Current Medical Research and Opinion

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Evaluating the effectiveness of reformulated

extended-release oxycodone with abuse-deterrent
properties on reducing non-oral abuse among
individuals assessed for substance abuse
treatment with the Addiction Severity Index-
Multimedia Version (ASI-MV)

Rachelle D. Rodriguez, Taryn Dailey Govoni, Venkat Rajagopal & Jody L.

Green

To cite this article: Rachelle D. Rodriguez, Taryn Dailey Govoni, Venkat Rajagopal & Jody L.
Green (2023) Evaluating the effectiveness of reformulated extended-release oxycodone with abuse-
deterrent properties on reducing non-oral abuse among individuals assessed for substance abuse
treatment with the Addiction Severity Index-Multimedia Version (ASI-MV), Current Medical Research
and Opinion, 39:4, 579-587, DOI: 10.1080/03007995.2023.2178080

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CURRENT MEDICAL RESEARCH AND OPINION
2023, VOL. 39, NO. 4, 579–587
https://doi.org/10.1080/03007995.2023.2178080
Article RT-0888.R1/2178080

RESEARCH ARTICLE

Evaluating the effectiveness of reformulated extended-release oxycodone with abuse-

deterrent properties on reducing non-oral abuse among individuals assessed for
substance abuse treatment with the Addiction Severity
Index-Multimedia Version (ASI-MV)
Rachelle D. Rodrigueza, Taryn Dailey Govonib, Venkat Rajagopalc and Jody L. Greenb
a
Janssen Pharmaceuticals, LLC, Raritan, NJ, USA; bUprise Health/Inflexxion, Irvine, CA, USA; cEphicacy Consulting Group, Iselin, NJ, USA

ABSTRACT ARTICLE HISTORY

Objective: Original brand extended-release (ER) oxycodone tablets (OC) for oral use were reformulated (ORF) Received 15 November 2022
with abuse-deterrent properties (ADP) against inhalation and injection routes in August 2010. This product Revised 2 February 2023
transition provided an opportunity to compare “before and after” reformulation abuse trends. Our goal was to Accepted 5 February 2023
assess the change in abuse of brand oxycodone ER from before and after introduction of ORF.
KEYWORDS
Methods: Change in self-reported non-oral “OxyContin” abuse in the previous 30 days during two - years
Abuse-deterrent; opioid;
pre- and four years post-reformulation was assessed among adults evaluated for substance use and treatment OxyContin; reformulation;
planning using the Addiction Severity Index-Multimedia Version (ASI-MV). Comparator opioids were used to drug abuse; epidemiological
provide a frame of reference for changes in abuse due to competing popula- tion-level opioid abuse study; oxycodone
interventions and other factors unrelated to the reformulation. A proportion (PR) and abuse report dispensing
ratio (ARDR) are reported because a single measure of abuse has not been identified that can optimally
describe opioid abuse or changes in opioid abuse.
Results: Interrupted time-series analyses indicated an immediate decline in non-oral abuse measures post-
reformulation (PR = —52.1%; ARDR = —32.2%). Significant decreases from pre- to post-reformulation in non-oral
abuse overall were observed (PR [95% CI] = —30.7% [-46.9%, —9.5%]; ARDR = —29.3%
[-37.5%, —20.1%]). Comparator opioids did not demonstrate similar trends over the period.
Conclusions: Methodology applied in this study suitably assessed the effectiveness of an ADP product.
Among individuals assessed for substance use, a differential decline in non-oral abuse of brand ER oxycodone
was observed since introduction of ORF.

Introduction
An extended-release (ER) oral tablet formulation of oxycodone
hydrochloride (OxyContin) is approved for the management of
pain severe enough to require daily, around- the-clock, long-term
opioid treatment and for which alterna- tive treatment options are
inadequate1. When taken as intended (tablet swallowed intact),
OxyContin is designed to provide delivery of oxycodone over 12
h. Oxycodone is classi- fied as a Schedule II drug under the
Controlled Substances Act due to its potential for abuse, as well
as for psycho- logical and physical dependence. Original
OxyContin became a target of abuse after it was recognized that
breaking, crushing, or chewing could rapidly release oxycodone
from the extended-release matrix of the tablet, at which point it
was commonly manipulated for abuse via non-oral routes2,3.
Non-oral administration routes of opioid abuse (i.e. snort-
ing and injecting) have serious adverse health consequences
and are an important public health concern5–9. Abuse deter- rent
formulations of opioids aim to make abuse more diffi- cult and
have been considered to play a role in tackling the opioid abuse
and misuse epidemic4. To make the tablets more difficult to abuse
by the intranasal and intravenous routes, original brand ER
oxycodone (OC) was reformulated (ORF) in August 2010. Its
physicochemical abuse-deterrent properties (ADP) were designed
to make manipulation diffi- cult 10–12, while also retaining clinical
effectiveness13. The tab- let was designed to hinder the release of
more oxycodone in a shorter period of time than intended, as OC
was an extended-release formulation of oxycodone. ORF was not
intended to address abuse by swallowing the tablet or mul- tiple
tablets whole, similar to most abuse deterrent formula- tions of
opioid medications14. The reformulation of OxyContin was not
expected to reduce abuse of other prod- ucts or reduce overall
abuse of opioids or non-opioid drugs. Abuse-deterrent
formulations (ADFs) of prescription opioid

CONTACT Rachelle D. Rodriguez rachelle.d.rodriguez@gmail.com Janssen Pharmaceuticals, LLC, 1000 US Route 202 S, Raritan, NJ 08869, USA
RDR was an employee of Purdue Pharma L.P., Stamford, Connecticut, USA at the time of research conduct. Janssen Pharmaceuticals had no role in the research
conduct or development of this manuscript.
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.
0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon
in any way.
www.cmrojournal.com
580 R. D. RODRIGUEZ ET AL.
medications are but one part of a multi-faceted approach to
mitigate the opioid crisis, and FDA continues to encourage the
development of such formulations15. ADFs do not, how- ever,
reduce the risk of addiction15.
ORF was introduced with no change to the tradename or
reference to abuse deterrence in the label13. Shipment of OC to
wholesalers ceased in August 2010 and shipment of ORF
commenced a few days later13. By December 2010, 91% of brand
ER oxycodone prescriptions were filled with ORF [IQVIA
National Prescription Audit]. The abrupt and complete change in
product formulation enabled a pre/post compari- son to evaluate
the effects of the formulation change13. The National Addictions
Vigilance Intervention and Prevention Program (NAVIPPRO)
system collects data from clinical sites using the Addiction
Severity Index-Multimedia Version (ASI- MV) assessment tool
which is a practical dataset to assess benefits of interventions
aimed to reduce opioid abuse16.
This study was one in a series of four formal postmarket- ing
requirements (PMR) by the U.S. Food and Drug Administration
(FDA) designed in consultation with the FDA, including three
observational surveillance studies and one retrospective claims
study assessing overdose and overdose death risk changes in a
patient population17. Each study had its limitations, largely
because they each were observational studies in which the data
were originally collected for differ- ent purposes. As is typical of
these types of studies, when considered together, the design
limitations of a single study may be mitigated when its findings
are supported by the design strengths and findings of other
studies18. More reli- able answers to research questions are
obtained by integrat- ing results from several different
approaches, each with different and unrelated key sources of
potential bias.
A major challenge in measuring population-level changes in
abuse is described by FDA. Because there is not a direct measure
of the true at-risk or exposed population of persons who are
abusers or who are at risk for becoming abusers in the three PMR
surveillance studies of the four total studies, suitable proxy
measures were needed19. The general uncer- tainty about which
denominator to which to refer these data is acknowledged by
FDA19, with subsequent guidance rec- ommending two estimates
of population risk14.
The goal of this observational surveillance study was to assess
the change in previous 30-day non-oral abuse of brand
oxycodone ER from before (pre-) to after (post-) intro- duction of
ORF among adults evaluated with the ASI-MV.
Methods
Study population
The NAVIPPRO is a national surveillance system designed for
prescription drug abuse signal detection and verification used to
inform prevention and intervention programs20. NAVIPPRO
collects data from enrolled substance abuse treat- ment centers and
other sites nationally using the ASI-MV clinical tool 20,21. The
ASI-MV is a validated, electronic, self- administered clinical tool
used to collect information from individuals assessed for
substance use and treatment plan- ning including data on overall
abuse of specific drugs (legal
and illegal), abuse by routes of administration in the past 30
days and other respondent attributes.
The ASI-MV is based on a standardized clinical instrument, the
ASI, originally created and tested for reliability and valid- ity as a
paper version in 198522. The ASI was transferred to a multimedia
platform and tested for validity in 200121 and has been found to
be a more reliable method of collecting information than an
interviewer administered ASI assess- ment. The ASI-MV was
further tested against an interviewer administered survey in 2009
and concluded that the ASI-MV had improved self-disclosure23.
Study period
A two-year baseline period (pre-) compared to a four-year post-
reformulation period was evaluated, excluding a six- month
transition period. The baseline period, 1 July 2008 through 30
June 2010, provides a relatively stable estimate of OC
prescriptions, without the large fluctuations in brand versus
generic ER oxycodone prescriptions observed in early 2008 after
reinstatement of the brand ER oxycodone patent [IQVIA National
Prescription Audit]. The follow-up period, 1 January 2011 to 31
December 2014, provides an estimate of sustained effect over a
period prior to many interventions to reduce the prescribing,
overdose, abuse, addiction and diver- sion of opioids24. The
transition period, 1 July 2010 through 31 December 2010, was
excluded from analyses as it repre- sents the period of transition
after introduction of ORF to the market and the initial decrease
in supply and availability of OC.
Study design
This is an observational surveillance study of ASI-MV assess-
ment data among adults aged 18 to 90 years.
Study analytic sample
The ASI-MV network is dynamic in nature as new sites can be
added and individual sites within the ASI-MV network contribute
data on varying schedules, with varying sample size. When
evaluating trends over time, including all ASI-MV sites could
result in an inconsistent sampling fraction across study periods25.
A consistent sampling fraction over the study period is important
to assess change in abuse over time 25. Therefore, the analytic
sample included only those sites contributing at least one
assessment during each quar- ter of the pre- and post-
reformulation periods. Sensitivity analyses included a less-
restrictive set of sites, only ASI-MV sites contributing at least
one assessment each year during the pre- and post-reformulation
periods. By relaxing the restrictions on the set of sites to generate
a dataset with a constant sampling fraction, more data from the
original data- set was retained. Furthermore, only the respondent
three- digit ZIP Codes contributing at least five ASI-MV
assessments from the start of the baseline period (1 July 2008)
through the four-year follow-up period are included. By
restricting data to sites which contributed a minimum
number of

assessments during the study period, the possibility of spor- adic
and possibly outlying reports was reduced.
A total of 34 sites provided data for the analyses, repre-
sented by 10 states. With the less restrictive site definition for
sensitivity analyses, sites which contributed at least one
assessment/year, a total of 175 sites provided data for the
sensitivity analyses, represented by 23 states.
Repeat assessments, defined as assessments completed by
individuals who had taken an ASI-MV assessment more than
once within a 30-day period, were removed from all analyses.
However, assessments completed by the same indi- vidual outside
the 30-day window were allowed and counted independently.
They accounted for 10.2% of assessments included in the analytic
sample.
Note that individuals who reported past 30-day abuse of a
product could select use of multiple routes of abuse as part of the
ASI-MV assessment.
An individual was considered to have abused brand ER
oxycodone in the post-reformulation period if that person selected
“Old OxyContin” or “OxyContin Reformulated” as a product
abused in the past 30 days in the assessment. The ASI-MV
collects real-world patient reported behaviors from clinical
settings. Abuse reports by individuals within the ASI- MV
clinical tool are counted and used as the numerator for measures
of abuse evaluated in this study. The ASI-MV System does not
have information about diagnoses of opioid use disorder, as the
ASI-MV is an assessment instrument, not a diagnostic instrument.
Therefore, the term “abuse” is used here to refer to a report by an
individual rather than a med- ical diagnosis for that individual.
Study comparators
Comparators were used to assess whether changes in out- comes
following the introduction of ORF were specific to ORF,
accounting for secular trends or other opioid abuse interventions
that might affect opioid abuse rates in general. Characteristics of
opioid products can vary and therefore careful consideration is
warranted when selecting appropri- ate comparators and
interpreting relative results14. The drugs, as set forth by FDA14,19,
used for comparison to brand ER oxycodone were ER morphine,
immediate release (IR) hydrocodone combination products, and
other Schedule II opioids (excluding brand ER oxycodone and
methadone). Other Schedule II opioids included analgesic tablets
that con- tained ER oxymorphone, ER hydromorphone, or IR
oxy- codone. It excluded methadone, transdermal fentanyl, and
Table 1. Summary of statistical regression models.
Model name Regression structure
Model 1 (PR) GEE Poisson with log-link function
Model 2 (ARDR) GEE Poisson with log-link function
Model 2a (ARDR) GEE Poisson with log-link function
Model 3 GEE Poisson with log-link function
Model 3a GEE Poisson with log-link function
Abbreviations. ARDR, abuse report dispensing ratio; ASI-MV, Addiction Severity Index-Multimedia Version; GEE, Generalized Estimating Equations; N/A, not applic-
able; PR, proportion.
CURRENT MEDICAL RESEARCH AND OPINION 581
ER tapentadol (because it entered the market after the refor-
mulation of OxyContin).
Descriptive analysis
Population characteristics of non-oral abuse and abuse by
inhaling and injecting were evaluated for brand ER oxy- codone
and comparator opioids. Characteristics included age, gender,
race, self-reported pain, the expected treatment modality (the
treatment setting anticipated by the clinician prior to assessment
completion; e.g. inpatient, outpatient), history of injection abuse
of prescription opioids, and the number of prescription opioid
products abused in the past 30 days.
Measures of abuse
Since opioid abuse is a multidimensional concept 19, three
measures of abuse were estimated in this study and imple-
mented in five statistical models. For the abuse risk meas- ures,
abuse count for studied opioids were used for the numerator,
while the number of assessments (proportion [PR]) and dosage
units dispensed (abuse report dispensing ratio [ARDR]) in a
region were used as the denominators. Abuse count, adjusted for
dosage units dispensed, was used for the third measure of abuse.
Statistical models
Five generalized linear models were employed to evaluate and
test for differences between the pre- and post-reformu- lation
periods on estimates of past 30-day non-oral abuse of brand ER
oxycodone and comparator opioids (Table 1). Model 1 uses
Poisson regression of abuse counts with a log- link function and
the number of assessments is used as an offset. Similarly, Model
2 uses Poisson regression of abuse counts with a log-link function
and dosage units dispensed within the respondents’ three-digit
ZIP Code is used as an offset. Model 2a adds the number of
assessments as a covari- ate to Model 2. Model 3 uses Poisson
regression of abuse counts with a log-link function but instead of
an offset, uses dosage units dispensed as a covariate. Model 3a
adds the number of assessments as a covariate to Model 3. The
regression structure used a generalized estimating equation
(GEE) to estimate the parameters of a generalized linear model
with a possible unknown correlation between outcomes.
Offset term Covariate
Total ASI-MV assessments N/A
Retail pharmacy units dispensed volume N/A
Retail pharmacy units dispensed volume Total ASI-MV assessments
N/A Retail pharmacy units dispensed volume
N/A Retail pharmacy units dispensed volume,
total ASI-MV assessments
582 R. D. RODRIGUEZ ET AL.
The statistical models used aggregate-level (area-level based
on respondent three-digit ZIP Code) counts of self- reported
abuse. Note that the repeated subject component of the Poisson
regression models was excluded in instances in which
convergence issues arose due to sparse data. When the model did
not converge with the repeated statement, the model was re-run
without it. With the dataset aggre- gated to the respondent three-
digit ZIP Code level by calen- dar quarter, the proposed research
question(s) while accounting for temporal correlation of
respondent three-digit ZIP Code level drug-specific probabilities
of abuse could be assessed.
Figures of the measures of abuse-time were generated.
Percent change from baseline and associated 95% confi- dence
intervals (CIs) were calculated. The statistical model estimates
were used to estimate ratios of risk ratios (RORR) and 95%
confidence intervals for brand ER oxycodone versus comparator
opioids. All analyses performed used the general linear modeling
procedure (GENMOD) in SAS 9.4. LSMESTIMATE statements
of the GENMOD procedure were used to estimate and test
parameters of interest (SAS 9.4, Cary, NC, USA).
For the interrupted time series analysis, applied to each of
these models, calendar quarters were ordered and represented by an
ordinal variable with unit increments per quarter during the
period from July 2008 to December 2014, with the six-month
transition period excluded. Log-linear regression was conducted
for the pre- and post-reformulation periods separately. Then, the
pre- and post-period slopes were compared, and the immediate
shift was evaluated as the per- cent difference between the model-
fitted last quarter of the pre-reformulation period to the first
quarter of the post- reformulation period.
Model assumption assessments were conducted for each
model to determine whether the relationships in the varia- bles
met the model assumptions by evaluating a residual versus linear
predictor plot. Model goodness-of-fit was assessed using Akaike
information criteria (AIC), AIC cor- rected (AICc) and Bayesian
information criteria (BIC) statistics, residual plots and observed
versus predicted plots.
The proportion (PR, Model 1) and the abuse report dis-
pensing ratio adjusted for the total number of assessments
(ARDR, Model 2a) are presented. Additional analyses and sen-
sitivity analyses were conducted and submitted to the FDA26.
Many of the additional analyses and sensitivity analyses were
conducted as a matrix with multiple combinations of attrib- utes
applied. While there were minor differences in the results for each
of the other analyses and sensitivity analyses compared to the
principal analyses presented here, none affected the
interpretations of the principal analyses.
Ethics
This study uses anonymized, de-identified data collected dur- ing
the course of ongoing clinical assessment at treatment facilities in
the NAVIPPRO Network. As such, it is exempt from
requirements for institutional review board review.
Informed consent
Not applicable due to our study design (non-human subject
research).
Results
A total of 66,897 assessments were included in this study. The
study sample in the pre-/post-reformulation periods included
989/2866 reports of non-oral brand ER oxycodone abuse, 90/641
of ER morphine, 820/4009 of IR hydrocodone combination
products, and 1924/6101 of other Schedule II opioids. The age,
ethnicity, and gender distribution of respondents was similar
across all brand ER oxycodone and primary comparator groups;
the male population proportion was slightly greater than the
female population in all groups (Table 2). Most subjects were age
21 to 34 years, white, had an expected treatment modality of
residential/inpatient or outpatient/non-methadone treatment, and
reported abusing approximately 6 to 8 different prescription
opioids in the past 30 days. Among brand ER oxycodone and
comparator opioid assessments, the expected treatment modality
was most frequently residential/inpatient and outpatient/non-
methadone treatment facilities. Among total assessments, the
treatment modality frequency of residential inpatient was less
than half of that reported in the opioid abuse reports groups and
DUI/DWI modality was higher (21.5% ver- sus 0.9% to 2.4%).
Individuals who reported ER morphine abuse had a higher
proportion of history of injection of pre- scription opioids
(75.9%) compared to abusers of brand ER oxycodone or other
comparator opioids (range: 31.3% to 54.1%).
Modeled brand ER oxycodone PR of non-oral abuse (Model 1;
Figure 1(A)) indicates a decline in non-oral abuse during the
post-reformulation period as compared to the pre-reformulation
period. The interrupted time series ana- lysis, shown in Figure
1(B), also demonstrates a decline in non-oral abuse, with a 52.1%
decrease in the last quarter of the pre-period model to the first
quarter of the post-period
(immediate shift; Table 3) for the PR. The average PR pre-to- post
decline was —30.7% (95% CI = —46.9, —9.5; Table 4). The PR
results from the comparator opioids, together with
the modeled abuse measure-time profiles, were significantly
different from the trends observed for brand ER oxycodone over
the post-reformulation period. Specifically, brand ER oxycodone
had the earliest as well as the largest reduction in abuse
comparatively across all study groups.
The non-oral ARDR (Model 2a; Figure 1(C)) also indicates a
decline in reports of non-oral abuse during the post-reformu-
lation period as compared to the pre-reformulation period,
however it was not as pronounced as the PR (Model 1). The
interrupted time series analysis, shown in Figure 1(D), also
demonstrates the decline for the non-oral brand ER oxy- codone
ARDR, with a 32.2% decrease in the last quarter of the pre-period
model to the first quarter of the post-period (immediate shift;
Table 3). The average pre-to-post ARDR
decline was —29.3% (95% CI = —37.5, —20.1; Table 4). The
ARDR results from the comparator opioids were different
 CURRENT MEDICAL RESEARCH AND OPINION 583

Table 2. Population characteristics of individuals who reported opioid abuse via non-oral routes among ASI-MV sites contributing quarterly assessment data.
Response Category Brand ER oxycodone ER morphine IR hydrocodone Other Schedule II All study assessments
N Pre 223 156 232 461 18923
Post 766 334 588 1473 41625
Age (%) Younger than 21 16.7% 16.0% 20.4% 16.7% 11.1%
21 to 34 62.6% 65.8% 52.8% 57.6% 42.0%
35 to 54 19.5% 18.0% 24.6% 23.8% 40.6%
55 and older 1.2% 0.2% 2.2% 1.8% 6.3%
Gender (%) Male 56.6% 52.1% 51.6% 54.2% 69.3%
Female 43.4% 47.9% 48.4% 45.8% 30.7%
Race (%) White 78.6% 89.9% 78.3% 76.9% 61.4%
Black 8.8% 2.5% 8.8% 10.4% 19.5%
Hispanic 9.0% 4.5% 8.2% 9.2% 11.0%
Other 3.5% 3.1% 4.7% 3.5% 8.1%
Self-reported pain (%) No 51.2% 46.1% 45.1% 46.8% 70.2%
Yes 48.7% 53.7% 54.7% 53.0% 29.6%
Unknown/missing 0.1% 0.2% 0.2% 0.3% 0.2%
Modality (%) Residential/inpatient 55.4% 54.6% 43.2% 49.0% 21.4%
Outpatient/non-methadone 27.9% 37.7% 37.2% 31.4% 31.8%
Methadone/LAAM 5.4% 2.2% 3.7% 5.2% 2.1%
Drug court 1.2% 0.9% 1.8% 1.3% 5.2%
Probation/parole 4.2% 1.4% 4.7% 4.6% 7.3%
DUI/DWI 1.2% 0.9% 2.4% 2.4% 21.5%
Other corrections 0.8% 0.5% 1.9% 1.3% 4.1%
TANF (welfare) 0.3% 0.0% 0.0% 0.0% 0.2%
Other 3.6% 1.8% 5.2% 4.8% 6.6%
Unknown/missing 0.0% 0.0% 0.0% 0.0% 0.0%
History of injection (%) At least one prescription 54.1% 75.9% 31.3% 42.4% 5.6%
opioid injected
Number of prescription Mean 6.6 7.5 5.6 5.2 0.4
opioids abused in past
30 days Median 6.0 6.0 5.0 4.0 0.0
Note: Total 66,897 assessments.
Abbreviations. ASI-MV, Addiction Severity Index-Multimedia Version; DUI, driving under the influence; DWI, driving while intoxicated; ER, extended release; IR
hydrocodone, immediate release hydrocodone combination products; LAAM, levacetylmethadol; TANF, temporary assistance for needy families.

Figure 1. Non-oral abuse-time and interrupted time series modeled data (selected models) for Oxycontin and opioid comparators for (A) modeled brand ER oxycodone
and comparator groups PR of non-oral abuse reports, (B) interrupted time series models of brand ER oxycodone and comparator groups PR of non-oral abuse reports,
(C) modeled brand ER oxycodone and comparator groups ARDR of non-oral abuse reports, and (D) interrupted time series models of brand ER oxycodone and compara-
tor groups ARDR of non-oral abuse reports. Abbreviations. ARDR, abuse report dispensing ratio; ER, extended release; IR, immediate release; PR, proportion.
584 R. D. RODRIGUEZ ET AL.

Table 3. Interrupted time series selected models’ assessment of immediate shift in ASI-MV reports of non-oral abuse.
Opioid Model Immediate shift (95% CI) [log risk] p Value
Brand ER oxycodone Model 1 (PR) —0.521 (—0.870, —0.172) Referent
Model 2a (ARDR) —0.322 (—0.773, 0.128) Referent
ER morphine Model 1 (PR) —0.079 (—0.577, 0.420) .15
Model 2a (ARDR) —0.065 (—0.713, 0.583) .52
IR hydrocodone Model 1 (PR) 0.139 (—0.291, 0.569) .02
Model 2a (ARDR) —0.088 (—0.648, 0.473) .52
Other Schedule II Model 1 (PR) 0.181 (—0.102, 0.465) .00
Model 2a (ARDR) 0.099 (—0.268, 0.467) .16
Note: Immediate shift = modeled last timepoint in pre-period to modeled first timepoint in the post-period.
Abbreviations. ARDR, abuse report dispensing ratio; ASI-MV, Addiction Severity Index-Multimedia Version; CI, confidence interval; ER, extended
release; IR, immediate release; PR, proportion.

Table 4. Pre- to post-period Poisson regression selected model results for ASI-MV reports of non-oral abuse.
Opioid Model Percentage change (95% CI) RoRR (95% CI)
Brand ER oxycodone Model 1 (PR) —30.7 (—46.9, —9.5) Referent
Model 2a (ARDR) —29.3 (—37.5, —20.1) Referent
ER morphine Model 1 (PR) —9.6 (—32.9, 21.7) 1.30 (0.87, 1.94)
Model 2a (ARDR) —24.5 (—37.0, —9.6) 1.07 (0.86, 1.33)
IR hydrocodone Model 1 (PR) 19.3 (—7.7, 54.3) 1.72 (1.19, 2.49)
Model 2a (ARDR) —8.2 (—20.6, 6.1) 1.30 (1.07, 1.57)
Other schedule II Model 1 (PR) 31.6 (—0.3, 73.7) 1.90 (1.29, 2.79)
Model 2a (ARDR) 14.5 (3.7, 26.4) 1.62 (1.38, 1.90)
Abbreviations. ARDR, abuse report dispensing ratio; ASI-MV, Addiction Severity Index-Multimedia Version; CI, confidence interval; ER, extended
release; IR, immediate release; IR hydrocodone, IR hydrocodone combination products; PR, proportion; RORR, ratio of risk ratios.

from the trend observed for brand ER oxycodone over the post-
reformulation period; ER morphine was the only com- parator
that showed a statistically significant decrease in non-oral abuse
(although not until 2012, Figure 1(C)) while a statistically
significant increase in abuse was discovered in the Other
Schedule II comparator group.
Sensitivity analyses
A narrower 95% confidence was observed for brand ER oxy-
codone percent change estimates for the sites contributing at least
one assessment per year, as expected with the add- itional data.
However, the width of the confidence intervals varied for the
comparator opioids. While the brand ER oxy- codone point
estimates for the percent change were gener- ally similar
according to site selection method, the estimates varied for
comparator opioids. The observed variation in point estimates
and occasional decreases in the precision of the estimates support
the assertion that the variation in sites may impact non-oral abuse
rates. The value in restricting the data set to the sites which
provided consistent reporting, is the provision of estimates from a
similar source population and appropriate data sources.
Therefore, the main analyses which restrict the data to the sites
which contributed data for at least 1 assessment/quarter in each
of the quarters dur- ing the pre- and post-reformulation periods,
was considered to be a more appropriate estimate of the change in
abuse measures in this population.
Discussion
We measured changes in non-oral abuse before and after
introduction of the reformulated brand ER oxycodone tab- lets,
employing five analytical models, applied with and
without interrupted time series approaches. These methods, along
with sensitivity analyses, provide evidence to support
effectiveness of reformulated brand ER oxycodone on reduc- tion
of non-oral abuse when evaluated against comparator opioids
within a sentinel population of adults evaluated for substance use
problems and treatment planning using the ASI-MV assessment.
As a condition of the U.S. FDA approval of the reformula-
tion of OxyContin in 2010, Purdue conducted a variety of
postmarketing epidemiology studies to monitor and quantify the
impact of the reformulation on abuse of OxyContin and its
consequences. As evaluating the effects of abuse-deter- rent
formulations was a new and unprecedented area of investigation,
numerous studies were conducted across a range of populations,
data sources, outcomes and time hori- zons. The study described
in this paper was one in a series of what FDA ultimately defined
as the four formal postmar- keting requirements (PMR), issued by
FDA in 2016, and designed in consultation with FDA, including
three observa- tional surveillance studies and one retrospective
claims study assessing overdose and overdose death risk changes
in a patient population17. In 2020, FDA held a public Advisory
Committee meeting where the committees discussed the results of
the required PMR26.
Since there is not consensus for one measure of abuse19, three
measures were selected. Each measure has strengths and
limitations and together provide a more complete assessment of
changes in abuse13. The first measure is the proportion of non-oral
abuse counts per number of assess- ments, a method that accounts
for the size of a population from which the opioid abuse cases
arose. The second meas- ure is non-oral abuse report dispensing
ratio per dosage units dispensed in the region from which the
cases arose, a drug availability denominator which is intended to
quantify abuse for the available product in the community. The
third

measure is a non-oral abuse count adjusting for dosage units
dispensed, a measure similar to the second measure, but
employing statistical methods that allow the model more
flexibility to estimate percent change with fewer assumptions
about the relationship between abuse counts and dosage units
dispensed. The ARDR and adjusted abuse count meas- ures of
abuse each had a variation for which the number of assessments
was also adjusted.
Several Poisson regression modeling approaches were
employed to assess changes in the selected measures of non-oral
abuse and abuse by route pre- and post-reformula- tion with
ADP. Model 1 used the number of assessments as an offset;
Model 2 used the dosage units dispensed, a utiliza- tion measure,
as an offset; Model 2a used the dosage units dispensed, a
utilization measure, as an offset and adjusted for the number of
assessments; Model 3 used dosage units dispensed as a
continuous covariate; Model 3a used dosage units dispensed and
number of assessments as covariates.
While the dosage units dispensed as a denominator for
the ARDR may be appropriate for other purposes, it has limi-
tations and complexities in interpretability in a population of
individuals who abuse opioids. Limitations include diversion of
the dosage units dispensed and related factors. Many indi- viduals
who abuse opioids are thought to abuse drugs that are both
available and cost the least, irrespective of the type of opioid24.
Therefore, price and availability are important considerations for
abuse over which specific opioid is abused, which limits the
utility of a utilization denominator. Variability in dose of each
tablet and pharmacokinetics (IR vs ER) further complicate
interpretability. Additionally, care should be taken in evaluating
models associated with dos- age units dispensed as they could be
direct causation or mediation variables. In other words, if it is
observed that a significant fraction of the change in abuse can be
explained by a decrease in demand among individuals who abuse
the product, then measuring the reformulation effect using this
model may lead to errors.
Overall, following the introduction of reformulated brand ER
oxycodone, self-reported non-oral brand ER oxycodone abuse
was significantly reduced among those assessed for substance use
problems and treatment planning. This reduc- tion was
distinguished from changes observed in comparator opioids. This
aligns with the expected effect of an abuse deterrent opioid
formulation which employs physicochemical barriers to deter
manipulation of the product for non-oral routes of abuse. This
study also illustrates convergent validity with other published
studies from a variety of data sources and summarized by Dart et
al. 24.
Modeled brand ER oxycodone PR and ARDR of non-oral
abuse reports indicated a decline in non-oral abuse during the
post-reformulation period as compared to the pre- reformulation
period. The interrupted time series analysis demonstrates a
decline in the immediate shift. The immedi- ate decline further
supports a reformulation effect based upon the temporal changes.
The average PR and ARDR pre-
to-post declines were —30.7% and —29.3, respectively, which
supports a sustained effect of the reformulation beyond the
immediate shift.
CURRENT MEDICAL RESEARCH AND OPINION 585
Comparator opioids (ER morphine, IR hydrocodone prod-
ucts, and other Schedule II opioids) were evaluated to pro- vide a
frame of reference for declines in abuse due to the effects of
numerous other opioid abuse interventions and other confounding
factors versus the effects due to the brand ER oxycodone
reformulation. The PR and ARDR results from the comparator
opioids were different from the trend observed for brand ER
oxycodone over the post-reformula- tion period. The differences
in the pre-post reformulation changes in non-oral abuse for the
comparator opioids rela- tive to brand ER oxycodone separate the
effectiveness of the reformulation of brand ER oxycodone from
other population- based interventions.
Strengths and limitations
A strength of the study is the broad surveillance system which
captures data from a hard-to-reach population of indi- viduals
who abuse prescription opioids. The centers utilizing the ASI-
MV in standard clinical practice are distributed throughout the
US. The reliability testing and validation of the assessment tool
provides assurance in the data collected. Another strength is the
variety and granularity of information collected from the
individuals assessed for substance use and treatment planning,
including route of abuse.
The variety of statistical approaches applied along with the
internal consistency in the results in the study provides another
strength of this study. Furthermore, the many sensi- tivity
analyses having results consistent with the principal analyses
were also a strength, demonstrating the robustness of the results.
To disentangle the effect of reformulation from other initiatives
aimed to curb prescription opioid abuse, comparator opioids were
studied for secular trends. The results from the diverse statistical
approaches and com- parator groups reinforce the interpretations
from the primary analysis, supporting a reformulation effect of
reduced non- oral abuse.
While the results provide evidence that the reformulation of
brand ER oxycodone was effective at reducing non-oral abuse, a
number of limitations in this study were present. First, the ability
to generalize results from adults evaluated with the ASI-MV for
substance use problems and treatment planning to the entire US
population of individuals who abuse prescription opioids may not
be completely appropri- ate. The data for this study were all self-
reported data which has limitations particularly for the population
of individuals who abuse opioids, which may be reluctant to
provide infor- mation for fear of legal implications or to admit
having a substance abuse problem. However, a previous study
indi- cated that use of the ASI-MV improved self-disclosure over
in-person ASI interviews with a clinician23. Another limitation is
the inclusion of repeat assessments outside a 30-day win- dow
which could bias the results toward the reports of abuse of the
repeat individuals.
As with any data source using self-reported data, mis-
classification could impact the results. However, the ASI-MV
assessment includes photographs of medications and popu- lar
slang terms to minimize recall bias. This study also
586 R. D. RODRIGUEZ ET AL.
assessed reports of OC or ORF, minimizing any misclassifica- tion
between the original and reformulated branded ER oxycodone.
For assessments completed by the same individual over time
(outside of a 30-day window), the probability of an indi- vidual
abusing certain opioid products would likely be corre- lated with
the probability of the same individual abusing the same or other
opioid products during same period when reassessed at other
points in time. However, such within-sub- ject correlation cannot
be addressed when the data are aggregated to the respondent 3-
digit ZIP Code level.
Due to the limitations in the study design, this study does not
allow for direct evaluation of causality, hence the breadth of
sensitivity analyses used to identify differential changes that
cannot be explained by secular trends or other opioid-wide
interventions.
Despite these limitations, many of which are commonly
present in epidemiologic studies, the ASI-MV provides a large
dataset employing a validated assessment instrument with
consistent and dedicated surveillance management. The var- iety
of statistical methods and robustness of the results fur- ther
provide confidence in the results.
Importantly, while a decline in non-oral abuse of reformu-
lated OxyContin was observed, abuse via inhalation and injection
routes, as well as the oral route, is still possible. Furthermore, the
reformulation of OxyContin was not expected to reduce abuse of
other products or reduce over- all abuse of opioids or non-opioid
drugs. ADFs of prescrip- tion opioid medications are but one part
of a multi-faceted approach to mitigate the opioid crisis. In
addition, the abuse- deterrent properties of reformulated
OxyContin do not change the risk of addiction. All prescription
opioids, includ- ing those with FDA-recognized ADP, carry risks
of addiction, abuse, and misuse, which can lead to overdose and
death.
Conclusions
The Poisson regression modeling applied to the ASI-MV sur-
veillance data in this study assessed the effectiveness of an ADP
product. Among individuals assessed for substance use and
treatment planning, a decline in non-oral abuse of brand ER
oxycodone was observed immediately after the six-month
transition period and the decline was sustained through the four
years of the follow-up period. The significant reductions in non-
oral abuse of brand ER oxycodone were not found in comparator
opioid products, thereby distinguishing the effectiveness of ORF
from competing population-based opi- oid abuse interventions or
other confounding factors.
Transparency
Declaration of funding
This work was supported by Purdue Pharma L.P., Stamford, CT. Uprise
Health/Inflexxion, Irvine, CA received funding from Purdue Pharma L.P. to
conduct this study and for the development of this manuscript. RDR was an
employee of Purdue Pharma L.P. at the time of the study. JLG and TDG are
employees of Inflexxion. VR is an employee of Ephicacy Consulting Group,
Iselin, New Jersey and collaborated as an external
consultant to Inflexxion for this study. Editorial support provided by Holly
Richendrfer, PhD of Evidera was funded by Purdue Pharma L.P.
Declaration of financial/other relationships
JLG and TDG are employees of, and VR is a consultant to, Inflexxion.
Inflexxion contracts with government agencies and multiple pharma- ceutical
companies that market some of the products included in the study groups
evaluated for this article. RDR was an employee of Purdue Pharma L.P., the
sponsor of OxyContin, at the time of the study. Peer reviewers on this
manuscript have no other relevant financial relation- ships or otherwise to
disclose.
Author contributions
Study conception/design: JLG, TDG, VR. Analysis/interpretation of data: RDR,
JLG, TDG, VR. Draft or revision of the manuscript: RDR, JLG, TDG, VR. All
authors have provided final approval of the version to be pub- lished. All
authors agree to be accountable for all aspects of the work.
Acknowledgements
The authors thank the Purdue Pharma L.P. Epidemiology Advisory Board for
their insights and feedback into the study design and Alec Walker for his
valuable contributions to the interpretation of the research. We also
acknowledge former Purdue Pharma L.P. researchers who had a role in early
study conceptualization and design aspects, and Stacy Baldridge, Jennifer
Giordano, and Nelson Sessler of Purdue Pharma L.P. for their insightful
feedback on the research. We thank Holly Richendrfer, PhD, of Evidera for
her editorial support.
Data availability statement
Source data are publicly available from the FDA and can be found at:
https://www.fda.gov/advisory-committees/advisory-committee-calendar/
september-10-11-2020-joint-meeting-drug-safety-and-risk-management-
advisory-committee-and-anesthetic.
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