Clinical Therapeutics/Volume ], Number ], 2015

Long-Term Safety and Efcacy of Tapentadol

Extended Release Following up to 2 Years of Treatment
in Patients With Moderate to Severe, Chronic Pain: Results
of an Open-Label Extension Trial
Robert Buynak, MD1; Stephen A. Rappaport, MD2; Kevin Rod, MD3;
Pierre Arsenault, MD4; Fabian Heisig, PhD5; Christine Rauschkolb, MD, PhD6; and
Mila Etropolski, MD6
Northwest Indiana Center for Clinical Research, Valparaiso, Indiana; 2Agewell Health, Indianapolis,
Indiana; 3Toronto Poly Clinic, Toronto, Ontario, Canada; 4Diex Research, Sherbrooke, Quebec, Canada;
5
Global Drug Safety, Grunenthal GmbH, Aachen, Germany; and 6Janssen Research & Development,
LLC, Raritan, New Jersey
1

ABSTRACT
Purpose: Tapentadol extended release (ER) has
demonstrated efcacy and safety for the management
of moderate to severe, chronic pain in adults. This
study evaluated the long-term safety and tolerability
of tapentadol ER in patients with chronic osteoarthritis or low back pain.
Methods: Patients were enrolled in this 1-year,
open-label extension study after completing one of
two 15-week, placebo-controlled studies of tapentadol
ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain
(NCT00449176), a 7-week crossover study between
tapentadol immediate release and tapentadol ER for
low back pain (NCT00594516), or a 1-year safety
study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After
titrating the drug to an optimal dose, patients received
tapentadol ER (100250 mg BID) for up to 1 year
(after nishing treatment in the preceding studies);
patients who were previously treated with tapentadol
ER in the 1-year safety study received tapentadol ER
continuously for up to 2 years in total.
Findings: Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were
female; 50.1% had mild baseline pain intensity. Mean
(SD) pain intensity scores (11-point numerical rating
scale) were 3.9 (2.38) at baseline (end of preceding
study) and 3.7 (2.42) at end point, indicating that
pain relief was maintained during the extension
study. Improvements in measures of quality of life

] 2015

(eg, EuroQol-5 Dimension and the 36-item Short Form

Health Survey [SF-36]) health status questionnaires)
achieved during the preceding studies were maintained
during the open-label extension study. Tapentadol ER
was associated with a safety and tolerability prole
comparable to that observed in the preceding studies.
The most common treatment-emergent adverse events
(incidence Z10%; n 1154) were headache (13.1%),
nausea (11.8%), and constipation (11.1%). Similar
efcacy and tolerability results were shown for patients
who received up to 2 years of tapentadol ER treatment.
Implications: Pain relief and improvements in quality
of life achieved during the preceding studies were maintained throughout this extension study, during which
tapentadol ER was well tolerated for the long-term
treatment of chronic osteoarthritis or low back pain over
up to 2 years of treatment. (ClinicalTrials.gov identier:
NCT00487435.) (Clin Ther. 2015;]:]]]]]]) & 2015
Published by Elsevier HS Journals, Inc.
Key words: chronic pain, extension study, low back
pain, osteoarthritis pain, tapentadol ER.

INTRODUCTION
Opioid analgesics have demonstrated efcacy for the
management of moderate to severe, chronic osteoarthritis
Accepted for publication August 20, 2015.
http://dx.doi.org/10.1016/j.clinthera.2015.08.014
0149-2918/$ - see front matter
& 2015 Published by Elsevier HS Journals, Inc.

Clinical Therapeutics
pain,13 as well as low back pain,1,4,5 and are recommended for the management of chronic pain in patients
who have failed to respond to other analgesics.3,6,7
However, strong evidence regarding the efcacy of opioid
analgesics for the long-term management of chronic
nonmalignant pain is scarce.4,8,9 Long-term pain management with opioids can be limited by the occurrence of
adverse effects, such as nausea, vomiting, and constipation.10 These adverse effects may lead patients to stop
taking their opioid analgesics,11 resulting in a disruption
of pain relief. Physicians may also be hesitant to prescribe
opioids for the management of chronic pain because of
the risk of tolerance development and dependence and the
risk of adverse effects associated with long-term opioid
therapy.12
Tapentadol is a centrally acting analgesic that has
m-opioid receptor agonist and norepinephrine reuptake
inhibitor activities, both of which contribute to its
analgesic efcacy.1315 Phase III studies have shown
the efcacy and safety of tapentadol extended release
(ER; 100-250 mg BID) for the management of moderate to severe, chronic pain.1625 Tapentadol ER has
been evaluated in patients with chronic osteoarthritis
pain,1618,24 low back pain,1719,24 neuropathic pain
associated with diabetic peripheral neuropathy,20,25
and tumor-related pain.2123
The objective of the present 1-year, Phase III, openlabel extension study was to characterize the long-term
safety and tolerability prole of tapentadol ER
(100250 mg BID) in patients with moderate to severe,
chronic osteoarthritis hip or knee pain or low back
pain. The study also evaluated withdrawal symptoms
after discontinuation of tapentadol ER and the effects of
tapentadol ER treatment on pain intensity, health status
measures, and sleep quality and duration.

PATIENTS AND METHODS

The protocol and amendments of this study were
reviewed by independent ethics committees and institutional review boards. This study was conducted in
accordance with the principles of the Declaration of
Helsinki and Good Clinical Practice guidelines. All
patients signed an informed consent document to
conrm that they understood the study purpose and
procedures and were willing to take part in the study.

Patients
This 1-year, open-label extension study (NCT00487435)
included patients who had completed 1 of the 4

following studies: a 15-week, randomized, double-blind,

placebo-controlled, Phase III study that evaluated the
efcacy of tapentadol ER and oxycodone controlled
release (CR) for moderate to severe, chronic osteoarthritis
knee pain (NCT00421928)16; a 15-week, randomized,
double-blind, placebo-controlled, Phase III study that
evaluated the efcacy of tapentadol ER and oxycodone
CR for moderate to severe, chronic low back pain
(NCT00449176)19; a 7-week, randomized, doubleblind, Phase IIIb, crossover study that evaluated dose
conversion between tapentadol immediate release and
tapentadol ER for patients with moderate to severe,
chronic low back pain (NCT00594516)26; or a 1-year,
randomized, open-label, Phase III study that evaluated the
long-term safety of tapentadol ER and oxycodone CR for
moderate to severe, chronic osteoarthritis hip or knee
pain or low back pain (NCT00361504).18 Details of the
methods and results of these studies have been published
previously.16,18,19,26 Patients were willing to take tapentadol ER and rescue medication (acetaminophen) for the
duration of the extension study. Patients who were
expected to require major surgery during the study and
patients who had a clinically signicant disease or a
condition in addition to osteoarthritis or low back pain
that could affect efcacy or safety assessments were
excluded from the study.
Selective serotonin reuptake inhibitors and serotoninnorepinephrine reuptake inhibitors were permitted if
prescribed for a reason other than pain (ie, depression)
at a controlled, stable dose for at least 30 days before
screening for the extension study. Benzodiazepines, mood
stabilizers (used as minor tranquilizers or hypnotics), antiParkinsonian drugs, and anticonvulsants were permitted
for patients who were on a controlled, stable dose for at
least 30 days before screening. Transcutaneous electrical
nerve stimulation, acupuncture, and other similar interventional adjunctive therapies were permitted during the
study for patients who had been on regular therapy for
at least 14 days. Acetylsalicylic acid (r325 mg/d orally)
was allowed for cardiac prophylaxis. The occasional,
limited use of NSAIDs for reasons other than chronic
pain (eg, toothache, headache, fever) was allowed; patients
were required to discuss any NSAID use with the
investigator. All other analgesics except for tapentadol
ER and specied doses of acetaminophen (see Study
Design) were prohibited during the study. Neuroleptics
and monoamine oxidase inhibitors were prohibited within
14 days of screening and throughout the study; systemic
corticosteroids were also prohibited throughout the study.

Volume ] Number ]

R. Buynak et al.

Study Design
This Phase III, single-arm, multicenter, 1-year,
open-label, extension study consisted of the following
3 phases: a screening and titration period (up to 4
weeks), a maintenance period (up to 48 weeks), and a
follow-up period. During the titration period, patients
who had completed one of the two 15-week, doubleblind, efcacy studies16,19; a 7-week, double-blind,
crossover study26; or oxycodone CR treatment during
the 1-year, open-label, safety study18 were titrated
to their optimal therapeutic dose of tapentadol ER
(100250 mg BID). Patients who were taking
tapentadol ER during the 1-year, open-label safety
study18 continued on the same dose and did not
require titration.
The titration schedule could be tailored to suit the
needs of the individual patient because some patients
had been taking moderate to high doses of tapentadol
ER or oxycodone CR, while others were taking
placebo in the preceding studies. The speed of the
titration schedule was determined by the investigator
in agreement with the patient. For the standard
titration schedule, patients initiated treatment with
tapentadol ER 50 mg BID for the rst 3 days of the
titration period and then increased their doses to 100
mg BID for the next 4 days; doses could be increased
in 50-mg increments after a minimum of 3 days on the
same dose (to a maximum of 250 mg BID), and doses
could be decreased with no time restriction (to a
minimum dose of 100 mg BID) to achieve the dose
providing optimal therapeutic benets. For patients
who were previously treated with opioid analgesics
and required an accelerated titration schedule
(to minimize withdrawal symptoms or to quickly
achieve pain control), the dose level could be increased
after the starting 50-mg dose; the accelerated titration
schedule was determined by the investigator in collaboration with the patient, taking into consideration
the clinical status and treatment requirements of the
patient during the preceding study. For the accelerated
titration schedule, the same minimum (100 mg BID)
and maximum (250 mg BID) doses of tapentadol ER
were applied as in the standard titration schedule.
Titration was completed in 1, 2, or 3 weeks;
patients who achieved an optimal therapeutic dose
by the end of the rst or second week of titration
could continue on that dose into the maintenance
period. Patients were to continue taking the optimal
dose of tapentadol ER (100250 mg BID) determined

] 2015

during titration throughout the 48-week maintenance

period. Acetaminophen (r1000 mg/d) was permitted
during the titration and maintenance periods
(r7 consecutive days; r14 of 30 days).

Efficacy and Health Status Evaluations

All patients rated their average pain intensity over
the previous 24 hours at each monthly visit on an
11-point numerical rating scale (0 no pain to
10 pain as bad as you can imagine). Additional
efcacy and health status outcomes included the
Patient Global Impression of Change (PGIC), the
EuroQol-5 Dimension (EQ-5D),27,28 and the 36-item
Short Form Health Survey (SF-36)29 health status
questionnaires. For the PGIC, patients indicated their
perceived change in overall status by completing the
statement, Since I began study treatment, my overall
status is using a 7-point scale (1 very much
improved to 7 very much worse). Patients
completed the PGIC at baseline, at weeks 24 and
48, and at the end of treatment. The EQ-5D questionnaire was used to measure 5 dimensions of health
status (mobility, self-care, usual activities, pain or
discomfort, and anxiety or depression); each dimension was rated by using 1 of 3 possible responses
(no problems, some problems, or extreme problems).27,28 For the EQ-5D, patients also rated their
overall health state on a 0 to 100 visual analog scale
(0 = worst imaginable health state to 100 =
best imaginable health state). The SF-36 questionnaire was used to measure 8 dimensions of patients
physical, social, and mental well-being (physical functioning, role-physical, bodily pain, general health,
vitality, social functioning, role-emotional, and mental
health) on a scale from 0 to 100 (0 = poor health to
100 = good health).29 Both the EQ-5D and the
SF-36 questionnaires were assessed at screening; at
weeks 4, 8, 12, 16, 28, and 40; and at the end of
treatment for patients who had completed 1 of the
15-week, double-blind, efcacy studies16,19 or the
1-year, open-label, safety study.18 The EQ-5D and
SF-36 questionnaires were not required for patients
who had completed the 7-week, double-blind, crossover study26 because these assessments were not
recorded during the preceding study.

Safety and Tolerability Evaluations

Clinical laboratory tests were performed at the rst
visit and at weeks 1, 8, 20, 28, 40, and 52 or at the end

Clinical Therapeutics
of treatment; ECG measurements were recorded at the
rst visit and at weeks 1, 28, and 52 or at the end of
treatment. Although this trial was not designed to assess
the QT interval of tapentadol, the assessment was added
to evaluate patient safety throughout the trial. Vital sign
measurements were recorded at all visits. Adverse events
(AEs) were recorded through the nal visit. A treatmentemergent AE (TEAE) was dened as any AE that initially
occurred or worsened in intensity on or after the rst
intake of study drug during the present open-label
extension study. A serious AE was dened as any AE
that resulted in death, was life-threatening, required inpatient hospitalization or increased the duration of a
hospitalization event, resulted in persistent or signicant
disability or capacity, resulted in a congenital anomaly or
birth defect, or was considered medically important.
The severity of constipation-related symptoms was
evaluated by using the Patient Assessment of Constipation Symptoms (PAC-SYM), a patient-rated questionnaire that consists of 12 items rated on a 5-point
scale (0 absent to 4 very severe).30 The
PAC-SYM was evaluated at the rst visit, at weeks
12 and 28, and at week 52 or at the end of treatment.
Opiate withdrawal after discontinuation of study drug
in patients who did not take opioids following discontinuation was evaluated by using the Clinical Opiate Withdrawal Scale (COWS) and the Subjective Opiate
Withdrawal Scale (SOWS).31 The COWS, which was
evaluated at the follow-up visit after study completion or
discontinuation, is an 11-item, clinician-rated scale that
primarily evaluates the physical components of opiate
withdrawal (based on questions and clinical observations);
each item was rated on a scale from 0 to 4 or from 0 to 5,
depending on the item. A 15-item version of the SOWS,
which was scheduled for completion at 24, 48, and 72
hours after study drug discontinuation, was used in the
present study; 1 item of the original 16-item scale (which
has been used in detoxication settings with opioid
addicts) was not considered to be relevant to the present
study population and was not included.31
A 4-item sleep questionnaire was used to evaluate
sleep latency, time slept, number of awakenings, and
sleep quality experienced by patients during the previous
night32,33 at the rst visit; at weeks 4, 8, 12, 16, 28, and
40; and at week 52 or the end of treatment.

Statistical Analysis
A total of 1082 patients were planned to be
eligible for the open-label extension study from the

4 preceding studies based on the planned number of

patients to be randomized in each study (942 patients
for each of the 15-week, double-blind, efcacy studies;
650 patients in the North American sites of the 1-year,
open-label, safety study; and 75 patients in the
7-week, double-blind, crossover study) and the estimated discontinuation rate for these 4 preceding
studies (40% during the rst month of study treatment and 10% every month thereafter).16,18,19,26
The safety population included all patients who
received 1 dose of tapentadol ER during the openlabel extension study. The intention-to-treat population
comprised all patients included in the safety population,
except for the 5 patients treated at a site that had major
audit ndings identied before database lock. Analyses of
safety were performed by using the safety population;
analyses of efcacy were performed by using the
intention-to-treat population. Patients were grouped according to their preceding study and previous treatment
received during that study (placebo, tapentadol ER for up
to 15 weeks [includes patients who received tapentadol
ER in the 7-week study or in 1 of the 15-week studies],
tapentadol ER for 1 year, oxycodone CR for 15 weeks,
oxycodone CR for 1 year). Patients from the 2 doubleblind, efcacy studies16,19 and patients from the doubleblind, crossover study26 were grouped because those
studies were of similar duration (r15 weeks); patients
from the 1-year, open-label, safety study18 were grouped
separately. Baseline values were dened as the values
from the last available assessment (end point) of the
preceding study that were recorded before or on the day
of the rst dose of open-label tapentadol ER in the
present extension study.
The duration of study drug exposure, number of
dose changes, and the number of consecutive days
with no change in dose were summarized. Pain
intensity scores and changes from baseline in pain
intensity were summarized by using descriptive statistics at each time point and at end point. The last
observation carried forward (LOCF) was used for
imputing missing pain intensity scores at end point.
The incidence of TEAEs and TEAEs associated
with study discontinuation were summarized for the
overall treatment period, and incidence proportions of
treatment-emergent serious AEs were summarized for
the overall treatment period and according to age
group (Z65 and o65 years of age).
A separate analysis of efcacy and safety results
was performed for patients who had received

Volume ] Number ]

R. Buynak et al.
tapentadol ER for up to 2 years (those who received
tapentadol ER during the 1-year safety study18 and
then entered this 1-year, open-label extension study).

RESULTS
Patients

OLE study

Preceding study

This study was conducted from June 4, 2007 to

June 29, 2009. A total of 1154 patients from sites in
the United States, Canada, Australia, and New Zealand who enrolled in the present open-label extension
study and received 1 dose of study drug were
included in the safety population (Figure 1).
Of the 1154 patients in the safety population, 303
had previously received placebo, 358 had received
tapentadol ER for up to 15 weeks, 249 had received
tapentadol ER for 1 year, 199 had received oxycodone
CR for 15 weeks, and 45 had received oxycodone CR
for 1 year. Baseline and demographic characteristics for
the total safety population (collected at the beginning of
the preceding study, with the exception of baseline
pain intensity) are summarized in Table I; 82.7%
(954 of 1154) of patients were aged o65 years,
50.1% (578 of 1154) had mild baseline pain intensity,
and 98.5% (1137 of 1154) had a primary diagnosis of
osteoarthritis knee pain or low back pain. Baseline and
demographic characteristics were generally comparable
across the prior treatment groups.
Overall, 60.5% (697 of 1152) of patients completed
treatment. Two patients did not have an end-of-treatment

reason for discontinuation and are not included in this

summary. The most common reasons for treatment
discontinuation were AEs (13.0% [150 of 1152]) and
patient choice (10.6% [122 of 1152]). Patient disposition
according to treatment received during the preceding
study is summarized in Figure 1. The incidence of
treatment discontinuations was numerically lower for
patients who had received 1 year of prior treatment
with tapentadol ER (24.1% [60 of 249]) compared
with those who had previously received placebo (48.8%
[148 of 303]), tapentadol ER for up to 15 weeks (41.5%
[148 of 357]), oxycodone CR for 15 weeks (42.9%
[85 of 198]), or oxycodone CR for 1 year (31.1%
[14 of 45]; Table II).
The incidence of treatment discontinuation due to
AEs was relatively low (o20%) across all groups of
patients categorized according to their prior treatment. It was lowest for patients who had received
1 year of prior treatment with tapentadol ER (6.4%
[16 of 249]) and also lower for patients who received
tapentadol ER for up to 15 weeks (11.2% [40 of 357])
than for those who had previously received placebo
(18.2% [55 of 303]), oxycodone CR for 15 weeks
(15.7% [31 of 198]), or oxycodone CR for 1 year
(17.8% [8 of 45]; Table II).
During the open-label treatment period, 95.3%
(1100 of 1154) of patients in the safety population
took at least 90% of the BID doses of study drug.
Similar results were observed for patients divided

Received placebo
15 weeks
n = 656

Received tapentadol ER
15 weeks
n = 778

Received oxycodone CR
15 weeks
n = 670

Received tapentadol ER
1 year
n = 894

Received oxycodone CR
1 year
n = 223

Completed study
n = 355

Completed study
n = 418

Completed study
n = 251

Completed study
n = 412

Completed study
n = 78

Entered OLE and

received 1 dose
tapentadol ER
n = 303

Entered OLE and

received 1 dose
tapentadol ER
n = 358

Entered OLE and

received 1 dose
tapentadol ER
n = 199

Entered OLE and

received 1 dose
tapentadol ER
n = 249

Entered OLE and

received 1 dose
tapentadol ER
n = 45

Discontinued
n = 148
Completed OL
treatment
n = 155

Discontinued
n = 148*
Completed OL
treatment
n = 209

Discontinued
n = 85*
Completed OL
treatment
n = 113

Discontinued
n = 60
Completed OL
treatment
n = 189

Discontinued
n = 14
Completed OL
treatment
n = 31

Figure 1. Patient disposition and treatment in preceding study. ER extended release; CR controlled release;
OLE open-label extension; OL open-label. *Two patients did not have end-of-treatment data and
are excluded from this total. These patients were withdrawn prematurely from the study.

] 2015

Clinical Therapeutics
Table I. Baseline and demographic characteristics*
(safety population). Unless otherwise
indicated, values are given as mean (SD).
Characteristic

All Patients
(N 1154)

Age, y
54.3 (11.43)
Age category, no. (%)
o65 y
954 (82.7)
Z65 y
200 (17.3)
Sex, no. (%)
Male
486 (42.1)
Female
668 (57.9)
Race, no. (%)
White
911 (78.9)
Black
150 (13.0)
Hispanic
65 (5.6)
Other
28 (2.4)
33.1 (8.48)
Body mass index, kg/m2
Baseline pain intensity score
3.9 (2.38)
Baseline pain intensity category, no. (%)
Mild
578 (50.1)
Moderate
282 (24.4)
Severe
294 (25.5)
Primary diagnosis, no. (%)
Knee osteoarthritis
515 (44.6)
Hip osteoarthritis
17 (1.5)
Low back pain
622 (53.9)
*

With the exception of baseline pain intensity, baseline

and demographic characteristics were collected at the
beginning of the preceding study.

Overall population, n 1151.

Mild was dened as baseline pain intensity o4; moderate

was dened as baseline pain intensity Z4 to o6; and
severe was dened as baseline pain intensity Z6.

according to their prior treatment. A total of 58.6%

(676 of 1154) of patients were on a stable dose
(ie, their individual, most frequently used [modal]
total daily dose) for 490% of the time that they were
receiving open-label treatment. During the open-label
treatment period, 70.9% (819 of 1154) of patients
received at least 6 months of treatment; 16.9%
(195 of 1154) received at least 1 year of treatment.
For the total study population, the median duration of
tapentadol ER treatment during the present open-label

study was 339.0 days (range, 1435 days). Regardless

of prior treatment, the majority of patients received
open-label tapentadol ER treatment for at least
9 months (Table III).
During the study, 38.7% (447 of 1154) of patients
received a concomitant nonopioid analgesic, including
acetylsalicylic acid (18.4% [212 of 1154]), acetaminophen (8.4% [97 of 1154]), or ibuprofen (5.8% [67 of
1154]). The percentages of patients taking any non-opioid
analgesic during the study period were similar across all
prior treatment groups, as follows: placebo (36.3%
[110/303]), tapentadol ER for up to 15 weeks (39.4%
[141/358]), oxycodone CR for up to 15 weeks (31.2%
[62/199]), oxycodone CR for 1 year (37.8% [17/45]),
and tapentadol ER for 1 year (47.0% [117/249]).

Efficacy
In the intention-to-treat population, the mean pain
intensity score remained relatively stable throughout the
study; the mean (SD) pain intensity score was 3.87 (2.379)
at baseline and 3.65 (2.416) at end point (using the LOCF
for imputing missing scores), and the mean (SE) change
from baseline to end point in pain intensity was
0.20 (0.067). On average, patients who had received
placebo before entering the present trial had the largest
decrease in pain intensity scores. Mean (SE) changes from
baseline to end point in pain intensity according to prior
treatment were as follows: placebo, 0.89 (0.139);
tapentadol ER for up to 15 weeks, 0.00 (0.112);
tapentadol ER for 1 year, 0.26 (0.145); oxycodone CR
for 15 weeks, 0.19 (0.153); and oxycodone CR for
1 year, 0.12 (0.284).
On the PGIC, 61.4% (650 of 1059) of patients
reported that their overall status was very much
improved or much improved from baseline at end point
in the present study. An additional 25.7% (272 of 1059)
of patients reported that their overall status was
minimally improved. Across the 5 groups of patients
divided according to their prior treatment, the percentage of patients reporting improvement on the PGIC
(very much improved, much improved, or minimally
improved) ranged from 78.0% to 92.8% (placebo,
84.8% [240 of 283]; tapentadol ER r15 weeks,
86.3% [289 of 335]; tapentadol ER 1 year, 92.8%
[207 of 223]; oxycodone CR 15 weeks, 87.0% [154 of
177]; oxycodone CR 1 year, 78.0% [32 of 41]).
Mean changes from baseline to end point were small
among all treated patients, regardless of prior treatment,

Volume ] Number ]

] 2015
Table II. Disposition status according to prior treatment group and for all patients (safety population). Values are given as number (%).
Disposition Status or
Reason for Discontinuation

Placebo
(n 303)

Completed treatment
Discontinued treatment
Adverse event
Patient choice
Study medication
noncompliant
Lost to follow-up
Lack of efcacy
Pregnancy
Death
Resolution of pain
Other

155
148
55
37
11

(51.2)
(48.8)
(18.2)
(12.2)
(3.6)

16 (5.3)
14 (4.6)
0
1 (0.3)
0
14 (4.6)

Tapentadol
ER r15 Weeks
(n 357)*
209
148
40
42
19
10
14
2
1

(58.5)
(41.5)
(11.2)
(11.8)
(5.3)

(2.8)
(3.9)
(0.6)
(0.3)
0
20 (5.6)

Tapentadol ER
1 Year (n 249)
189
60
16
18
5

(75.9)
(24.1)
(6.4)
(7.2)
(2.0)

5 (2.0)
5 (2.0)
0
0
0
11 (4.4)

Oxycodone CR
15 Weeks
(n 198)*
113
85
31
23
9

(57.1)
(42.9)
(15.7)
(11.6)
(4.5)

12 (6.1)
3 (1.5)
0
0
1 (0.5)
6 (3.0)

Oxycodone CR
1 Year (n 45)
31
14
8
2
2

(68.9)
(31.1)
(17.8)
(4.4)
(4.4)

0
1 (2.2)
0
0
0
1 (2.2)

Total
(N 1152)
697
455
150
122
46

(60.5)
(39.5)
(13.0)
(10.6)
(4.0)

43
37
2
2
1
52

(3.7)
(3.2)
(0.2)
(0.2)
(0.1)
(4.5)

ER extended release; CR controlled release.

*
One patient did not have an end-of-treatment case report form and was excluded.

One additional death was reported, but treatment with tapentadol ER had been discontinued because of patient choice 3 days before death.

R. Buynak et al.

Clinical Therapeutics

Table III. Duration of open-label tapentadol extended release (ER) treatment according to prior treatment
group (safety population).*

Treatment Duration

Placebo
(n 303)

Tapentadol ER
r15 Weeks
(n 358)

Tapentadol ER
1 Year
(n 249)

Oxycodone CR Oxycodone CR
15 Weeks
1 Year
(n 199)
(n 45)

Duration of treatment category, no. (%)

40 to o3 mo
80 (26.4)
67 (18.7)
15 (6.0)
47 (23.6)
10 (22.2)
Z3 to o6 mo
35 (11.6)
41 (11.5)
15 (6.0)
22 (11.1)
3 (6.7)
Z6 to o9 mo
15 (5.0)
21 (5.9)
18 (7.2)
9 (4.5)
0
Z9 to o12 mo
125 (41.3)
165 (46.1)
165 (66.3)
85 (42.7)
21 (46.7)
Z1 y
48 (15.8)
64 (17.9)
36 (14.5)
36 (18.1)
11 (24.4)
Mean (SD) duration of 233.3 (146.14) 258.8 (133.77) 301.3 (92.61)
243.5 (146.46) 266.2 (147.90)
treatment, d
Median (range) duration 339.0 (4435) 346.0 (1399) 337.0 (21373) 348.0 (2388) 356.0 (1383)
of treatment, d
CR controlled release.
*
Includes total duration of treatment during the open-label extension study.

in the EQ-5D mobility, self-care, usual activities, pain or

discomfort, and anxiety or depression dimensions; the
health status index score; and the overall health state
visual analog scale score. These ndings indicate that
improvements observed in EQ-5D scores during the
preceding studies were maintained throughout and with
up to 1 year of open-label treatment with tapentadol
ER. In general, mean changes from baseline to end
point in all 8 SF-36 dimensions and the 2 summary
scores were small (o5 points) and similar across all
groups of patients divided according to their prior
treatment and in the overall population. These results
suggest that the improvements in health status observed
during the preceding studies were maintained throughout this 1-year open-label extension study. However,
clinically important changes (Z5 points)34 from
baseline to end point were observed in the SF-36
physical functioning score (mean [SE] change from
baseline, 7.1 [1.10]), role-physical score (6.4 [2.44]),
and bodily pain score (7.1 [1.24]) for patients who had
previously received placebo, and in the role-emotional
score for patients who previously received oxycodone
CR for 1 year (6.1 [6.27]).

Safety and Tolerability

For all laboratory parameters, the percentage
of patients overall who had a normal baseline value

and 1 postbaseline laboratory value that was considered potentially clinically important was low
(o1%). Less than 3% of patients with normal baseline vital sign values had ndings that were considered
potentially clinically important at any time during
open-label treatment with tapentadol ER. The incidence of ECG abnormalities at any time during treatment among patients with normal baseline ECG
values was also low (o3%). A QTc interval prolongation of Z500 ms was observed for 0.3% (4 of
1154) of patients who had a QTc interval o500
milliseconds at baseline. Three of these patients had a
cardiac-related medical history; the QTc interval
prolongation did not suggest a causal relationship to
the administration of tapentadol ER for these patients.
For the remaining patient, the QTc interval prolongation
occurred on the same day as a TEAE of myocardial
ischemia (assessed as unlikely related to study treatment).
For the safety population, the most common TEAEs
(incidence Z10%) reported during open-label tapentadol ER treatment were headache (13.1% [151
of 1154]), nausea (11.8% [136 of 1154]), and constipation (11.1% [128 of 1154]). Nausea and constipation were reported less frequently for patients
who had completed 1 year of tapentadol ER treatment
before entering the open-label extension study than for
those who had taken placebo, tapentadol ER, or

Volume ] Number ]

R. Buynak et al.
oxycodone CR for up to 15 weeks or oxycodone CR
for 1 year before entering the open-label extension
study (Table IV).
Treatment-emergent serious AEs were reported for
7.3% (84 of 1154) of patients; the incidence of
treatment-emergent serious AEs ranged from 4.5% to
8.8% across all groups of patients divided according to
their prior treatment. Overall, 0.9% (10 of 1154) of
patients experienced treatment-emergent serious AEs
that were considered to be at least possibly related to
study treatment. The serious AEs reported in this study
included 3 deaths (1 cardiac arrest, 1 myocardial
infarction, and a completed suicide). The patient who
died as a result of suicide had a medical history of
chronic depression and social problems; this patient
had become severely depressed after the loss of his job
and was treated with sertraline, trazodone, and lithium. The patient committed suicide 3 days after the
last intake of study medication.
The incidence of treatment-emergent serious AEs
was 9.5% (19 of 200) for patients aged Z65 years
and 6.8% (65 of 954) for patients aged o65 years.
For patients aged Z65 years, treatment-emergent
serious AEs were reported for 11.9% (8 of 67) of
patients who previously received placebo, 7.5%
(4 of 53) who previously received up to 15 weeks of
tapentadol ER treatment, 11.8% (6 of 51) who
previously received 1 year of tapentadol ER treatment,
4.3% (1 of 23) who previously received 15 weeks of
oxycodone CR treatment, and 0% (0 of 6) who
previously received 1 year of oxycodone CR treatment. Treatment-emergent serious AEs were reported
for similar percentages of patients aged o65 years
across all prior treatment groups (placebo, 6.4% [15
of 236]; tapentadol for r15 weeks, 7.5% [23 of 305];
tapentadol for 1 year, 8.1% [16 of 198]; oxycodone
CR for 15 weeks, 4.5% [8 of 176]; and oxycodone
CR for 1 year, 7.7% [3 of 39]).
TEAEs leading to discontinuation occurred in
12.0% (139 of 1154) of patients overall; these
occurred in a lower percentage of patients who
previously received 1 year of tapentadol ER treatment
(5.6% [14 of 249]) or up to 15 weeks of tapentadol
ER treatment (10.9% [39 of 358]) than in those who
previously received placebo (17.5% [53 of 303]),
15 weeks of oxycodone CR treatment (13.1% [26 of
199]), or 1 year of oxycodone CR treatment (15.6%
[7 of 45]). Overall, the most common TEAEs leading

] 2015

to discontinuation were nausea (1.4% [16 of 1154])

and dizziness (1.3% [15 of 1154]).
The COWS assessments performed 2 to 4 days after
abrupt discontinuation of study drug at the end of the
study (or after early withdrawal from the study)
showed that 88.8% (341 of 384) of patients had no
opiate withdrawal (total score, 04), 10.7% (41 of
384) had mild withdrawal (total score, 512), and
0.5% (2 of 384) had moderate withdrawal (total score,
1324). No patient had moderately severe (total score,
2536) or severe (total score, 3748) withdrawal
based on COWS assessments. The COWS assessments
performed Z5 days after discontinuation of study
drug found that 90.7% (291 of 321) of patients had
no opiate withdrawal, 8.7% (28 of 321) had mild
withdrawal, and 0.6% (2 of 321) had moderate
withdrawal. Results of COWS assessments according
to prior treatment group, which were performed 2 to 4
days after discontinuation of study drug, are summarized in Figure 2. The percentages of patients with no
opiate withdrawal based on COWS assessments
performed Z5 days after discontinuation of study
drug according to prior treatment were as follows:
placebo, 92.5% (74 of 80); tapentadol ER for up to
15 weeks, 92.3% (96 of 104); tapentadol ER for
1 year, 88.2% (60 of 68); oxycodone CR for 15 weeks,
87.3% (55 of 63); and oxycodone CR for 1 year,
100.0% (6 of 6).
TEAEs of drug withdrawal syndrome or withdrawal
syndrome were reported for 4.5% (52 of 1154) of
patients overall; the incidence of drug withdrawal
syndrome or withdrawal syndrome was low and similar
(o5%) for patients who previously received placebo,
tapentadol ER, or oxycodone CR for up to 15 weeks
or who received tapentadol ER for 1 year. Of the
52 patients in the safety population with a TEAE of
drug withdrawal syndrome or withdrawal syndrome,
COWS data were available for 44 of the patients. The
COWS data indicated no opiate withdrawal for 27 of
these patients, mild opiate withdrawal for 15 patients,
and moderate opiate withdrawal for 2 patients.
Overall, mean SOWS total scores for patients who
did not take opioids after study discontinuation ranged
from 4.5 to 9.3 (of a possible 60; higher scores
indicated more severe withdrawal31), with the highest
scores reported 2 to 3 days after the last intake of study
drug. Mean total SOWS scores were comparable across
all prior treatment groups.

Volume ] Number ]

System Organ Class

TEAE

Placebo
(n 303)

Tapentadol ER
r15 Weeks
(n 358)

Tapentadol ER
1 Year
(n 249)

Oxycodone CR
15 Weeks
(n 199)

Oxycodone CR
1 Year
(n 45)

Gastrointestinal disorders
Nausea
Constipation
Diarrhea
Vomiting
Dry mouth
Infections and infestations
Nasopharyngitis
Upper respiratory tract infection
Sinusitis
Urinary tract infection
Inuenza
Nervous system disorders
Headache
Dizziness
Somnolence
Musculoskeletal and connective tissue disorders
Arthralgia
Back pain
Psychiatric disorders
Insomnia
Anxiety
Withdrawal syndrome
General disorders and administration site conditions
Fatigue
Drug withdrawal syndrome
Chills
Skin and subcutaneous tissue disorders

153 (50.5)
56 (18.5)
51 (16.8)
27 (8.9)
27 (8.9)
27 (8.9)
102 (33.7)
19 (6.3)
21 (6.9)
15 (5.0)
19 (6.3)
12 (4.0)
117 (38.6)
48 (15.8)
49 (16.2)
25 (8.3)
63 (20.8)
15 (5.0)
8 (2.6)
62 (20.5)
21 (6.9)
13 (4.3)
9 (3.0)
69 (22.8)
38 (12.5)
1 (0.3)
5 (1.7)
42 (13.9)

128 (35.8)
45 (12.6)
38 (10.6)
29 (8.1)
26 (7.3)
12 (3.4)
133 (37.2)
29 (8.1)
29 (8.1)
26 (7.3)
21 (5.9)
13 (3.6)
116 (32.4)
62 (17.3)
27 (7.5)
17 (4.7)
87 (24.3)
28 (7.8)
18 (5.0)
70 (19.6)
31 (8.7)
17 (4.7)
10 (2.8)
57 (15.9)
18 (5.0)
4 (1.1)
2 (0.6)
47 (13.1)

60 (24.1)
8 (3.2)
17 (6.8)
17 (6.8)
9 (3.6)
1 (0.4)
89 (35.7)
15 (6.0)
9 (3.6)
12 (4.8)
12 (4.8)
16 (6.4)
59 (23.7)
14 (5.6)
11 (4.4)
7 (2.8)
48 (19.3)
11 (4.4)
6 (2.4)
31 (12.4)
17 (6.8)
9 (3.6)
2 (0.8)
25 (10.0)
5 (2.0)
5 (2.0)
2 (0.8)
16 (6.4)

74 (37.2)
23 (11.6)
21 (10.6)
29 (14.6)
10 (5.0)
4 (2.0)
59 (29.6)
11 (5.5)
12 (6.0)
9 (4.5)
10 (5.0)
4 (2.0)
48 (24.1)
26 (13.1)
9 (4.5)
11 (5.5)
40 (20.1)
10 (5.0)
6 (3.0)
47 (23.6)
22 (11.1)
17 (8.5)
9 (4.5)
37 (18.6)
14 (7.0)
4 (2.0)
4 (2.0)
23 (11.6)

14 (31.1)
4 (8.9)
1 (2.2)
8 (17.8)
1 (2.2)
1 (2.2)
11 (24.4)
3 (6.7)
0
1 (2.2)
1 (2.2)
2 (4.4)
11 (24.4)
1 (2.2)
2 (4.4)
1 (2.2)
3 (6.7)
0
0
18 (40.0)
9 (20.0)
5 (11.1)
4 (8.9)
9 (20.0)
2 (4.4)
4 (8.9)
3 (6.7)
4 (8.9)
(continued)

Clinical Therapeutics

10

Table IV. Treatment-emergent adverse events (TEAEs) reported by Z5% of patients in any prior treatment group (safety population).* Values are
given as number (%).

] 2015

0
3 (6.7)
1 (2.2)
ER extended release; CR controlled release.
*
Incidences are based on the number of patients experiencing 1 adverse event (not the number of events).

8 (4.0)
18 (9.0)
13 (6.5)
2 (0.8)
21 (8.4)
16 (6.4)
15 (5.0)
24 (7.9)
6 (2.0)
Pruritus
Vascular disorders
Hypertension

13 (3.6)
24 (6.7)
9 (2.5)

Placebo
(n 303)
System Organ Class
TEAE

Table IV. (continued).

Tapentadol ER
r15 Weeks
(n 358)

Tapentadol ER
1 Year
(n 249)

Oxycodone CR
15 Weeks
(n 199)

Oxycodone CR
1 Year
(n 45)

R. Buynak et al.
For the safety population, mean (SE) changes from
baseline to end point in the PAC-SYM abdominal,
rectal, and stool subscale scores were 0.0 (0.02), 0.0
(0.02), and 0.1 (0.02), respectively; the mean (SE)
change from baseline to end point in the overall
PAC-SYM score was 0.0 (0.02). Mean changes from
baseline in PAC-SYM scores generally indicated an
increase in constipation symptom severity for patients
who previously received placebo in a preceding study,
no change in symptom severity for patients who
previously received tapentadol ER, and a decrease in
symptom severity for patients who previously received
oxycodone CR (Table V). Results of the PAC-SYM
were also summarized for patients who did and did not
report a TEAE of constipation. Among patients who
reported a TEAE of constipation, results similar to
those for the overall safety population were shown;
mean changes from baseline in PAC-SYM scores
generally indicated an increase in constipation symptom severity for patients who had received placebo, no
change for patients who had received tapentadol ER,
and a decrease in constipation symptom severity for
patients who had received oxycodone CR. Among
patients who did not report a TEAE of constipation,
mean changes from baseline in PAC-SYM scores were
minimal for patients who received placebo or tapentadol ER in the previous study, indicating few changes in
constipation symptom severity; mean changes from
baseline in PAC-SYM scores generally indicated a
decrease in constipation symptom severity for patients
who had received oxycodone CR in the previous study.
For the overall population, the mean (SE) decrease
in the number of hours required to get to sleep (sleep
latency) from baseline to end point was 0.4 (0.06)
hour. The mean (SD) number of hours slept for the
overall population remained relatively constant from
baseline (6.6 [1.71] hours) to end point (6.5 [1.69]
hours). At end point, 68.0% of all patients reported
no more than 2 awakenings during the night, and the
majority of patients reported excellent (7.9%) or good
(45.9%) sleep quality.

Efficacy and Safety of up to 2 Years of Tapentadol

ER Treatment
Of the 894 patients who received tapentadol ER in
the prior 1-year safety study, 249 patients continued
treatment and received 1 dose of tapentadol ER in the
present open-label extension study; 189 (75.9%) of
these patients completed the extension study (Figure 1).

11

Clinical Therapeutics

Mild withdrawal

No withdrawal

Moderate withdrawal
2.1

100
13.1

7.0
13.5

12.1

Percentage of Patients

80

60

86.9

100.0

93.0
84.4

40

87.9

20

0
Placebo (n = 99)

Tapentadol ER
15 weeks (n = 115)

Tapentadol ER
1 year (n = 96)

Oxycodone CR
15 weeks (n = 58)

Oxycodone CR
1 year (n = 16)

Figure 2. The Clinical Opiate Withdrawal Scale (COWS) withdrawal categories 2 to 4 days after the last
intake of study drug for patients who did not take opioids after treatment discontinuation
according to prior treatment group (safety population). No withdrawal was defined as a total
COWS score o5; mild withdrawal, from 5 to 12; moderate withdrawal, from 13 to 24; moderately
severe withdrawal, from 25 to 36; and severe withdrawal, 436. No patients experienced
moderately severe or severe withdrawal. ER extended release; CR controlled release.

For comparison, of the 223 patients who received

oxycodone CR in the prior 1-year safety study, 45
received Z1 dose of tapentadol ER in the open-label
extension study; 31 (68.9%) of those patients completed the extension study. A total of 53.8% (481 of
894) of patients discontinued during the rst year of
treatment with tapentadol ER (during the prior 1-year
safety study)18 and 24.1% (60 of 249) of patients
discontinued during the second year of treatment
(during the present open-label extension study). The
2 primary reasons for discontinuation during the
open-label extension study were patient choice
(7.2% [18 of 249]) and AEs (6.4% [16 of 249]).
Demographic and baseline characteristics were comparable for this subpopulation of patients who received tapentadol ER for up to 2 years and the overall
population in the open-label extension study.
During the rst year of treatment with tapentadol
ER (1-year safety study), mean (SD) pain intensity
decreased from 7.57 (1.557) at baseline to 3.41
(2.185) at end point, then remained relatively stable
during the open-label extension study (3.43 [2.230] at

12

baseline; 3.67 [2.379] at end point; Figure 3).

Similarly, for patients who had received oxycodone
CR during the preceding 1-year safety study, mean
(SD) pain intensity remained relatively stable with
tapentadol prolonged release treatment during the
open-label extension study. On the PGIC, 67.7%
(151 of 223) of patients rated their overall status as
very much improved or much improved at end point
of the open-label extension study compared with
27.8% (67 of 241) of patients during the rst week
of treatment in the 1-year safety study.
Measures of health status improved over both
the rst and second year of treatment with
tapentadol ER. Clinically meaningful improvements
(Z5 points)34 over 1 and 2 years of treatment with
tapentadol ER were observed in the SF-36 physical
functioning, role-physical, bodily pain, vitality, general health (during the rst year of treatment only),
social functioning, and physical component summary
scores (Table VI). The mean (SE) change from
baseline in the EQ-5D health status index score
exceeded the threshold for a minimally clinically

Volume ] Number ]

] 2015
Table V. Mean (SE) change from baseline in overall Patient Assessment of Constipation Symptoms (PAC-SYM) and subscale scores at end point
according to prior treatment group for all patients and for patients with and without a treatment-emergent adverse event of
constipation (safety population).
PAC-SYM Measure
Overall population
Overall
Subscale
Abdominal
Rectal
Stool
Constipation reported
Overall
Subscale
Abdominal
Rectal
Stool
No constipation reported
Overall
Subscale
Abdominal
Rectal
Stool

Placebo

Tapentadol ER
r15 Weeks

Tapentadol ER
1 Year

Oxycodone CR
15 Weeks

Oxycodone CR
1 Year

(n 239)
0.1 (0.03)

(n 258)
0.0 (0.03)

(n 241)
0.0 (0.02)

(n 166)
0.2 (0.04)

(n 38)
0.3 (0.14)

0.0 (0.04)
0.1 (0.04)
0.2 (0.04)
(n 45)
0.4 (0.11)

0.0 (0.04)
0.0 (0.03)
0.0 (0.04)
(n 25)
0.0 (0.13)

0.0 (0.03)
0.0 (0.02)
0.0 (0.03)
(n 17)
0.0 (0.11)

0.1 (0.06)
0.2 (0.05)
0.4 (0.06)
(n 21)
0.3 (0.12)

0.1 (0.16)
0.2 (0.14)
0.4 (0.17)
(n 1)
0.1

0.2 (0.12)
0.3 (0.11)
0.5 (0.13)
(n 194)
0.0 (0.03)

0.1 (0.18)
0.2 (0.15)
0.1 (0.14)
(n 233)
0.0 (0.03)

0.0 (0.19)
0.0 (0.13)
0.1 (0.13)
(n 224)
0.0 (0.02)

0.4 (0.17)
0.1 (0.16)
0.5 (0.13)
(n 145)
0.2 (0.05)

0.0
0.0
0.2
(n 37)
0.3 (0.15)

0.0 (0.04)
0.1 (0.04)
0.1 (0.04)

0.0 (0.03)
0.1 (0.03)
0.0 (0.04)

0.0 (0.03)
0.0 (0.02)
0.0 (0.03)

0.1 (0.06)
0.2 (0.05)
0.4 (0.06)

0.1 (0.17)
0.2 (0.15)
0.4 (0.17)

13

R. Buynak et al.

ER extended release; CR controlled release.

Clinical Therapeutics

Tapentadol ER 1 year/tapentadol ER
10

Oxycodone CR 1 year/tapentadol ER

1-year safety study

Open-label extension study

9
Mean (SE) Pain Intensity

8
7
6
5

4
3

2
1
0
BL 4

8 12 16 20 24 28 32 36 40 44 48 BL 4 8 12 16 20 24 28 32 36 40 44 48 52
Study Week

Tapentadol ER 1 year/
tapentadol ER, n

246 245 246 246 246 244 244 246 246 245 246 245 245 246 243 234 230

222

205

192

Oxycodone CR 1 year/
tapentadol ER, n

45 45 45 44 45 45 45 45 45 45 45 45 45 45 41 35 35

34

32

30

Figure 3. Mean (SE) pain intensity scores over time for patients who received prior tapentadol extended
release (ER) or oxycodone controlled release (CR) treatment in the 1-year safety study (intentionto-treat population). *Represents the baseline value for the open-label extension study and end
point value for the 1-year safety study.

important difference (0.074)35 after 4 weeks of

treatment with tapentadol ER in the 1-year safety
study (0.3 [0.02]); this improvement was maintained
through the end of the open-label extension study.
After the initial titration period in the 1-year, openlabel, safety study, mean total daily doses and pain
intensity scores remained relatively stable for the
duration of the 1-year safety study and the 1-year
open-label extension study. These results indicate that
there was no acquired tolerance associated with up to
2 years of tapentadol ER treatment.
For all patients who completed tapentadol ER
treatment during the prior 1-year safety study and
entered the present open-label extension study
(n 249), 75.1% (187 of 249) of patients reported
1 TEAE during the second year of tapentadol
ER treatment (the open-label extension study);
all individual TEAEs were reported by o7% of
patients during the second year of tapentadol
ER treatment (Table IV). For patients who received
treatment with tapentadol ER in the prior
study and continued into this open-label extension,

14

9.2% (23 of 249) of patients experienced treatmentemergent serious AEs during the up to 2-year period (ie,
in either the rst or second year of treatment), and no
unique medical concept was reported as a serious AE by
more than 3 (1.2%) patients; a total of 6.0% (15 of
249) of patients experienced TEAEs leading to study
discontinuation.

DISCUSSION
Results from this open-label extension study showed
that tapentadol ER (100250 mg BID) was well
tolerated for the management of moderate to severe,
chronic osteoarthritis pain or low back pain for up to
2 years. The percentages of patients who completed
treatment in this open-label extension study were
60.5% for all patients and 75.9% for the subgroup
of patients who received up to 2 years of tapentadol
ER treatment. These were patients who previously
received tapentadol ER in the 1-year safety study
before entering the open-label extension study.
In comparison, the completion rate in a similarly
designed, 1-year, open-label extension study of

Volume ] Number ]

R. Buynak et al.

Table VI. Mean (SE) changes from baseline of the 1-year safety study to end point of the 1-year safety study
and end point of the open-label extension study in 36-item Short Form Health Survey (SF-36) and
EuroQol-5 Dimension (EQ-5D) scores for patients who received prior treatment with tapentadol
extended release (intention-to-treat population).

Measure
SF-36 measure
Physical functioning
Role-physical
Bodily pain
General health
Vitality
Social functioning
Role-emotional
Mental health
Mental component summary
Physical component summary
EQ-5D measure
Mobility
Self-care
Usual activities
Pain/discomfort
Anxiety/depression
Health status index
VAS overall health state

1 Year of Treatment (End Point of

the 1-Year Safety Study; n 246)

2 Years of Treatment (End Point

of the Open-Label Extension
Study; n 243)

16.5
24.3
23.5
6.3
12.0
14.4
3.4
4.4
1.2
8.9

(1.41)
(2.95)
(1.34)
(0.96)
(1.25)
(1.65)
(2.84)
(1.10)
(0.73)
(0.63)

15.8
20.6
23.1
3.1
11.3
12.8
4.9
3.7
1.1
7.9

(1.41)
(2.78)
(1.28)
(1.07)
(1.36)
(1.66)
(3.00)
(1.26)
(0.82)
(0.63)

0.3
0.0
0.4
0.5
0.1
0.3
13.3

(0.03)
(0.03)
(0.04)
(0.04)
(0.03)
(0.02)
(1.40)

0.3
0.1
0.3
0.5
0.1
0.3
13.1

(0.03)
(0.03)
(0.04)
(0.04)
(0.04)
(0.02)
(1.46)

VAS visual analog scale.

oxymorphone ER (median daily dose, 40 mg) was

39.9%.36 In the present study, discontinuations
related to AEs were reported for a similar percentage
of patients who received placebo in the preceding
study (18.2%) and patients who received oxycodone
CR in the preceding study (15 weeks, 15.7%; 1 year,
17.8%). Results of this study compare favorably with
those evaluating the long-term safety of other opioids
for the management of chronic pain.3739
In the previously mentioned 1-year, open-label
extension study of oxymorphone for moderate to
severe, chronic osteoarthritis pain,36 32.0% of
patients discontinued treatment because of AEs
compared with 13.0% in the present open-label
extension study of tapentadol ER. The incidence of
some common opioid-related TEAEs was also lower
in the present open-label extension study than in

] 2015

previous open-label extension studies of opioids for

chronic pain,3639 although it is unclear whether the
same method for reporting TEAEs was used in those
trials. In an 18-month, open-label extension study of
oxycodone CR (1020 mg BID) for moderate to
severe, chronic osteoarthritis pain,39 nausea and
constipation were reported by 23.6% and 51.9% of
patients, respectively, compared with 11.8% and
11.1% of patients in the present open-label extension
study of tapentadol ER. In addition, the incidence of
treatment-emergent serious AEs was relatively low,
even among elderly (Z65 years of age) patients. Most
treatment-emergent serious AEs reported in the overall
study population were considered by the investigator
to be unrelated or unlikely related to study treatment.
More than 55% of patients in this open-label
extension study were on a stable dose (ie, their

15

Clinical Therapeutics
individual, most frequently used total daily dose) of
tapentadol ER for 490% of the study period,
indicating that few dose adjustments were necessary
to maintain analgesic efcacy. In addition, mean
tapentadol ER doses and mean pain intensity scores
remained relatively constant through the course of up
to 2 years of treatment, indicating that tapentadol ER
treatment was not associated with acquired tolerance.
Assessment of withdrawal by using the COWS and
SOWS supported the low physical dependence for
tapentadol ER with extended treatment previously shown
in the 1-year safety study.18 The incidence of withdrawal
after abrupt discontinuation without tapering of
tapentadol ER was low and, when present, was of mild
to moderate severity. The results of COWS and SOWS
assessments suggest that, for 90% of patients,
treatment with tapentadol ER can be stopped abruptly
without tapering (if necessary) in clinical practice.
Gastrointestinal adverse effects associated with
opioid therapy can be severe and may limit the longterm utility of opioids in some patients.40 Opioidinduced constipation is particularly problematic for
patients on long-term analgesic therapy because it
rarely improves over the course of treatment and is
often unresponsive to laxative therapy.11,41,42 For
patients who had previously received oxycodone
HCl CR (2050 mg BID) in a preceding study, the
severity of constipation symptoms (as reported on the
PAC-SYM) decreased with tapentadol ER (100250
mg BID) treatment during this open-label extension
study. In addition, the incidence of constipation
during the second year of tapentadol ER treatment
(the open-label extension study) for patients who
initially received 1 year of tapentadol ER treatment
during the 1-year safety study was low (6.8%). These
results indicate that tapentadol ER may have a lower
constipating effect than oxycodone CR.
Although efcacy was not a primary end point in
this open-label extension study, pain intensity scores
decreased slightly during the rst month and remained
stable thereafter, suggesting the long-term effectiveness of tapentadol ER. Changes in pain intensity
scores were relatively small across all groups of
patients divided according to their prior treatment;
however, clinically relevant improvements in health
status measures (such as the EQ-5D and SF-36 health
status questionnaires) and corresponding numerical
improvements in PGIC ratings were observed for all
patients, regardless of prior treatment. Ratings on the

16

PGIC encompass not only specic pain relief but also

include patient assessments of improvements in functioning and the impact of drug-related adverse effects,43 and they may provide a more complete picture
of tapentadol ERrelated efcacy in patients overall
status than pain intensity scores alone.
Limitations, such as the open-label design and the
lack of a placebo or active comparator, have to be
taken into account when interpreting results. Overall,
ndings from this study were consistent with the safety
and tolerability prole that has been established in
previous randomized, placebo- and/or active-controlled
studies of tapentadol ER with durations of 15 weeks
and 1 year,1620,24,25 as well as in previous randomized,
placebo- and/or active-controlled, Phase III studies of
tapentadol immediate release.4447 Given that longterm studies of opioid therapy for chronic pain are
rare, this 1-year study in a relatively large group of
patients is somewhat unusual for a strong analgesic and
provides valuable insights into the efcacy and tolerability of tapentadol ER during prolonged use.

CONCLUSIONS
Results of this 1-year, open-label extension study,
including safety data from the subgroup of patients
who received tapentadol ER for up to 2 years, indicate
that tapentadol ER is a well-tolerated treatment
option that seems to maintain long-term efcacy
and safety for the management of moderate to
severe, chronic osteoarthritis hip or knee pain or
low back pain.

ACKNOWLEDGMENTS
This study was supported by Janssen Research &
Development, LLC, and Grnenthal GmbH. Editorial
support for the writing of the manuscript was provided by Megan Knagge, PhD, of MedErgy, and was
funded by Janssen Research & Development, LLC,
and Grnenthal GmbH. The authors retained full
editorial control over the content of the manuscript.
All authors approved the nal article.
Dr. Buynak, Dr. Rod, and Dr. Arsenault participated in the collection of study data. Dr. Rappaport
participated in the collection, analysis, and interpretation of the data. Dr. Heisig participated in the
analysis and interpretation of study data. Dr. Rauschkolb and Dr. Etropolski participated in the design
of the study and in the collection, analysis, and

Volume ] Number ]

R. Buynak et al.
interpretation of study data. All authors critically
reviewed and revised this manuscript.

CONFLICTS OF INTEREST
Dr. Heisig is an employee of Grnenthal GmbH.
Drs. Rauschkolb and Etropolski are employees of
Janssen Research & Development, LLC, and Johnson
& Johnson stockholders. During the last 5 years,
Dr. Arsenault has received consulting fees, speaker
fees, and honoraria from Janssen, Eli Lilly, Pzer,
Purdue Pharma, Valeant Pharmaceuticals International, and Merck; has served on advisory boards
for AstraZeneca; and has served as a principal investigator on clinical trials for Purdue Pharma, Shionogi,
Sano, and Janssen. The authors have indicated that
they have no other conicts of interest regarding the
content of this article.
This research was nancially supported by Janssen
Research & Development, LLC, and Grnenthal
GmbH. Janssen and Grnenthal assisted with the
design of the study, interpretation of the results, and
development of the manuscript.

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Address correspondence to: Mila Etropolski, MD, Janssen Research &

Development, LLC, 1125 Trenton Harbourton Road, Titusville,
NJ 08560. E-mail: metropol@its.jnj.com

] 2015

19