, North Carolina (King Pharmaceuticals was
acquired by Pfizer Inc in March 2011);
†
Lifetree Clinical Research and Pain Clinic, Salt Lake
City, Utah, USA
Reprint requests to: Beatrice Setnik, PhD, Pfizer Inc.
4000 Centre Green Way, Suite 300, Cary, NC 27513,
USA. Tel: 919-653-7071; Fax: 919-653-7022; E-mail:
[email protected].
Abstract
Objectives. Remoxy® is a water-insoluble, highly
viscous oral formulation of oxycodone extended
release (ER) currently in development. The primary
objective was to determine the abuse potential of
Remoxy under fed conditions relative to oxycodone
ER and immediate release (IR) under fasted conditions and compared with placebo (treatment group
X). A secondary objective was to evaluate abuse
potential under reversed fed/fasted conditions
(treatment group Y).
Design. Phase I randomized double-blind tripledummy placebo- and active-controlled 6-way crossover study.
Setting. A single US site.
Patients. Healthy men and women aged 18–50
years who were nondependent, recreational opioid
users.
Interventions. Remoxy 40 mg whole and chewed,
oxycodone ER 40 mg whole and crushed, oxycodone IR 40 mg crushed, and placebo.
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Outcome Measures. The primary endpoint was
the drug liking subscale of the drug effects questionnaire assessed by various pharmacodynamic
parameters. Secondary endpoints included additional pharmacodynamic measures, chewing duration, and safety measures.
Results. In treatment group X, Remoxy whole (fed)
and chewed (fed) had a significantly lower abuse
potential compared with oxycodone ER (crushed,
fasted) and IR (fasted) based on the majority of pharmacodynamic parameters of interest for the primary
endpoint (drug liking subscale) as well as secondary
endpoints. Treatment group Y showed generally
similar results.
Conclusions. The abuse potential of Remoxy when
taken whole or chewed was significantly lower
than two comparators with known abuse potential,
including oxycodone IR and crushed oxycodone
ER, under the fed/fasted conditions tested. Remoxy
may be associated with a reduced risk potential for
abuse.
Key Words. Abuse; Liability; Oxycodone; Potential;
Remoxy
Introduction
More than one in four American adults experience pain
lasting a day or more, and in general, pain affects more
Americans than diabetes, heart disease, and cancer combined [1]. Opioids are an important treatment option for
the management of moderate to severe chronic pain [2],
and their availability and use for acute and chronic pain
have increased over the past few decades [3]. Unfortunately, as prescription opioid use has increased so has its
abuse, with nearly 12 million persons (4.8%) 12 years of
age or older reporting nonmedical use of prescription pain
relievers in the past year [4]. Admissions to substance
abuse treatment centers for primary abuse of opiates
other than heroin has increased from 1% of all admissions
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Original Research Article
The Abuse Potential of Remoxy®, an
Extended-Release Formulation of
Oxycodone, Compared with Immediate- and
Extended-Release Oxycodone
Abuse Potential of Remoxy (Oxycodone ER)
in 1997 to 5% in 2007; however, overall substance abuse
admissions increased only 13% during this time [5]. Nearly
three quarters (72%) of these admissions reported the
route of administration as oral (whole and crushed);
however, 16% reported inhalation and 10% reported
injection [5]. National results of adolescent drug use found
that 1 in 10 twelfth-graders reported recreational use of
Vicodin® (Abbott Laboratories, Abbott Park, IL) and 1
in 20 reported use of OxyContin® (Purdue Pharma LP,
Stamford, CT) [6].
Remoxy® (King Pharmaceuticals, Inc., Bristol, TN) is
an encapsulated, water insoluble, highly viscous ER oral
formulation of oxycodone currently in development for
the treatment of moderate to severe chronic pain and
was designed to limit the release of oxycodone following
manipulation or tampering. In previous studies, Remoxy
has demonstrated that its formulation limits the release of
oxycodone following manipulation, including crushing and
extraction in alcohol or water [10]. The true impact that the
Remoxy formulation may have on reducing misuse and
abuse associated with tampering cannot be established
until it is evaluated in the community at large.
Abuse potential studies provide a means of predicting
the likelihood of abuse by recreational users before
larger patient populations are exposed to a drug [14,15].
Generally, a drug’s ability to produce pleasurable effects,
such as euphoria, and to become reinforcing may be
Methods
Study Design and Patients
This study was conducted in accordance with Good Clinical Practice requirements as described in the International
Conference on Harmonisation guidelines. The protocol
was reviewed and approved by the appropriate local institutional review board, and all patients provided written
informed consent.
This was a phase I randomized double-blind triple-dummy
placebo- and active-controlled 6-way crossover study in
healthy male and female, nondependent, recreational
opioid users aged 18–50 years (inclusive) with a body
mass index between 18 and 33 kg/m2. Recreational
opioid use was defined as having recreationally abused
opioids to achieve a “high” on at least five occasions in the
12 months before screening and at least once in the 90
days before screening (visit 1). Patients who abused multiple drugs were to express a preference for opioids. Urine
drug screens and alcohol breath tests were conducted at
each clinic admission to confirm compliance with study
restrictions. Concomitant medications were not permitted
within 14 days before or during the study. Acetaminophen
(1000 mg/dose; maximum 4000 mg/day) was permitted
to treat an adverse event (AE) provided that the administration was ⱖ8 hours before and/or ⱖ6 hours after any
pharmacodynamic (PD) measurement.
Figure 1 illustrates the study design. Following the screening visit (visit 1), patient eligibility was confirmed by the
naloxone challenge phase (treatment visit 2, day 0) and
the drug discrimination phase (treatment visit 2, days 1–2).
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Extended-release (ER) opioid formulations were developed to allow a slow release of the drug to manage
chronic pain. Oxycodone ER (e.g., OxyContin) was originally believed to have reduced abuse liability owing to the
slow release of oxycodone from the formulation and the
resulting lack of an immediate rush or high [7], although no
abuse liability studies of the product had been published
to support this. Furthermore, oxycodone ER exhibits a
biphasic absorption pattern that may lead to an initial
immediate release of more than 30% of the oxycodone
dose [8]. It was later noted that potency and formulation of
oxycodone ER may have actually made it more attractive
for abuse. The controlled release formulation is easily
compromised, and the original safety warning may have
inadvertently provided this information to abusers [7].
Current ER opioid formulations remain a frequent target
for drug abusers because the products can be easily
compromised to release the full opioid dose [9]. For
example, the rate of absorption of oxycodone ER can be
increased through various means of tampering such as
chewing, crushing and snorting, or dissolving the product
in water and injecting the solution [10]. In April 2010, the
Food and Drug Administration approved a new formulation of OxyContin that was designed to help discourage
misuse and abuse of the medication [11]. In 2009, it was
estimated that nearly 1.7 million Americans had used the
previous formulation of OxyContin nonmedically in the
past year [12]. Whether the new formulation reduces
misuse and abuse relative to the previous version will not
be known until the results of a required post-market study
are available [13].
predictive of abuse and addiction. The primary objective of
the current study was to determine the abuse potential of
orally administered Remoxy (whole and chewed) under
fed conditions relative to oxycodone immediate release
(IR) and oxycodone ER (whole and crushed) under fasted
conditions, and compared with placebo. Conditions of
manipulation (i.e., crushing or chewing) were chosen individually for each drug to include a condition of tampering
that was relatively easy to perform, could be applied to
the drug based on its physical/chemical properties, and
would result in an increased amount of the drug when
administered orally. As abuse potential is expected to be
greater when the maximum amount of drug is delivered in
the shortest amount of time, the comparison between
Remoxy administered in the fed state and oxycodone ER
and IR in the fasted state was considered most appropriate for this study. Previous studies have shown that oxycodone ER and IR demonstrate a lower bioavailability
when administered in a fed relative to a fasted state [16].
In contrast, pharmacokinetic (PK) studies of Remoxy
have demonstrated an opposite effect with food (i.e., an
increase in bioavailability in the fed vs the fasted state)
[10]. Secondary objectives included a comparison of the
safety of Remoxy to oxycodone IR and ER and an assessment of the duration and subjective experience of chewing
Remoxy.
Setnik et al.
During the naloxone challenge, 0.2 mg of naloxone HCl
was intravenously administered, followed by a second
injection of 0.6 mg if no signs of withdrawal were present. Withdrawal symptoms were rated using the clinical
opiate withdrawal scale (COWS) following each injection; patients with no withdrawal (COWS score <5 was
considered as showing no signs of withdrawal) were eligible to continue in the study. The drug discrimination
phase was conducted to confirm that patients could tolerate treatment and discriminate between the effects of
oxycodone IR (20 mg) and placebo. Both drugs were
administered as single, oral doses in a double-blind randomized order on two consecutive days and were followed by serial PD and safety assessments at pre-dose
and up to 5 hours post-dose. Patient eligibility was based
on the ability to tolerate study treatments (i.e., no episodes
of vomiting within the first 2 hours post-dose), to follow
study procedures, and to distinguish oxycodone from
placebo on selected PD measures (i.e., ⱖ25-point difference on the visual analog scale [VAS] for drug liking and
drug high for oxycodone relative to placebo, at both
0.5 and 1 hour post-dose). In the abuse potential phase
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(treatment visits 2–5, days 3–24), patients were randomly
assigned in a 3:1 ratio to 1 of 2 treatment groups, referred
to as treatment groups X and Y (Table 1). Treatment group
X was considered the primary analysis group because
treatments were administered under the fed/fasted states
that produce the highest bioavailability for each drug (i.e.,
Remoxy administered in the fed state and oxycodone
administered in the fasted state). Treatment group Y
(Remoxy in the fasted state and oxycodone ER and IR in
the fed state) was considered an exploratory analysis
implemented to maintain the double-blind nature of the
study. Therefore, the results from treatment group Y are
not fully detailed.
In each group, patients were randomized to one of six
treatment sequences and received, in a double-blind
fashion, single oral doses of the investigational drug
(Remoxy administered whole and chewed), the active
comparators oxycodone IR and oxycodone ER (administered whole and crushed), and placebo, as shown in
Table 1. Serial PD and safety measures were assessed
pre-dose and for up to 24 hours post-dose following each
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Figure 1 Study design. *Discharge following all 24-hour
post-dose procedures and
†
Restudy
assessments.
admission to clinic on afternoon/
evening prior to next dosing.
Abuse Potential of Remoxy (Oxycodone ER)
Table 1 Description of treatment groups X and Y
Treatment
Treatment
Group Y
(N = 12)
Fed
Fed
Fasted
Fasted
Fed
Fasted
Fasted
Fed
Fasted
Fed
Fasted
Fed
Outcomes and Assessments
ER = extended release; IR = immediate release.
drug administration. Dosing of each treatment was separated by a washout period of at least 92 hours.
Study Drugs and Dosing
Naloxone HCl was supplied as a 0.4 mg/mL solution for
intravenous administration. During the drug discrimination
phase, oxycodone IR and placebo were administered
orally in solution, as described below. In the abuse potential phase, treatments were administered orally in a tripledummy fashion where patients consumed two different
capsules (each blinded for Remoxy and oxycodone ER)
and 150 mL of a solution containing active study drug
or placebo. Oxycodone IR was sourced as 5-, 15-, and
30-mg tablets and prepared for oral administration of 20and 40-mg doses by crushing the appropriate tablets with
a mortar and pestle for 2 minutes. Crushed tablets were
then mixed with 150 mL of artificially sweetened, noncarbonated, flavored beverage at room temperature. Oxycodone ER (crushed) was prepared using 40-mg
OxyContin tablets, which were crushed with a mortar and
pestle and mixed with 150 mL of the previously described
beverage. A placebo solution was prepared using the
beverage containing aliquoted amounts of inactive ingredients (i.e., glycerol distearate, microcrystalline cellulose,
and sodium lauryl sulfate) to mimic the texture of crushed
tablets. Oxycodone ER was prepared by overencapsulating OxyContin 40-mg tablets in size #DB AA el Swedish
Orange opaque capsules backfilled with microcrystalline
cellulose as the diluent. A matching placebo capsule was
prepared by filling Swedish Orange capsules with microcrystalline cellulose.
During the drug discrimination and abuse potential phases
(for fasted treatments only), study drugs were administered orally following an overnight fast of at least 8 hours.
For treatments administered in a fed state (abuse potential
phase only), patients received a standard breakfast consisting of 8 ounces of orange juice, two fried eggs, and
two slices of toast with butter and preserves that was
consumed within 30–60 minutes before dosing. No addi-
The primary PD endpoint to assess abuse potential was
the unipolar 100-mm VAS for drug liking, which ranged
from 0 (“none”) to 100 (“extremely”) and is 1 of 9 subscales of the drug effects questionnaire (DEQ). The
remaining subscales of the DEQ included assessments for
high, any drug effects, good effects, bad effects, feel sick,
nausea, sleepy, and dizzy, which were also ranked on a
unipolar 100-mm VAS.
Several secondary assessments were also performed.
The Cole/Addiction Research Center Inventory Morphine
Benzedrine Group (Cole/ARCI MBG) scale consists of 16
statements from which the patients rate their answers on
a four-point scale (0 = false, 1 = more false than true,
2 = more true than false, and 3 = true) [17,18]. The take
drug again assessment is based on a single question
“Would you take the drug you just received again, if given
the opportunity?” categorized on a bipolar 100-mm VAS
scale where 50 is neutral (“do not care”) and the two polar
ends are 0 (“definitely would not”) and 100 (“definitely
would”). The price value assessment questionnaire (PVAQ)
was adapted from the street value assessment questionnaire described by Cole et al. [19] and asked of the patient
“What is the most that you would be willing to pay for a
single [1] dose of the drug that you have just taken, if it
was offered to you on the street?” Responses were provided in increments of $5 amounts, ranging from $0 to
$100. This questionnaire has been adjusted to increased
values ranging from $0 to $100 rather than the previous
range of $0–10. This increase is reflective of the more
recent illicit street prices of OxyContin, estimated between
$0.50 and $1.00 per milligram [20]. Pupil size was measured by pupillometry (Colvard Pupilometer; OASIS, Glendora, CA) in a dimly lit room with standardized light; the
same eye was used for all measurements.
Exploratory parameters included the chewing duration of
study drug, and subjective ratings of taste and texture (of
chewed study drug) using a bipolar 100-mm VAS that was
developed for this study and ranged from 0 (“extremely
unpleasant”) to 100 (“extremely pleasant”), with a “neutral”
anchor at 50. Any patient who chewed for the entire
10-minute duration would be asked to estimate the
amount of capsule content remaining in their mouth (%
relative to total amount at the start of chewing) and
whether they felt that the remaining content was comprised of 1) equal amounts of both gelatin capsule and
drug content material, 2) mostly drug content, or 3) mostly
gelatin capsule.
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Treatment A: Placebo
Treatment B: Remoxy 40 mg
(whole)
Treatment C: Remoxy 40 mg
(chewed)
Treatment D: Oxycodone HCl
ER 40 mg (whole)
Treatment E: Oxycodone HCl
ER 40 mg (crushed)
Treatment F: Oxycodone HCl
IR 40 mg
Treatment
Group X
(N = 36)
tional food/water was permitted following all dosing for up
to 2 hours post-dose. Dosing during the abuse potential
phase was conducted using a triple-dummy paradigm for
each treatment; patients swallowed two intact capsules,
chewed one capsule, and ingested 150 mL of solution,
each containing active drug or placebo. A period of 10
minutes was allotted for chewing, and patients were
instructed to vigorously chew the capsule, containing
either Remoxy or placebo, for as long as possible.
Setnik et al.
Safety assessments included AEs, vital signs (i.e., heart
rate, respiratory rate, and systolic/diastolic blood pressure), oxygen saturation (SpO2), and end tidal carbon
dioxide (CO2). Additional assessments included clinical
laboratory tests (i.e., hematology, chemistry, urinalysis,
and serology), electrocardiograms, and serum/urine pregnancy tests.
Sample Size
This study was to screen approximately 90 male and
female patients to ensure enrollment of 48 patients into
the abuse potential phase. Of these, 36 patients were to
be enrolled into treatment group X to allow at least 18
patients to complete the study, and 12 were to be enrolled
into treatment group Y to allow at least six patients to
complete the study. In total, at least 24 patients were
expected to allow the study. The study was not formally
powered for any single analysis. However, power calculations for select analyses were performed given the anticipated enrollment and completion sizes provided above.
The comparison within treatment group X of Remoxy
40 mg chewed (fed) vs oxycodone IR 40 mg (fasted), of
AUE0–2 hours for drug liking, was expected to have at least
80–90% power, assuming a mean difference of 30–35
hours·mm and an SD of the paired differences of 40–45
hours·mm, based on a paired t-test for analysis and a
significance level of 5%. Because the mean differences of
AUE0–2 hours for drug liking were expected to be larger for
the comparison within treatment group X of Remoxy
40 mg whole (fed) vs oxycodone IR 40 mg (fasted), the
power was also expected to be larger.
Statistical Analyses
In general, all statistical testing was two sided and performed at the 0.05 significance level. Multiple comparison
adjustments for all pair wise treatment comparisons of the
principle parameters for the primary endpoint were made
622
using the Benjamini-Hochberg method [21]. Data are provided as least squares (LS) means for all treatments and
LS mean differences for pairwise treatment comparisons
with 95% confidence intervals. Linear interpolation was
used for missing AUE values in cases where sample collection was not drawn or was invalid. Continuous variables
were summarized with descriptive statistics (e.g., means,
SDs, medians, minima, and maxima) and categorical
values were summarized by count and percentage of
patients in corresponding categories.
PD parameters for treatment group X were analyzed using
an analysis of variance linear mixed model with fixed
effects for sequence, period, and treatment, and a
random effect for patients nested in sequence to test the
hypothesis that there is no difference in abuse potential
between Remoxy (whole/chewed, fed) and each of
the active comparators separately, compared with the
alternative hypothesis that there is a difference. Similar
methods were used for treatment group Y, with fixed
effects for period and treatment, and a random effect for
patients, but not for sequence as the sample size was too
small. The primary endpoint, drug liking, was also summarized as a responder analysis based on percent change
in drug liking for Remoxy relative to oxycodone IR and ER.
The primary population used for PD analyses was
the completer population, which included all randomly
assigned patients who received all six treatments and who
contributed post-dose data for each treatment period in
the abuse potential phase. This population was analyzed
as randomized. Analyses of the primary PD endpoint (drug
liking) and the drug high endpoint were also performed
using the per protocol (PP) population. The PP population
included all completer population patients who did not
have a major protocol violation. Major protocol violations,
including deviations related to study drug intake (such as
any vomiting occurring within 2 hours post-dose), were
defined as those that could potentially affect the PD or
safety conclusions of the study. These violations were
determined before unblinding the study database. The PP
population was also analyzed as randomized.
The safety populations were defined by study phase
and included all patients who received at least one
dose of study drug in the naloxone challenge phase,
the drug discrimination phase, and the abuse potential
phase, respectively. These populations were analyzed as
treated.
Results
Patient Disposition and Baseline Characteristics
Of the 65 patients enrolled in the study, all successfully
completed the naloxone challenge phase and proceeded
to the drug discrimination phase. During this phase, 20
patients discontinued; 17 patients were not able to distinguish between oxycodone and placebo, two patients
vomited within 2 hours post-dose, and one patient voluntarily withdrew consent. A total of 45 patients were
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To evaluate abuse potential, the following parameters
were assessed as the principal parameters for all PD
endpoints (with the exception of the take drug again and
PVAQ): area under the effect curve (AUE0–1 hour and
AUE0–2 hours), maximum effect (Emax), and time to maximum
(peak) effect (TEmax) or minimum effect and time to minimum effect (Emin and TEmin, respectively) for pupil size. Emax
and TEmax were calculated using all post-dose data, up to
24 hours post-dose. Additional secondary parameters
calculated for all PD endpoints (with the exception of the
take drug again and PVAQ) were: AUE0–3 hours, AUE0–4 hours,
AUE0–8 hours, AUE0–12 hours, AUE0–24 hours, and effects at designated time points (E0.5 hour, E1 hour, E1.5 hours, and E2 hours).
For the take drug again assessment and PVAQ, the data
were collected and analyzed at 12 and 24 hours postdose and at the maximum (peak) effect (Emax [the
maximum effect at either 12 or 24 hours]). Chewing duration and VAS scores for taste and texture were summarized (for Remoxy chewed only) using descriptive statistics
(n, arithmetic mean, median, standard deviation [SD],
range, and coefficient of variation).
Abuse Potential of Remoxy (Oxycodone ER)
Enrolled
Completed
Naloxone
Challenge
Phase
N=65
Completed Drug
Discrimination
Phase
N=65
Enrolled into Abuse
Potential Phase (3:1)
N=45
Drug Liking Visual Analog Scale
Tx: X
N=34
Tx: Y
N=11
Tx: X
N=32
Tx: Y
N=11
Figure 2 Patient disposition. Tx = treatment group.
enrolled into the abuse potential phase, 34 patients
were randomized to treatment group X, and 11 patients
were randomized to treatment group Y (Figure 2). During
the abuse potential phase, two patients in treatment
group X discontinued the study, one upon request and
one because of noncompliance.
The completer population consisted of the 32 patients in
treatment group X and the 11 patients in treatment group
Y who completed the study. Three patients had a major
protocol violation (i.e., emesis within 2 hours of taking
study drug), resulting in their removal from the PP population in treatment group X following administration of
oxycodone IR 40 mg or oxycodone ER 40 mg (crushed).
Baseline characteristics for completed patients in treatment group X are presented in Table 2. The majority of
patients were white (94%) and male (78%), and the mean
age was approximately 25 years (range, 18–38 years).
Pharmacodynamic Analyses
Figures 3A–E present the positive subjective effects PD
endpoints and pupillometry endpoint arithmetic mean data
across time for each treatment group, demonstrating the
time course of effect from time 0 (dosing) to 8 hours
post-dose. Figures 4A–D present each treatment’s LS
means of the principal parameters for the primary endpoint
of drug liking. Study validity was confirmed by the comparison of oxycodone IR 40 mg (fasted) vs placebo (fed). Mean
drug liking for oxycodone IR 40 mg (fasted) was statistically
For comparisons of Remoxy vs active control on the
parameters of Emax and AUE for the primary endpoint,
drug liking, a negative difference in the LS means indicates
that Remoxy is liked less than the comparator, whereas a
positive difference indicates that Remoxy is liked more
than the comparator. For TEmax, a positive difference indicates that the time to maximum (peak) drug liking effect is
longer for Remoxy.
Table 2 Patient characteristics (completer
population)
Characteristic
Age, y
Mean (SD)
Median
Range
Gender, N (%)
Men
Women
Ethnicity, N (%)
Not Hispanic or Latino
Hispanic or Latino
Race, N (%)
White
Asian
Native Hawaiian or Pacific Islander
Weight, lb
Mean (SD)
Median
Range
Height, in
Mean (SD)
Median
Range
BMI, kg/m2
Mean (SD)
Median
Range
Treatment
Group X
(N = 32)
25.2 (4.65)
24.5
18, 38
25 (78)
7 (22)
30 (94)
2 (6)
30 (94)
1 (3)
1 (3)
167.2 (35.03)
167.5
117.0, 251.0
70.0 (3.67)
70.0
62.5, 77.0
23.8 (3.47)
22.8
18.9, 32.7
BMI = body mass index; SD = standard deviation.
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Completed
Study
significantly greater than that observed with placebo based
on the principal parameters of interest (i.e., AUE0–1 hour,
AUE0–2 hours, and Emax) (P < 0.0001). Study validity was also
supported by the significant differences observed for pupil
size, drug high, good effects, Cole/ARCI MBG scale, take
drug again assessment, and PVAQ between oxycodone IR
40 mg (fasted) and placebo (fed). Additionally, there were
no significant differences observed between active controls, oxycodone IR 40 mg (fasted), and oxycodone ER
40 mg (crushed, fasted) on all principal parameters for drug
liking (P ⱖ 0.2665) and on all principal parameters for drug
high, good effects, Cole/ARCI MBG scale, take drug again
assessment, and PVAQ (P ⱖ 0.0892).
N=65
Setnik et al.
A. Drug Liking
100
Treatment
Placebo fed (n=32)
Remoxy® 40 mg (chewed) fed (n=32)
Oxycodone HCl ER 40 mg (crushed) fasted (n=32)
Remoxy® 40 mg (whole) fed (n=32)
Oxycodone HCl ER 40 mg (whole) fasted (n=32)
Oxycodone HCl IR 40 mg fasted (n=32)
90
Mean DEQ (mm)
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (h) Post-Dose
B. Drug High
100
Treatment
Placebo fed (n=32)
Remoxy® 40 mg (chewed) fed (n=32)
Oxycodone HCl ER 40 mg (crushed) fasted (n=32)
Remoxy® 40 mg (whole) fed (n=32)
Oxycodone HCl ER 40 mg (whole) fasted (n=32)
Oxycodone HCl IR 40 mg fasted (n=32)
90
Mean DEQ (mm)
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (h) Post-Dose
Note: Visual analog scale from 0 to 100 mm, where 0=’None’ and 100=’Extremely’. At pre-dose, only questions 6–9 were assessed per protocol,
question #5 is set to zero for plotting purposes.
Figure 3 A–E. Mean visual analog scale (VAS) scores for positive patient effects (drug liking, drug high, and
good drug effects subscales of the drug effects questionnaire and the Cole/Addiction Research Center
Inventory Morphine Benzedrine Group scale) and pupillometry endpoints for the completer population
(treatment group X), demonstrating the time course of effect from dosing through 8 hours post-dose.
DEQ = drug effects questionnaire; ER = extended release; IR = immediate release.
Table 3 summarizes the analysis of variance results for
drug liking in the completer population for treatment
group X. All treatments demonstrated a significantly
higher abuse potential compared with placebo. The
comparisons of interest were Remoxy (whole, fed) and
Remoxy (chewed, fed) vs oxycodone IR (fasted) and vs
oxycodone ER (whole and crushed, fasted). In general,
Remoxy (whole and chewed) had a lower abuse potential than the active comparators of oxycodone IR and
crushed oxycodone ER during the time intervals
assessed.
Mean drug liking was statistically significantly lower for
Remoxy 40 mg (whole, fed) and Remoxy 40 mg (chewed,
624
fed) compared with oxycodone IR 40 mg (fasted)
and oxycodone ER 40 mg (crushed, fasted) for Emax,
AUE0–1 hour, and AUE0–2 hours (P ⱕ 0.0461). In addition, the
time to peak drug liking was significantly delayed for
Remoxy (whole and chewed) compared with oxycodone
IR and oxycodone ER (crushed) (P ⱕ 0.0193). Mean drug
liking for Remoxy 40 mg (whole, fed) was also statistically
significantly lower than oxycodone ER 40 mg (whole,
fasted) for both AUE0–2 hours and Emax (P ⱕ 0.0374). Mean
drug liking for Remoxy 40 mg (chewed, fed), however,
was statistically significantly higher than oxycodone ER
40 mg (whole, fasted) based on AUE0–1 hour and AUE0–2 hours
(P ⱕ 0.0275), but was not significantly different for both
Emax and TEmax (P ⱖ 0.3423).
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on October 21, 2016
Note: Visual analog scale from 0 to 100 mm, where 0=’None’ and 100=’Extremely’. At pre-dose, only questions 6–9 were assessed per protocol,
question #4 is set to zero for plotting purposes.
Abuse Potential of Remoxy (Oxycodone ER)
C. Good Drug Effects
100
Treatment
Placebo fed (n=32)
Remoxy® 40 mg (chewed) fed (n=32)
Oxycodone HCl ER 40 mg (crushed) fasted (n=32)
Remoxy® 40 mg (whole) fed (n=32)
Oxycodone HCl ER 40 mg (whole) fasted (n=32)
Oxycodone HCl IR 40 mg fasted (n=32)
90
Mean DEQ (mm)
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (h) Post-Dose
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Note: Visual analog scale from 0 to 100 mm, where 0=’None’ and 100=’Extremely’. At pre-dose, only questions 6–9 were assessed per protocol,
question #2 is set to zero for plotting purposes
D. Cole/Addiction Research Center MBG Scale
100
Placebo fed (n=32)
Remoxy® 40 mg (chewed) fed (n=32)
Oxycodone HCl ER 40 mg (crushed) fasted (n=32)
Remoxy® 40 mg (whole) fed (n=32)
Oxycodone HCl ER 40 mg (whole) fasted (n=32)
Oxycodone HCl IR 40 mg fasted (n=32)
90
80
Mean Total Score
Treatment
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (h) Post-Dose
E. Pupillometry Endpoints
100
Treatment
Placebo fed (n=32)
Remoxy® 40 mg (chewed) fed (n=32)
Oxycodone HCl ER 40 mg (crushed) fasted (n=32)
Remoxy® 40 mg (whole) fed (n=32)
Oxycodone HCl ER 40 mg (whole) fasted (n=32)
Oxycodone HCl IR 40 mg fasted (n=32)
90
Mean Pupil Size (mm)
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Time (h) Post-Dose
Figure 3 Continued.
The LS mean values for each of the principal parameters
are graphically depicted in Figure 4A–D for drug liking and
demonstrate general consistency in the overall abuse
potential of Remoxy (whole and chewed, fed) relative to
the oxycodone comparators (fasted). For all of the principal PD parameters, Remoxy (whole and chewed, fed) was
liked less compared with the oxycodone comparators
(fasted), except for Remoxy (chewed, fed) vs oxycodone
625
**
* **
*
* **
* **
* **
D. Drug Liking TEmax
* **
*
**
**
* **
* **
* **
* **
Figure 4 A–D. Least squares means of the principal parameters of drug liking (primary endpoint) for the completer population (treatment group X),
demonstrating general consistency in the overall abuse potential of Remoxy (whole and chewed, fed) relative to the oxycodone comparators (fasted).
* P < 0.05 vs Remoxy (chewed). ** P < 0.05 vs Remoxy (whole). ER = extended release; IR = immediate release; LS = least squares.
* **
*
B. Drug Liking AUE0−2 hours
*
**
* **
* **
C. Drug Liking Emax
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626
*
A. Drug Liking AUE0−1 hour
Setnik et al.
12.8
(1.2, 24.5)
0.0372
30.7
(22.5, 38.8)
<0.0001
3.4
(2.4, 4.4)
<0.0001
AUE0–1 hour (h·mm)
LS mean difference*
95% CI*
Adjusted P value†
AUE0–2 hours (h·mm)
LS mean difference*
95% CI*
Adjusted P value†
Emax (mm)
LS mean difference*
95% CI*
Adjusted P value†
TEmax (h)
LS mean difference*
95% CI*
Adjusted P value†
2.2
(1.2, 3.1)
<0.0001
-26.4
(-34.6, -18.3)
<0.0001
-71.6
(-83.2, -60.0)
<0.0001
-32.2
(-38.1, -26.3)
<0.0001
2.0
(1.1, 3.0)
<0.0001
-21.6
(-29.8, -13.4)
<0.0001
-65.9
(-77.6, -54.3)
<0.0001
-28.8
(-34.7, -22.9)
<0.0001
Oxycodone ER
40 mg (Crushed,
Fasted) (N = 32)
0.9
(-0.1, 1.8)
0.0836
-8.9
(-17.1, -0.8)
0.0374
-21.2
(-32.8, -9.6)
0.0007
-2.8
(-8.6, 3.1)
0.3718
Oxycodone ER
40 mg (Whole,
Fasted) (N = 32)
2.6
(1.6, 3.5)
<0.0001
43.7
(35.6, 51.8)
<0.0001
49.8
(38.2, 61.5)
<0.0001
13.7
(7.9, 19.6)
<0.0001
Placebo
(Fed)
(N = 32)
1.4
(0.4, 2.3)
0.0089
-13.4
(-21.5, -5.2)
0.0022
-34.6
(-46.3, -23.0)
<0.0001
-22.6
(-28.5, -16.7)
<0.0001
Oxycodone IR
40 mg (Fasted)
(N = 32)
1.2
(0.2, 2.2)
0.0193
-8.6
(-16.7, -0.4)
0.0461
-28.9
(-40.6, -17.3)
<0.0001
-19.1
(-25.0, -13.3)
<0.0001
Oxycodone ER
40 mg (Crushed,
Fasted) (N = 32)
Remoxy 40 mg (Chewed, Fed) Vs
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0.1
(-0.9, 1.0)
0.9033
4.1
(-4.0, 12.3)
0.3423
15.8
(4.2, 27.5)
0.0109
6.9
(1.0, 12.8)
0.0275
Oxycodone ER
40 mg (Whole,
Fasted) (N = 32)
AUE = area under the effect curve; CI = confidence interval; Emax = maximum effect; ER = extended release; IR = immediate release; LS = least squares; PD = pharmacodynamics;
TEmax = time to maximum effect; VAS = visual analog scale.
* LS means, 95% CIs, and unadjusted P values were from a linear mixed model with fixed effects for sequence, period, and treatment, and a random effect for patients nested in
sequence.
†
P values for the primary endpoint only were based on the Benjamini–Hochberg adjustment for multiplicity.
4.1
(-1.8, 10.0)
0.1879
PD Parameter
Oxycodone
IR 40 mg
(Fasted)
(N = 32)
Remoxy 40 mg (Whole, Fed) Vs
LS mean difference in VAS score for drug liking in treatment group X (completer population)
Placebo
(Fed)
(N = 32)
Table 3
Abuse Potential of Remoxy (Oxycodone ER)
627
Setnik et al.
ER (whole, fasted). Of note, Figure 4D illustrates that the
difference in the time to maximum drug liking was smallest
for the Remoxy (chewed, fed) vs oxycodone ER (whole,
fasted) and Remoxy (whole, fed) vs Remoxy (chewed, fed)
comparisons.
Remoxy (chewed, fed) demonstrated a statistically significantly larger mean pupil size compared with oxycodone
IR (fasted) for AUE0–1 hour (P = 0.0027) and oxycodone
ER (crushed, fasted) for AUE0–1 hour and AUE0–2 hours
(P ⱕ 0.0384). Compared with oxycodone ER (whole,
fasted), Remoxy (chewed, fed) had a statistically
significantly smaller mean pupil size for AUE0–1 hour and
AUE0–2 hours (P ⱕ 0.0136).
Other Endpoints
Secondary PD Endpoints
In general, among patients in treatment group X, the LS
mean differences in the principal parameters for the drug
high and good effects subscales of the DEQ and the
Cole/ARCI MBG scale supported the trends identified with
the drug liking subscale.
The means for drug high, good effects, and Cole/ARCI
MBG scale were statistically significantly lower (greater for
TEmax; no significant difference in TEmax on the Cole/ARCI
MBG Scale) for Remoxy (whole, fed) compared with
oxycodone IR (fasted) and oxycodone ER (crushed,
fasted) based on the principal parameters of interest
(P ⱕ 0.0130). In addition, the means for drug high and
good effects were significantly lower (greater for TEmax) for
Remoxy (chewed, fed) compared with oxycodone IR
(fasted) and oxycodone ER (crushed, fasted) for all principal parameters (P ⱕ 0.0347). The means for the Cole/
ARCI MBG scale were statistically significantly lower
for Remoxy (chewed, fed) compared with oxycodone IR
(fasted) and oxycodone ER (crushed, fasted) based on
AUE0–1 hour and AUE0–2 hours (P ⱕ 0.0183).
Figure 3 demonstrates the consistency of effect across
the various positive subjective endpoints. The results of
any drug effect and the negative subjective effect endpoints showed similar trends as the primary PD endpoint of drug liking and the other positive subjective
effect endpoints (e.g., Remoxy [whole, fed] had lower
mean negative subjective effects than oxycodone IR
[fasted] and oxycodone ER [crushed, fasted]). However,
mean differences between treatments were not as great
as those observed for positive subjective effect
endpoints.
628
No patient was able to chew the capsules for the allotted
10 minutes. The mean chewing time for Remoxy was
<1 minute (0.8 minutes), with a maximum reported
chewing time of 1.5 minutes. The VAS for assessing
pleasantness of chewing found that the majority of
patients reported the taste (mean VAS score = 17.7)
and texture (mean VAS score = 21.6) of Remoxy as
unpleasant.
Treatment Group Y Results
In brief, results from treatment group Y were similar to
those for treatment group X. Even under conditions of
lesser bioavailability (fasted for Remoxy and fed for oxycodone IR and ER), the trends in treatment group Y were
consistent with those seen in treatment group X, demonstrating lower abuse potential for Remoxy (whole) and
Remoxy (crushed) relative to oxycodone IR and oxycodone ER (crushed) during the time intervals assessed.
Safety
The AEs associated with Remoxy and oxycodone IR and
ER were typical of those that occur with any opioidcontaining drug, with the most common (occurred in
ⱖ10% of patients) being pruritus, dizziness, somnolence,
nausea, and vomiting during the abuse potential phase.
Most AEs were considered mild in intensity. There were
no serious AEs, deaths, or discontinuations due to AEs
during the study. There were no clinically important
changes from baseline in vital signs or laboratory values.
Mean end tidal CO2 demonstrated an opioid treatment
effect in the active treatment groups relative to placebo;
however, mean SpO2 and end tidal CO2 remained within
normal ranges.
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The responder analysis based on percent change in Emax
for drug liking demonstrated that 88% and 75% of
patients had some degree of reduced drug liking after
receiving Remoxy 40 mg (whole, fed) and Remoxy 40 mg
(chewed, fed), respectively, compared with oxycodone IR
40 mg (fasted). Of the 9% and 19% with any increase
(nine patients), only three patients had increases greater
than 10% and all three were in the Remoxy 40 mg
(chewed, fed) treatment group. From the responder analysis, relative to oxycodone ER (crushed, fasted), 78% and
66% of patients had some degree of reduced drug liking
after receiving Remoxy 40 mg (whole, fed) and Remoxy
40 mg (chewed, fed), respectively. Of the 19% and 28%
with any increase (14 patients), respectively, half (seven
patients) had increases greater than 10%, two from the
Remoxy 40 mg (whole, fed) group and five from the
Remoxy 40 mg (chewed, fed) group.
For treatment group X, LS mean values for the take drug
again assessment and PVAQ for Remoxy whole and
chewed (fed) were generally lower (indicating less willingness to take the drug again or pay more for the drug)
compared with the other active treatments; however, the
majority of these comparisons were not statistically significant. For assessments of pupil size, larger values indicate less pupil constriction (i.e., a lesser drug effect). The
mean pupil size was statistically significantly larger for
Remoxy 40 mg (whole, fed) compared with oxycodone IR
40 mg (fasted) and oxycodone ER 40 mg (crushed,
fasted) (P ⱕ 0.0371) based on the principal PD parameters, and for AUE0–2 hours when compared with oxycodone
ER (whole, fasted) (P = 0.0303).
Abuse Potential of Remoxy (Oxycodone ER)
Discussion
Study validity was confirmed by demonstrating statistically
significant increases in drug liking, as well as other positive
subjective effect endpoints (i.e., drug high, good effects,
Cole/ARCI MBG scale) and significant decreases in pupil
size, following administration of oxycodone IR 40 mg relative to placebo. In general, all active treatments containing
oxycodone showed, on the majority of parameters, significantly higher ratings on drug liking and the positive
subjective drug effects, and significant decreases in pupil
size compared with placebo.
With respect to the active controls, the results of this study
demonstrated that when crushed, oxycodone ER showed
a similar abuse potential to oxycodone IR. Remoxy 40 mg,
administered either whole or chewed, had statistically
significantly lower ratings on all principal parameters
assessed for drug liking and for the majority of secondary
endpoints and parameters assessed, compared with both
oxycodone IR and oxycodone ER (crushed), indicating a
relative decrease in abuse potential. A responder analysis
also demonstrated that the majority of patients showed
some degree of reduced drug liking following Remoxy
whole and chewed treatments, compared with oxycodone IR and oxycodone ER (crushed). Hence, even
under conditions of tampering, Remoxy demonstrated
decreased abuse potential compared with a manipulated
oxycodone ER tablet.
Under conditions of intact administration, Remoxy whole
had significantly decreased maximum (peak) effect and
In general, the trends observed in the PD analyses were
similar to those noted in pupillometric response, in that
peak pupil constriction showed a similar trend to peak
positive subjective response across treatments.
Overall, based on the primary endpoint analyses and supported by the secondary endpoint analyses, the key findings are: 1) Remoxy whole or chewed has significantly less
abuse potential than oxycodone IR and oxycodone ER
crushed, 2) Remoxy whole has a slight trend toward
less abuse potential than oxycodone ER whole, and 3)
Remoxy chewed has a slight trend toward greater abuse
potential than oxycodone ER whole. These results
suggest that Remoxy whole or chewed is less likely to be
abused than oxycodone IR and ER when it is manipulated.
Owing to the highly viscous nature of the liquid formulation
of Remoxy, previous studies have not explored the
chewing duration or analyzed the taste or texture of
Remoxy capsules. Remoxy contains sucrose acetate
isobutyrate; therefore, this study assessed chewing duration and pleasantness of taste/texture. Although the formulation is highly viscous, no patient was able to chew
Remoxy for more than 1.5 minutes, and the taste and
texture of Remoxy were rated as unpleasant or neutral by
all of the patients.
No unexpected safety findings were observed in this
study. The majority of AEs reported were those commonly
associated with opioid use and were mild in severity. There
were no deaths or other serious AEs. No patient discontinued owing to an AE during the study. Vital signs and
laboratory safety test results during the study do not
suggest a safety concern for treatment with Remoxy
40 mg whole or chewed.
Conclusions
Abuse potential studies provide a means to anticipate the
likelihood of abuse of a drug before exposure to the
629
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Remoxy is a water-insoluble, highly viscous ER oral formulation of oxycodone developed to resist physical and
chemical challenges. To date, the integrity of the Remoxy
formulation has only been studied nonclinically and in
human PK studies following a variety of challenges.
Because the Remoxy formulation is highly viscous and
therefore is not easily injected and/or crushed, the most
likely method of misuse/abuse is anticipated to be chewing
in an attempt to extract an immediate release of the oxycodone. To evaluate the abuse potential of Remoxy when
taken whole and when chewed, this study was designed as
a placebo- and active-controlled six-way crossover study
in recreational opioid users using various PD measures to
assess subjective drug effects. To assess each treatment
under conditions that led to the greatest bioavailability, a
condition that would be sought after by recreational drug
users, the study focused on conditions where Remoxy was
administered in a fed condition and the active comparators
oxycodone IR and ER were administered under fasted
conditions. Assessment of abuse potential was based on
the primary endpoint of drug liking and supported by other
subjective endpoints (i.e., high, good effects, Cole/ARCI
MBG scale, take drug again, and PVAQ) that indicate
pleasurable drug effects and/or reinforcing properties.
Furthermore, assessments of Emax, TEmax, and AUE curves
within the first 2 hours, to demonstrate the magnitude of
effect over time, were selected as the principal parameters
of interest to assess potential for abuse.
area under the effect curve (within 2 hours post-dose) for
drug liking and showed decreases in secondary endpoints, the majority of which, however, were not statistically significant when compared with intact oxycodone ER
(whole). A trend toward reduced abuse potential was
apparent; however, it was not as pronounced compared
with the active oxycodone IR and oxycodone ER controls.
Remoxy crushed, compared with intact oxycodone ER,
showed significant increases in the area under the effect
curves within 1 and 2 hours post-dosing; however, it did
not show significant changes for peak drug liking and time
to peak drug liking. The majority of secondary endpoints
and parameters did not show statistically significant differences between Remoxy chewed and oxycodone ER
(whole), although there was a trend for slightly higher
ratings on measures for Remoxy chewed, indicating a
trend toward slightly higher abuse potential. Similar findings were also observed for all treatment comparisons
under reverse fed/fasted states (treatment group Y).
Setnik et al.
general population [14]. The results of this trial confirm that
Remoxy is associated with a reduced potential for abuse,
including conditions in which the product is manipulated,
compared with oxycodone products with known abuse
potential. Although the impact of the novel formulation of
Remoxy will not be established until it has had ample time
in the marketplace for a complete assessment, further
analysis in the real world setting will confirm if the reduced
abuse potential observed translates to lower rates of
actual abuse and misuse.
Acknowledgments
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Drs. Setnik and Roland and Ms. Cleveland are employed
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