Current Medical Research and Opinion® 0300-7995

Vol. 22, No. , 2006, 1391–1401 doi:10.1185/030079906X115595

© 2006 LibraPharm Limited All rights reserved: reproduction in whole or part not permitted

ORIGINAL ARTICLE

Extended-release tramadol in
the treatment of osteoarthritis:
a multicenter, randomized,
double-blind, placebo-controlled
clinical trial
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Theophilus J. Gana a, Maria Luz G. Pascual b, Rosa

Rosanna B. Fleming b, Jeff R. Schein c, Carmela C.
Janagap c, Jim Xiang d, and Gary J. Vorsanger e on behalf
of the 023 Study Group*
a
Biopharmatech Consulting, Inc., Leesburg, VA, USA
b
Clinical Development, Biovail Technologies, Ltd., Bridgewater, NJ, USA
c
Outcomes Research, Ortho-McNeil Janssen Scientific Affairs, LLC, Raritan,
For personal use only.

NJ, USA
d
Quantitative Methodology, Ortho-McNeil Janssen Scientific Affairs, LLC,
Raritan, NJ, USA
e
Medical Affairs, PriCara, Unit of Ortho-McNeil, Inc., Raritan, NJ, USA

Address for correspondence: Gary J. Vorsanger, PhD, MD, PriCara, Unit of Ortho-McNeil, Inc.,
1000 Route 202, Raritan, NJ 08869‑0602, USA. Tel.: +1 908 927 3089; Fax: +1 908 218 7051;
email: gvorsang@janus.jnj.com
Key words: Chronic pain – Delayed-action preparations – Drug dose–response relationship – Once-
daily administration – Osteoarthritis – Randomized controlled trial – Tramadol

ABSTRACT

Objective: This study evaluated the efficacy and safety of tramadol comparison of subject global assessment of disease activity was
extended-release (tramadol ER) tablets once daily in subjects with not statistically significant ( p = 0.079). All doses of tramadol
osteoarthritis pain. ER once daily were more effective than placebo ( p ≤ 0.050) for
Methods: This 12‑week, multicenter, randomized, double-blind, WOMAC Osteoarthritis Index joint stiffness subscale, WOMAC
placebo-controlled, parallel-group clinical trial included 1020 Osteoarthritis Index composite score, pain intensity of the index
adults with osteoarthritis of the knee or hip and baseline pain joint, and daily pain intensity scores. Tramadol ER 200 and 300 mg
intensity ≥ 40 on a 100‑mm pain visual analog scale (0 = no pain, were significantly more effective than placebo ( p ≤ 0.050) for
100 = extreme pain). Subjects took placebo or were titrated to a subject global assessment of disease activity and pain intensity
target dose of tramadol ER 100, 200, 300, or 400 mg once daily. of non-index joints. Adverse events (e.g., constipation, dizziness,
Main outcome measures: The co-primary efficacy variables were nausea, somnolence, headache) occurred most often with
pain and physical function subscales of the WOMAC Osteoarthritis tramadol ER 400 mg.
Index and subject global assessment of disease activity. Conclusions: Tramadol ER 100–300 mg once daily was
Results: Mean changes in WOMAC Osteoarthritis Index pain and associated with significant improvement in pain intensity and
physical function subscales were significantly different between physical function, and was well tolerated, despite the use of a
tramadol ER and placebo, overall ( p ≤ 0.021) and for each dose fixed-dose study design not reflective of usual clinical practice.
( p ≤ 0.050). However, the protocol-specified decision rule for the Tramadol ER is a useful treatment option for patients with
3 co-primary endpoints was not satisfied because the overall osteoarthritis pain.

*Members of the 023 Study Group are listed in the Acknowledgments

Paper 3486 1391

 Introduction or an opioid for at least 75 of the previous 90 days
to treat osteoarthritis pain in the most painful hip or
Osteoarthritis pain is a leading cause of disability in knee (index joint). After washout of previous analgesic
the United States, with an estimated annual cost of treatment for 2–7 days, subjects were required to have
$7.11 billion in lost productive work time1. Tramadol baseline index joint pain of ≥ 40 mm on a 100‑mm pain
is a centrally acting analgesic that binds to µ‑opioid visual analog scale (VAS) (0 = no pain, 100 = extreme
receptors and weakly inhibits re-uptake of norepineph­ pain).
rine (NE) and serotonin (5HT)2. Clinical guidelines Key exclusion criteria included any medical condition
from the American College of Rheumatology (ACR) other than osteoarthritis that was not well controlled;
recommend the use of tramadol in patients with any other form of arthritis or joint disease at the index
osteoarthritis who do not achieve adequate pain relief joint; a chronic pain syndrome or fibro­myalgia; any
with acetaminophen or non-steroidal anti-inflam­ contraindication for the use of tramadol; a history of
matory drugs (NSAIDs)3. substance abuse in the previous 6 months; and any
Immediate-release tramadol has been available condition that was likely to influence the absorption,
commercially since 1977 in Europe and since 1995 in efficacy, or safety of tramadol ER. Subjects were not
the United States. In clinical trials, immediate-release permitted to take another investigational medication,
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tramadol provided greater pain relief than placebo a corticosteroid, a medication that could interact with
when it was taken every 4–6 h as needed to treat tramadol (e.g., carbamazepine), or another medication
osteoarthritis pain4–6. An extended-release formulation for pain (e.g., analgesics, anti­depressants) during the
of tramadol (tramadol ER) (ULTRAM ER [tramadol study. However, subjects could take up to 2000 mg/
HCl] extended-release tablets; manufactured by day of acetaminophen for no more than 3 consecutive
Biovail Corporation, Mississauga, Canada; distributed days for reasons other than osteoarthritis or chronic
by PriCara, Unit of Ortho-McNeil, Inc., Raritan, NJ, pain. The use of acetamino­phen was prohibited during
USA) was formulated to be taken once daily, potentially the washout period and in the 48 h before each study
facilitating long-term therapy. Tramadol ER 100– visit after the screening visit.
300 mg once daily is indicated for the management of Before study enrollment, a randomization schedule
For personal use only.

moderate to moderately severe chronic pain in adults was generated with permuted blocks of 10 subjects.
who require around-the-clock treatment of their pain Each site received study medication kits that were
for an extended period of time7, based on the results marked with the randomization numbers. Investigators
of controlled clinical trials. In one of those studies, a used an interactive voice-response system to assign
flexible-dose clinical trial, tramadol ER was shown to randomization numbers to subjects. Eligible subjects
be more effective than placebo when subjects with were randomly assigned in a 1:1:1:1:1 ratio to placebo,
osteoarthritis pain took between 200 and 400 mg once tramadol ER 100 mg, tramadol ER 200 mg, tramadol
daily8. A second trial, presented here, was conducted ER 300 mg, or tramadol ER 400 mg once daily,
to evaluate the efficacy and safety of fixed doses of respectively. To preserve blinding, study medication
tramadol ER 100, 200, 300, or 400 mg once daily for tablets were similar in appearance and size and
12 weeks in subjects with osteoarthritis pain. contained either tramadol ER 100 mg or placebo.
Subjects received four tablets of study medication once
daily. Subjects taking tramadol ER began with a dose
Methods of 100 mg and the dose was to be titrated as follows: to
200 mg on Day 5 (in the 200, 300, and 400 mg groups),
Study design
to 300 mg on Day 10 (in the 300 and 400 mg groups),
The study protocol was conducted in accordance and to 400 mg on Day 15 (in the 400 mg group). After
with the Declaration of Helsinki and approved by an 12 weeks, tramadol ER was to be discontinued without
institutional review board at each site, and every subject tapering and subjects were allowed to take non-opioid
gave written informed consent prior to screening. analgesics, if necessary for pain relief, until the follow-
Sixty-six investigators throughout the United States up visit at Week 13.
conducted this study between August 2002 and August
2003. A total of 1020 men/women 18–74 years of age Assessments
with radiographically confirmed ACR Func­tional Class
I–III osteoarthritis of the knee or hip were eligible for Study visits occurred at screening, baseline, and at
this multicenter, randomized, double-blind, placebo- Weeks 1, 2, 3, 6, 9, 12, and 13. At each post-screening
controlled, fixed-dose, parallel-group clinical trial. study visit, subjects completed the Western Ontario
Subjects were required to have taken acetamino­phen, and McMaster Universities (WOMAC) Osteoarthritis
an NSAID, a cyclooxygenase-2 (COX-2) inhibitor, Index9, and they rated arthritis pain intensity in the

1392 Tramadol ER in the treatment of osteoarthritis © 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22()
 index joint and in non-index joints during the past 48 h assessments of disease activity. To assess efficacy for
using a 100‑mm VAS (0 = no pain, 100 = extreme signs and symptoms of osteoarthritis, the hypothesis
pain). Subject and physician global assessments of testing procedure, which was designed to control the
disease activity were recorded at each post-screening overall type I error rate, was performed in stepwise
visit on a 100‑mm VAS (0 = very good, 100 = very fashion for each of the co-primary variables as follows:
poor). At each post-screening visit, subjects responded (1) the overall test for treatment effect was assessed for
to the following sleep-related questions using a significance; (2) tramadol ER 400 mg was compared to
100‑mm VAS (0 = never, 100 = always) for each placebo; (3) each of the lower doses was compared to
question: trouble falling asleep, the need for sleep placebo in sequential order. The procedure was to be
medication, how often they were awakened by pain stopped after the first statistically non-significant result.
during the night, and how often they were awakened To demonstrate efficacy for any particular dose for the
by pain in the morning. In addition, subjects assessed signs and symptoms of osteoarthritis, the 3 hypotheses
the overall quality of sleep at each post-screening visit associated with the co-primary efficacy variables
using a 100‑mm VAS (0 = very poor, 100 = excellent) needed to be rejected. Regardless of the results of the
in response to the question, ‘Over the past week, how planned analyses, all hypotheses were tested for the
would you rate the overall quality of your sleep?’; the individual efficacy variables to assess efficacy for pain.
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overall sleep quality score was not an aggregate of the The least-squares mean change from baseline was
other four sleep-related questions. At baseline and at calculated at each visit for the following outcomes:
Weeks 6 and 12, subjects completed the Short Form- WOMAC Osteoarthritis Index subscale scores and the
36 (SF-36) Health Survey10,11. Starting at the baseline composite score; pain intensity of the index joint and
visit, subjects maintained daily diaries of osteoarthritis non-index joints at study visits; physician and subject
pain intensity, rated at approximately 8:00 pm daily global assessments of disease activity; sleep indices; and
with a 100‑mm VAS (0 = no pain, 100 = extreme physical and mental component scores of the SF-36.
pain) in response to the question, ‘Overall, how much Analyses of covariance (ANCOVA) with treatment,
pain have you experienced in your study joint today?’ index joint (knee, hip), and study site as factors and
Safety assessments included reports of adverse events, baseline value as a covariate were performed for the
For personal use only.

either spontaneously or in response to non-directed overall treatment effect and the between-group
questioning, and results of physical examinations, vital comparisons at the final visit. WOMAC Osteoarthritis
signs, clinical laboratory tests, and electrocardiograms Index subscale scores at all other clinic visits were
at study visits. Subjects completed a 16‑item question­ analyzed with similar ANCOVA methods. Daily pain
naire at baseline, Week 12 (or early discontinuation), intensity scores were analyzed with repeated-measures
and Week 13 (or 1 week after early discontinuation) to ANCOVA models that used the same factors and
record the presence or absence of common symptoms covariate. Pearson’s chi-square was used to analyze the
of physical dependence12. incidences of adverse events.
Assuming α = 0.05 (2-tailed) and β = 0.20 (80%
Statistical analysis power), a total of 162 randomized subjects per
treatment group would detect a 44‑point difference
Statistical analyses were performed using SAS Version in the WOMAC Osteoarthritis Index pain subscale
6.12 or above (SAS Institute, Cary, NC). All statistical score, 124 subjects per treatment group would detect
tests were performed as 2-tailed tests, and an effect a 158‑point difference for the WOMAC Osteoarthritis
was considered statistically significant if p ≤ 0.05. Index physical function subscale score, and 175
Analyses were conducted on an intent-to-treat (ITT) subjects per treatment group would detect a 9‑point
population, defined as all randomized subjects who difference for subject global assessment of disease
took at least one dose of study medication, using the activity. To allow for a slight departure from the
last-observation-carried-forward approach to replace above assumptions, a sample size of 200 subjects per
missing post-baseline efficacy data. treatment group was used.
Baseline variables were compared among all
treat­ment groups using 1-way analysis of variance
(ANOVA) with treatment as the factor for continuous Results
variables and Pearson’s chi-square for categorical
Study participants
variables. The final visit was defined as Week 12 or the
time of early discontinuation. The co-primary efficacy A total of 1020 subjects were randomized and 1011
variables were the changes from baseline to final visit received study treatment, of whom 558 (55.2%)
in WOMAC Osteoarthritis Index pain and physical completed 12 weeks of treatment. Disposition of study
function subscale scores, and the subject global subjects is summarized in Figure 1. The leading reason

© 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22() Tramadol ER in the treatment of osteoarthritis Gana et al. 1393
 for early discontinuation in the placebo and tramadol Efficacy
ER 100 mg groups was lack of efficacy (22.4% and Pain, physical function, and subject global
15.3%, respectively). The leading reason for early assessment of disease activity
discontinuation in the tramadol ER 200, 300, and
400 mg groups was adverse events (19.9%, 26.9%, and Mean improvement in the pain subscale of the
29.7%, respectively). WOMAC Osteoarthritis Index was significantly greater
At baseline, statistically significant differences were for tramadol ER compared to placebo, both for the
observed among the treatment groups for race and overall comparison and for the pairwise comparisons to
weight, but these differences were not considered placebo for each dose (Table 2). Mean improvement in
clinically meaningful (Table 1). Mean age of the the physical function subscale of the WOMAC Osteo­
treatment groups ranged from 56.4 to 59.1 years, and arthritis Index also was significantly greater overall and
631 (62.4%) of all subjects were female. Mean subscale for each dose of tramadol compared to placebo (Table
scores at baseline for the WOMAC Osteoarthritis 2). The mean change in subject global assessment of
Index ranged from 296.6 to 315.2 for pain (0 = no disease activity was not significantly different among
pain, 500 = extreme pain) and from 1010.9 to 1096.2 the treatment groups for the overall comparison
for physical function (0 = no functional impairment, ( p = 0.079). According to the protocol-specified
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1700 = extreme functional impairment). Mean decision rule, efficacy for the signs and symptoms
baseline scores for subject global assessment of disease of osteo­arthritis was not established. In pairwise
activity ranged from 61.4 to 67.4 (0 = very good, comparisons to placebo, the change from baseline
100 = very poor). Mean baseline scores for sleep in subject global assessment of disease activity was
quality ranged from 40.8 to 46.9 (0 = very poor, significantly greater in the tramadol ER 200 mg
100 = excellent). Mean scores at baseline on the sleep ( p ≤ 0.05) and 300 mg ( p ≤ 0.01) groups, but not in
impairment questions (0 = never, 100 = always) ranged the 400 mg ( p = 0.084) or 100 mg ( p = 0.055) groups
from 49.0 to 52.3 for trouble falling asleep, from (Table 2).
23.3 to 31.1 for the need for sleep medication,
from 49.3 to 54.4 for how often subjects were WOMAC Osteoarthritis Index
For personal use only.

awakened by pain during the night, and from 48.0 to

52.8 for how often subjects were awakened by pain in Mean improvement in WOMAC Osteoarthritis Index
the morning. scores from baseline to the final visit was significant

Discontinued (90)
Assigned to placebo (205) Adverse event (21)
Did not receive placebo (0) Lack of efficacy (46) Completed (115)
Safety Subject choice (9)
Other (14)

Discontinued (82)
Assigned to tramadol ER 100 mg (203) Adverse event (29)
Did not receive treatment (1) Lack of efficacy (31) Completed (120)
Safety/ITT population (202) Subject choice (11)
Other (11)

Discontinued (85)
Assigned to tramadol ER 200 mg (203) Adverse event (40)
Randomized (1020) Did not receive treatment (2) Lack of efficacy (29) Completed (116)
Safety/ITT population (201) Subject choice (6)
Other (10)

Discontinued (97)
Assigned to tramadol ER 300 mg (204) Adverse event (54)
Did not receive treatment (3) Lack of efficacy (18) Completed (104)
Safety/ITT population (201) Subject choice (14)
Other (11)

Discontinued (99)
Assigned to tramadol ER 400 mg (205) Adverse event (60)
Did not receive treatment (3) Lack of efficacy (23) Completed (103)
Safety/ITT population (202) Subject choice (8)
Other (8)

Figure 1. Subject disposition

1394 Tramadol ER in the treatment of osteoarthritis © 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22()
 Table 1. Baseline demographic and clinical characteristics

Tramadol ER
Placebo 100 mg 200 mg 300 mg 400 mg
Characteristic (n = 205) (n = 202) (n = 201) (n = 201) (n = 202) p-value
Age, years
Mean ± SD 56.4 ± 9.8 58.4 ± 10.9 59.1 ± 9.9 58.5 ± 9.4 58.4 ± 9.7 0.082
Range 25–73 22–74 33–74 28–74 27–74
Gender, n (%)
Male 64 (31.2) 76 (37.6) 73 (36.3) 82 (40.8) 85 (42.1) 0.178
Female 141 (68.8) 126 (62.4) 128 (63.7) 119 (59.2) 117 (57.9)
Race/ethnic origin, n (%)
White 167 (81.5) 146 (72.3) 153 (76.1) 164 (81.6) 161 (79.7) 0.015
Black 32 (15.6) 37 (18.3) 40 (19.9) 31 (15.4) 34 (16.8)
Hispanic 4 (2.0) 9 (4.5) 7 (3.5) 5 (2.5) 7 (3.5)
Asian 1 (0.5) 6 (3.0) 0 (0.0) 1 (0.5) 0 (0.0)
Other 1 (0.5) 4 (2.0) 1 (0.5) 0 (0.0) 0 (0.0)
Height, cm
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Mean ± SD 167.7 ± 10.2 167.6 ± 10.1 169.2 ± 9.7 169.0 ± 12.5 169.6 ± 10.0 0.204
Range 139.7–198.1 137.2–193.0 144.8–195.6 127.0–200.7 146.1–195.6
Weight, kg
Mean ± SD 93.6 ± 23.6 94.1 ± 23.1 98.6 ± 24.5 95.1 ± 22.2 98.9 ± 23.3 0.050
Range 45.4–186.1 47.7–190.7 51.8–204.3 47.7–172.5 52.2–166.2
Index joint, n (%)
Knee 150 (73.2) 151 74.8) 148 (73.6) 149 (74.1) 150 (74.3) 0.997
Hip 55 (26.8) 51 (25.2) 53 (26.4) 52 (25.9) 52 (25.7)
Osteoarthritis duration
(index joint), years
Mean ± SD 7.7 ± 7.4 7.8 ± 7.6 7.7 ± 6.9 8.0 ± 7.4 7.9 ± 7.0 0.996
For personal use only.

Range 0.1–40 0.2–41 0.3–35 0.3–43 0.3–40

Functional class of
osteoarthritis, n (%)
Class I 21 (10.2) 24 (11.9) 21 (10.4) 19 (9.5) 25 (12.4) 0.967
Class II 171 (83.4) 162 (80.2) 166 (82.6) 164 (81.6) 162 (80.1)
Class III 13 (6.3) 16 (7.9) 14 (7.0) 18 (9.0) 15 (7.5)
WOMAC
Osteoarthritis Index
score, mean ± SD
Pain (0–500) 305.9 ± 95.2 308.2 ± 99.3 315.2 ± 92.4 296.6 ± 96.3 298.0 ± 93.7 0.271
Physical function
(0–1700) 1058.7 ± 340.3 1071.6 ± 331.2 1096.2 ± 298.7 1026.6 ± 337.6 1010.9 ± 331.7 0.067
Subject global assess-
ment of disease activity
(0–100), mean ± SD 66.6 ± 21.5 65.4 ± 22.3 67.4 ± 20.1 64.6 ± 20.7 61.4 ± 22.6 0.054
Overall quality of sleep
(0–100), mean ± SD 45.0 ± 28.4 43.8 ± 25.9 42.9 ± 25.5 40.8 ± 26.8 46.9 ± 27.1 0.210
Pain intensity, daily
diary (0–100),
mean ± SD 69.2 ± 20.2 71.1 ± 20.8 71.5 ± 20.0 67.9 ± 19.8 65.8 ± 21.8 0.039

overall – and for all doses of tramadol ER compared to of osteoarthritis symptom relief with tramadol ER
placebo – for the joint stiffness subscale score and the therapy (Table 3). At the first follow-up study visit at
composite score (Table 2). Significant improvement Week 1, tramadol ER was associated with significant
from baseline to the final visit for pain walking on a improvement from baseline compared to placebo
flat surface was reported in the tramadol ER 200, 300, for the mean subscale scores for pain (200, 300, and
and 400 mg groups compared to the placebo group 400 mg), physical function (all doses), joint stiffness
(Table 2). (200, 300, and 400 mg), and pain walking on a flat
Additional analyses of WOMAC Osteoarthritis surface (300 mg), as well as for the mean composite
Index scores were performed to assess the time course score (all doses).

© 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22() Tramadol ER in the treatment of osteoarthritis Gana et al. 1395
 Table 2. Change from baseline for efficacy outcomes at Week 12, using the last observation carried forward

Change from baseline, least-squares mean ± SE

Tramadol ER
Placebo 100 mg 200 mg 300 mg 400 mg Overall
Outcome (range) (n = 205) (n = 202) (n = 201) (n = 201) (n = 202) p-value
WOMAC Osteoarthritis Index
Pain (0–500) 74.2 ± 8.5 107.2 ± 8.6† 111.5 ± 8.7† 103.9 ± 8.7* 107.8 ± 8.7† 0.009
Physical function (0–1700) 234.3 ± 28.1 331.7 ± 28.5* 350.2 ± 29.0† 336.1 ± 28.8† 329.8 ± 28.8* 0.021
Pain walking on flat surface
(0–100) 13.6 ± 1.8 18.0 ± 1.9 20.5 ± 1.9† 19.4 ± 1.9* 19.7 ± 1.9* 0.051
Joint stiffness (0–200) 32.2 ± 3.7 43.0 ± 3.8* 46.8 ± 3.8† 48.0 ± 3.8† 45.0 ± 3.8* 0.016
Composite score (0–2400) 340.5 ± 39.3 481.5 ± 39.8† 510.0 ± 40.5† 486.4 ± 40.3† 479.2 ± 40.3* 0.014
Arthritis pain intensity
Index joint (0–100) 20.2 ± 2.0 27.8 ± 2.1† 29.9 ± 2.1† 30.2 ± 2.1† 28.0 ± 2.1† 0.002
Non-index joints (0–100) 14.5 ± 2.0 19.3 ± 2.0 23.3 ± 2.1† 23.5 ± 2.0† 21.3 ± 2.1* 0.006
Global assessment of disease activity (0–100)
Subject (0–100) 16.2 ± 1.9 21.3 ± 1.9 21.8 ± 2.0* 23.5 ± 2.0† 20.8 ± 2.0 0.079
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Physician (0–100) 17.2 ± 1.9 22.9 ± 1.9* 22.4 ± 1.9* 23.8 ± 1.9† 22.90 ± 1.9* 0.072
SF-36 health survey
Physical component (0–100) 2.4 ± 0.6 3.6 ± 0.6 3.9 ± 0.6 3.6 ± 0.6 3.2 ± 0.6 0.403
Mental component (0–100) –0.3 ± 0.6 1.1 ± 0.6 0.6 ± 0.6 –0.7 ± 0.6 –0.5 ± 0.6 0.100
Note: positive changes represent improvement from baseline
*p ≤ 0.05 vs. placebo; †p ≤ 0.01 vs. placebo

Table 3. Change from baseline at each study visit for WOMAC Osteoarthritis Index scores (see Table 2 for values at Week 12)

Change from baseline, least-squares mean ± SE

Tramadol ER
For personal use only.

Outcome (range) Placebo (n = 205) 100 mg (n = 202) 200 mg (n = 201) 300 mg (n = 201) 400 mg (n = 202)
Pain (0–500)
Week 1 42.0 ± 7.2 56.9 ± 7.3 63.7 ± 7.4* 69.9 ± 7.4† 64.1 ± 7.4*
Week 2 63.6 ± 7.7 74.9 ± 7.8 90.3 ± 7.9* 92.8 ± 7.9† 86.5 ± 7.8*
Week 3 68.6 ± 7.9 85.9 ± 8.0 100.2 ± 8.1† 100.6 ± 8.1† 103.1 ± 8.1†
Week 6 77.1 ± 8.3 102.5 ± 8.4* 106.6 ± 8.5* 107.1 ± 8.5† 113.0 ± 8.5†
Week 9 75.7 ± 8.4 105.6 ± 8.5† 107.5 ± 8.7† 103.5 ± 8.6* 112.6 ± 8.6†
Physical function (0–1700)
Week 1 119.6 ± 23.0 192.4 ± 23.3* 206.8 ± 23.7† 225.8 ± 23.6† 205.3 ± 23.5†
Week 2 187.4 ± 25.1 235.1 ± 25.4 279.4 ± 25.9† 296.9 ± 25.7† 271.1 ± 25.7*
Week 3 211.7 ± 26.6 272.4 ± 27.0 316.1 ± 27.4† 327.9 ± 27.3† 326.0 ± 27.3†
Week 6 234.3 ± 27.3 301.8 ± 27.7 329.5 ± 28.2* 346.5 ± 28.0† 348.0 ± 28.0†
Week 9 223.9 ± 27.9 329.3 ± 28.2† 335.2 ± 28.7† 332.4 ± 28.6† 343.0 ± 28.6†
Joint stiffness (0–200)
Week 1 18.6 ± 3.2 23.6 ± 3.3 29.5 ± 3.3* 33.4 ± 3.3† 31.8 ± 3.3†
Week 2 27.6 ± 3.4 31.2 ± 3.4 38.5 ± 3.5* 42.4 ± 3.4† 37.5 ± 3.4*
Week 3 29.3 ± 3.5 35.6 ± 3.6 44.2 ± 3.6† 47.8 ± 3.6† 43.7 ± 3.6†
Week 6 30.8 ± 3.7 37.4 ± 3.7 45.1 ± 3.8† 49.5 ± 3.8† 46.8 ± 3.8†
Week 9 31.8 ± 3.7 42.0 ± 3.7* 45.1 ± 3.8† 46.0 ± 3.8† 46.8 ± 3.8†
Pain walking on a flat surface (0–100)
Week 1 7.4 ± 1.6 9.3 ± 1.6 10.4 ± 1.7 12.2 ± 1.7* 10.5 ± 1.7
Week 2 11.2 ± 1.7 12.0 ± 1.7 16.5 ± 1.7* 17.9 ± 1.7† 15.1 ± 1.7*
Week 3 11.8 ± 1.7 15.2 ± 1.7 18.3 ± 1.8† 18.3 ± 1.7† 18.3 ± 1.7†
Week 6 14.5 ± 1.8 18.3 ± 1.8 19.8 ± 1.8* 19.6 ± 1.8* 20.4 ± 1.8*
Week 9 14.2 ± 1.8 18.4 ± 1.8 19.5 ± 1.9* 19.2 ± 1.9* 20.2 ± 1.9*
Composite score (0–2400)
Week 1 179.7 ± 32.1 273.1 ± 32.5* 305.3 ± 33.1† 326.2 ± 32.9† 299.2 ± 32.9†
Week 2 278.3 ± 34.9 341.2 ± 35.4 409.0 ± 36.0† 429.1 ± 35.8† 393.7 ± 35.8*
Week 3 309.5 ± 37.0 393.7 ± 37.5 460.8 ± 38.1† 473.7 ± 38.0† 469.6 ± 37.9†
Week 6 342.1 ± 38.3 441.2 ± 38.8 481.5 ± 39.5† 501.8 ± 39.3† 504.2 ± 39.2†
Week 9 331.8 ± 39.0 476.9 ± 39.5† 489.3 ± 40.2† 479.2 ± 40.0† 501.5 ± 40.0†
Note: positive changes represent improvement from baseline. Subscale scores of the WOMAC Osteoarthritis Index are based on the sum of
individual items (each of which is scored from 0 to 100) as follows: pain, 5 items; physical function, 17 items; and joint stiffness, 2 items. The
composite score includes all 24 items. Pain walking on a flat surface is evaluated sepa rately but is also included in the pain subscale
*p ≤ 0.05 vs. placebo; †p ≤ 0.01 vs. placebo

1396 Tramadol ER in the treatment of osteoarthritis © 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22()
 Arthritis pain intensity of index and non-index Rescue medications
joints at study visits
Unauthorized rescue medications for pain were used
Scores for arthritis pain intensity of the index joint more commonly in the placebo group (6.8%) than in
improved significantly from baseline to the final visit in the tramadol ER 100, 200, 300, and 400 mg groups
all tramadol ER dose groups compared to the placebo (3.0%, 3.0%, 1.5%, and 2.5%, respectively; p ≤ 0.05 for
group (Table 2). Arthritis pain intensity of non-index 300 mg vs. placebo and 400 mg vs. placebo).
joints improved significantly from baseline to the final
visit in the tramadol ER 200, 300, and 400 mg groups SF-36 scores
compared to the placebo group (Table 2).
Mean changes for the physical and mental component
Pain intensity scores in daily diaries scores of the SF-36 from baseline to the final visit were
not significantly different between any of the tramadol
A significant difference was observed across treatment ER groups and the placebo group (Table 2).
groups for the daily pain intensity scores at baseline,
which ranged from 65.8 to 71.5 ( p = 0.039). In Sleep
Curr Med Res Opin Downloaded from informahealthcare.com by University of Queensland on 06/14/14

accordance with the study protocol, analyses of daily

pain intensity scores during follow-up included base­ Changes from baseline to the final visit for sleep scores
line score as a covariate. Using this approach, repeated- are summarized in Figure 3. The mean score for each
measures analyses determined that the overall changes question of the sleep questionnaire improved from
in daily pain intensity from baseline in the tramadol baseline to the final visit in all treatment groups. All
ER 100, 200, 300, and 400 mg groups (23.5, 24.2, doses of tramadol ER were associated with significant
27.1, and 24.2, respectively) were significantly improvement from baseline to the final visit compared
different from the overall change from baseline in the to placebo in sleep quality, trouble falling asleep, and
placebo group (15.0; p < 0.001 vs. each dose group being awakened by pain during the night. Tramadol ER
of tramadol ER). The mean change in daily pain 100, 200, and 300 mg were significantly more effective
For personal use only.

intensity scores in the pooled tramadol ER groups (n = than placebo for the change from baseline to the
806) separated significantly from the mean scores in final visit for being awakened by pain in the morning.
the placebo group ( p < 0.05) beginning on the first Tramadol ER 100 mg was significantly more effective
day of study and continuing throughout treatment than placebo for the change from baseline to the final
(Figure 2). visit for the need for sleep medication.

40 Initial dose 100 mg once daily

Titration to 200 mg once daily (tramadol ER 200, 300, and 400 mg groups)
35 Titration to 300 mg once daily (tramadol ER 300 and 400 mg groups)
Mean (SE) improvement from baseline

Titration to 400 mg once daily (tramadol ER 400 mg group)

30
Pain intensity VAS

25

20

15

10

5 Tramadol ER 100/200/300/400 mg (n = 806)

Placebo (n = 205)

0
0 7 14 21 28 35 42 49 56 63 70 77 84
Number of days

Figure 2. Mean (± SE) change in daily arthritis pain intensity visual analog score over 12 weeks from subject diaries; last
observation carried forward. Data were pooled for the tramadol ER dose groups. Statistically significant differences between
the pooled tramadol ER groups and the placebo group were observed on each day of study treatment ( p < 0.05)

© 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22() Tramadol ER in the treatment of osteoarthritis Gana et al. 1397
 30 Tramadol ER 100 mg
Tramadol ER 200 mg
Tramadol ER 300 mg

LS mean change from baseline to final visit

25 Tramadol ER 400 mg †
† Placebo †
†
† † † †
20
* *
† *
*
15 * *

*
10

5
Curr Med Res Opin Downloaded from informahealthcare.com by University of Queensland on 06/14/14

0
Sleep quality Trouble Need sleep Awakened by Awakened by
falling asleep medication pain at night pain in the
morning
Least-squares (LS) mean change in sleep scores from baseline to final visit. Improvement is shown as a positive
Figure 3. ����������������������������������������������������������������������������������������������������������������
change by reporting the inverse for all questions except sleep quality. Pairwise p-values: *p ≤ 0.05 vs. placebo group.
†p ≤ 0.01 vs. placebo group. Overall p-values: sleep quality, p = 0.071; trouble falling asleep, p = 0.001; need sleep
medication, p = 0.173; awakened by pain at night, p = 0.002; awakened by ���������������������
pain in the morning, p = 0.005
For personal use only.

Adverse events event. Each case of withdrawal syndrome occurred

after the subject completed 12 weeks of treatment and
The proportion of subjects reporting at least one then abruptly discontinued treatment in accordance
adverse event, regardless of relationship to study with the study protocol. Symptoms from the physical
treatment, was 71.3%, 73.1%, 76.1%, and 84.2% in dependence questionnaire reported with significantly
the tramadol ER 100, 200, 300, and 400 mg groups, different frequency between treatment groups
respectively, compared to 55.6% of subjects in the 1 week after discontinuation ( p ≤ 0.036) – but not at
placebo group. The most commonly reported adverse baseline or at the time of treatment discon­tinuation
events in the tramadol ER groups were constipation, – included trouble with sleeping, sneezing, nervousness
dizziness, nausea, somnolence, headache, flushing, or restlessness, weakness, increased yawn­ing, and
pruritus, and insomnia (Table 4). gooseflesh.
Most adverse events were mild or moderate – 126 Constipation, nausea, dizziness, and somnolence
subjects (12.5%) had at least one severe adverse event each resulted in early discontinuation of ≥ 5% of
– and no deaths were reported during study treatment. subjects in at least one treatment group. Discontinua­
At least one serious adverse event was reported by tion rates for constipation, nausea, and somnolence
1.0%, 1.5%, 2.0%, 1.5%, and 3.0% of subjects in the were significantly different among treatment groups
placebo and tramadol ER 100, 200, 300, and 400 mg ( p ≤ 0.004) and increased with an increasing dose of
groups, respectively. Serious adverse events that were tramadol ER. Discontinuation of tramadol ER often
reported by more than one subject receiving tramadol occurred soon after titration to the final target dose; the
ER but were not considered related to study treatment majority of subjects who discontinued treatment did so
included cholelithiasis (0.4%), chest pain (0.4%), and by Day 11 in the 100 mg group (11 days at the target
pancreatitis (0.2%). One serious adverse event – drug dose), by Day 11 in the 200 mg group (6 days at the
withdrawal syndrome in a subject in the tramadol ER target dose), by Day 14 in the 300 mg group (4 days at
400 mg group – was considered related to study treat­ the target dose), and by Day 19 in the 400 mg group
ment. Drug withdrawal syndrome was reported as (4 days at the target dose). Treatment with tramadol
a non-serious adverse event for 3 other subjects who ER had no clinically meaningful effects on clinical
received tramadol ER (2 on 200 mg and 1 on 400 mg); laboratory tests, vital signs, physical examination
thus, a total of 4 of 815 (0.5%) subjects reported this findings, or electrocardiographic findings.

1398 Tramadol ER in the treatment of osteoarthritis © 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22()
 Table 4. Adverse events reported by ≥ 5% of subjects in any treatment group*

Tramadol ER
Placebo 100 mg 200 mg 300 mg 400 mg
(n = 205) (n = 202) (n = 201) (n = 201) (n = 202) p-value
Constipation 12 (5.9) 26 (12.9) 33 (16.4) 45 (22.4) 60 (29.7) < 0.001
Dizziness 13 (6.3) 34 (16.8) 37 (18.4) 41 (20.4) 57 (28.2) < 0.001
Nausea 15 (7.3) 30 (14.9) 47 (23.4) 49 (24.4) 52 (25.7) < 0.001
Somnolence 5 (2.4) 17 (8.4) 21 (10.4) 18 (9.0) 41 (20.3) < 0.001
Headache 17 (8.3) 29 (14.4) 30 (14.9) 21 (10.4) 32 (15.8) 0.104
Flushing 11 (5.4) 18 (8.9) 20 (10.0) 19 (9.5) 32 (15.8) 0.011
Pruritus 3 (1.5) 12 (5.9) 16 (8.0) 13 (6.5) 24 (11.9) 0.001
Insomnia 7 (3.4) 16 (7.9) 13 (6.5) 17 (8.5) 23 (11.4) 0.042
Vomiting 6 (2.9) 11 (5.4) 15 (7.5) 14 (7.0) 19 (9.4) 0.094
Dry mouth 2 (1.0) 11 (5.4) 13 (6.5) 22 (10.9) 18 (8.9) < 0.001
Fatigue 2 (1.0) 9 (4.5) 11 (5.5) 13 (6.5) 13 (6.4) 0.054
Sweating increased 1 (0.5) 5 (2.5) 7 (3.5) 7 (3.5) 13 (6.4) 0.018
Anorexia 1 (0.5) 3 (1.5) 4 (2.0) 11 (5.5) 12 (5.9) 0.002
Curr Med Res Opin Downloaded from informahealthcare.com by University of Queensland on 06/14/14

Postural hypotension 6 (2.9) 1 (0.5) 9 (4.5) 3 (1.5) 11 (5.4) 0.020

Diarrhea 5 (2.4) 7 (3.5) 12 (6.0) 14 (7.0) 10 (5.0) 0.198
Pain 7 (3.4) 7 (3.5) 7 (3.5) 10 (5.0) 5 (2.5) 0.757
*Presented in order of decreasing frequency in the tramadol ER 400 mg group

Discussion inhibitors and nonselective NSAIDs3. Controlled clinical

trials in patients with osteoarthritis pain demonstrated
Despite the availability of numerous oral medications the efficacy and safety of immediate-release tramadol
with demonstrated efficacy for the management of taken every 4–6 h daily as mono­therapy14, as adjunctive
osteoarthritis pain, many patients respond inadequately therapy to NSAIDs for breakthrough pain 5, or to
For personal use only.

to treatment or are poor candidates for oral treatments reduce the dose of NSAID therapy6. Once-daily and
due to toxicity concerns. Clinical treatment guidelines twice-daily formulations of tramadol not available
from the ACR recommend use of the simple analgesic, for use in the United States were reported to relieve
acetaminophen, in patients with mild-to-moderate osteoarthritis pain comparably to multiple daily doses
osteoarthritis pain 3. However, the guidelines note of immediate-release trama­dol15,16, with the potential
that many patients fail to obtain adequate pain relief clinical benefits of prolonged action and less frequent
with full doses of acetaminophen alone. Alternative or dosing.
additional treatment with NSAIDs is recommended Tramadol ER is a new formulation designed for
after evaluation of risk factors for serious upper once-daily dosing that was recently approved for
gastrointestinal or renal toxicity, which include common marketing in the United States. The analgesic efficacy
co-morbid conditions in patients with osteoarthritis, and safety of tramadol ER were documented in a
such as age ≥ 65 years, hypertension, or congestive previous flexible-dose, placebo-controlled clinical
heart failure, and use of angiotensin-converting enzyme trial among patients with osteoarthritis who were
inhibitors. The ACR guidelines, which were published permitted to titrate the dose of tramadol ER 8. The
in 2000, note that COX-2-specific inhibitors are present study used fixed doses of tramadol ER 100,
associated with comparable risks of renal toxicity but 200, 300, or 400 mg once daily. Overall, the results
they may be appropriate in patients at increased risk confirm the analgesic efficacy and safety of once-daily
of gastro­intestinal toxicity. Subsequent data from large tramadol ER in osteoarthritis pain. Tramadol ER was
clinical trials confirmed the improved gastrointestinal associated with statistically significant improvement in
toler­ability of COX-2-specific inhibitors, but evidence pain and physical function subscales of the WOMAC
of an apparent class-effect of cardiovascular toxicity Osteoarthritis Index. However, the overall test for
has led to recent clinical guidelines from another panel subject global assessment of disease activity did not
recommending careful consideration of the risks and reach statistical significance between tramadol ER and
benefits of NSAIDs and COX-2-specific inhibitors placebo. Tramadol ER 200 and 300 mg were associated
before prescribing them for arthritis pain13. with significant improvement in subject global assess­
The centrally acting analgesic, tramadol, is recom­ ment of disease activity, but 100 and 400 mg were
mended in the management of patients with moderate not. Patients in an analgesic study with a fixed-dose
or severe osteoarthritis pain who either respond poorly design are not permitted to increase their dose of study
to, or have contraindications to, COX-2-specific medication to manage increased pain during disease

© 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22() Tramadol ER in the treatment of osteoarthritis Gana et al. 1399
 exacerbations (i.e., osteoarthritis flare), nor can they Generalization of these study results may be limited
decrease the dose of study medication to alleviate by the study dosing regimen. Use of prespecified doses
adverse events. of tramadol ER is not reflective of usual clinical practice,
Additional evidence of the analgesic efficacy of where analgesic therapy is titrated until the optimal
tramadol ER was provided by secondary outcome balance of efficacy and tolerability is achieved. In this
measures, including the joint stiffness subscale and study, subjects were required to discontinue all chronic
composite scores of the WOMAC Osteoarthritis Index, pain medications for up to 7 days before initiating study
pain intensity scores for index joints, and pain intensity treatment. When patients switch analgesic therapy
scores in daily subject diaries. Improvement of pain in in usual clinical practice, the new analgesic is titrated
non-index joints with select doses was notable; unlike the upward as the previous one is tapered downward, or the
hip and knee, many non-index joints are not candidates new medication is added to existing treatment, and then
for surgical intervention and thus may only be manageable the previous medication is discontinued.
with long-term analgesic therapy. Despite the reported Abrupt discontinuation of tramadol ER without
improvements for the primary efficacy measure of tapering after 12 weeks of treatment in this study
physical function on the WOMAC Osteoarthritis Index, also is inconsistent with clinical practice and product
tramadol ER did not improve the secondary measure of labeling7. This may be the reason why, using a 16‑item
Curr Med Res Opin Downloaded from informahealthcare.com by University of Queensland on 06/14/14

physical component summary score on the SF‑36. One questionnaire, subjects reported selected symptoms of
possible explanation is that the WOMAC Osteoarthritis opiate withdrawal 1 week after abrupt discontinuation
Index measures the ability of subjects with impaired that had not been present at baseline or at the end
function to perform lower-level activities, whereas the of treatment. However, withdrawal syndrome was
SF‑36 measures the ability to perform more strenuous reported as an adverse event for only 4 of 815 subjects
activities. The reported adverse events in this study were (0.5%) who received tramadol ER.
generally mild or moderate in severity and were consistent One of the goals of using fixed doses of tramadol ER
with the established safety profile of immediate-release in this study was to evaluate the efficacy and safety of
trama­dol in the treatment of osteoarthritis pain4–6,15,16. individual doses. Tramadol ER 200 and 300 mg were
Tramadol ER improved sleep quality, reduced associated with significant improvement in all 3 primary
For personal use only.

trouble falling asleep, and reduced being awakened by efficacy variables beginning at the first follow-up visit
pain during the night. Sleep disturbances are approx­ at Week 1 and continuing until the final visit at Week
imately twice as common among patients with arthritis 12 (with the exception of subject global assessment of
compared to patients who do not have arthritis, but disease activity for 200 mg at Weeks 1 and 6). Rapid and
better pain management may reduce this discrepancy17. sustained improvement with tramadol ER was observed
In addition, one of the proposed benefits of once-daily for the daily pain scores in subject diaries from Day 1
analgesics such as tramadol ER is 24‑h coverage of throughout the study, with the greatest improvement
pain, potentially reducing nighttime or morning awake­ reported in the tramadol ER 300 mg group. A dose of
nings due to breakthrough pain, as observed in this tramadol ER 300 mg was also associated with the lowest
study. Sleep medication use generally did not improve rate of discontinuation due to lack of efficacy. Although
with tramadol ER, possibly due to subject reluctance tramadol ER 400 mg was efficacious for several study
to discontinue sleep medications, or the fact that variables, it was associated with the only serious adverse
many subjects required little or no sleep medication event considered related to study treatment, the highest
at baseline. Need for sleep medication also could have reported incidence of adverse events, and the most
been influenced by treatment-emergent insomnia, discontinuations due to adverse events. Therefore, the
which was reported by more subjects in the tramadol results of this study show that a dose of tramadol ER
ER groups than for placebo but was not necessarily higher than 300 mg appears to offer little added clinical
associated with pain-related sleep disturbance. benefit in subjects with osteoarthritis pain.
Rescue analgesia was not to be used in this study;
limited use of acetaminophen was permitted only for
the management of non-arthritis pain. Thus, subjects Conclusions
were able to achieve significant reductions in osteo­
arthritis pain with once-daily tramadol ER treatment, The overall test of subject global assessment of disease
without the need for complex pharmacotherapy activity did not reach statistical significance between
or multiple daily doses. Patient perceptions of the tramadol ER and placebo. However, tramadol ER once
convenience of once-daily analgesic monotherapy and daily was more effective than placebo for the other
the influence of these regimens on patient adherence 2 co-primary efficacy measures of pain and physical
to prescribed therapy remain to be determined. function. Several secondary measures of pain intensity
and pain-related sleep disturbance also improved

1400 Tramadol ER in the treatment of osteoarthritis © 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22()
 with tramadol ER therapy. Reported adverse events SC; Donald Taylor, Marietta, GA; Celeste Thomas, Conroe,
were consistent with the established safety profile of TX; Mikel Thomas, Prairie Village, KS; Michael Tivnon,
Bakersfield, CA; Antonio Wong, Pembroke Pines, FL; Carol
immediate-release tramadol. Tramadol ER 300 mg was
Young, Escondido, CA; Thomas Zizic, Baltimore, MD.
associated with the greatest improvement in daily pain
intensity and the lowest rate of discontinuation due
to lack of efficacy. The results of this fixed-dose study
suggest tramadol ER is a useful treatment option for
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CrossRef links are available in the online published version of this paper:
http://www.cmrojournal.com
Paper CMRO-3486_3, Accepted for publication: 25 May 2006
Published Online: 09 June 2006
doi:10.1185/030079906X115595

© 2006 LIBRAPHARM LTD – Curr Med Res Opin 2006; 22() Tramadol ER in the treatment of osteoarthritis Gana et al. 1401