Current Medical Research & Opinion Vol. 28, No.

5, 2012, 847–857

0300-7995 Article ST-0468.R1/681035

doi:10.1185/03007995.2012.681035 All rights reserved: reproduction in whole or part not permitted

Original article
Extended-release tramadol/paracetamol in
moderate-to-severe pain: a randomized,
placebo-controlled study in patients with
acute low back pain

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Abstract
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Ben Lasko

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Medical Director, Manna Research, Toronto, Ontario,

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Objective:

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Combinations of oral analgesics may offer several potential benefits compared with an individual agent. The
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Randy J. Levitt le is al
objective of this study was to investigate the efficacy and safety of an extended-release, twice-daily fixed
Labopharm Inc., Laval, Québec, Canada
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For personal use only.

combination of 75 mg tramadol/650 mg paracetamol (DDS-06C) in the treatment of moderate-to-severe

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K.D. Rainsford pain, using acute low back pain as a model.
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Emeritus Professor of Biomedical Sciences, Sheffield

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Hallam University, Sheffield, UK

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Research design and methods:

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Sylvie Bouchard In this phase III study, 277 patients with moderate-to-severe acute low back pain were randomized to 1–2
Clinical Faculty Lecturer, Faculty of Medicine, McGill tablets of DDS-06C or placebo every 10–12 h for 2.5 days during the double-blind phase. Following the
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University, and Emergency Physician at the Lakeshore double-blind phase, patients had the option to continue for a 2.5-day open-label phase.
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General Hospital, Montréal, Québec, Canada

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Clinical trial registration:

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Anna Rozova
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Clinicaltrials.gov (Identifier: NCT00643383)

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Sybil Robertson
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Labopharm Inc., Laval, Québec, Canada

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Main outcome measures:

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The primary end point was the sum of pain intensity differences (SPID) over the 50-h double-blind phase
Address for correspondence:
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(SPID50). Secondary end points included total pain relief score over the 50-h double-blind phase
au fo
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Randy J. Levitt, PhD, Paladin Labs Inc., 100 Alexis

(TOTPAR50), patient’s global impression of medication, and SPID over the first 4 h.
Nihon Blvd., Suite 600, Saint-Laurent, Québec,
Un t

Canada H4M 2P2.

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Tel.: þ1 514-669-5313; Fax: þ1 514-344-4675; Results:

rlevitt@paladinlabs.com
Key words:
Acute low back pain – Analgesic – Combination –
Extended-release – Paracetamol – Placebo-controlled
trial – Tramadol
Accepted: 21 March 2012; published online: 25 April 2012
Citation: Curr Med Res Opin 2012; 28:847–57
A statistically significant (p ¼ 0.038) greater decrease in pain intensity was observed in the DDS-06C group
(median SPID50: 6.0) versus placebo (median SPID50: 4.0). Greater pain relief was also observed in
patients randomized to DDS-06C: the median TOTPAR50 was 13.0 for the DDS-06C group and 11.0 for
placebo (p ¼ 0.026). DDS-06C demonstrated statistically significant superior efficacy compared with
placebo for the majority of the other secondary end points. Overall, 38% of patients treated with DDS-
06C experienced at least one adverse event; the intensity was mild-to-moderate in 81% of cases. The most
commonly reported adverse events (45% of patients receiving DDS-06C) were nausea, dizziness, vomiting,
and somnolence.

Conclusions:
Using acute low back pain, a model with a high degree of heterogeneity and intrinsic variability, DDS-06C
was superior to placebo on measures of pain intensity and relief, and was well-tolerated.

! 2012 Informa UK Ltd www.cmrojournal.com Extended-release tramadol/paracetamol for acute low back pain Lasko et al. 847
 Current Medical Research & Opinion Volume 28, Number 5
Introduction
Combinations of oral analgesics may offer several potential
benefits compared with an individual agent. Combining
analgesics into a single product may facilitate prescribing
and compliance by reducing the number of medications
that patients use to manage pain. Combining products
with different mechanisms of action may provide multi-
modal coverage of pain resulting from a broad spectrum of
pathologies, and the individual agents may act synergisti-
cally1. Additionally, lower doses of the respective analge-
sics used in the combination may result in a lower
incidence of adverse events (AEs). Given the multiple
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 03/11/13
physiological pathways involved in the perception of
pain, combination therapy has been recommended by var-
ious pain management guidelines2.
Tramadol is an atypical weak opioid used for the treat-
ment of moderate-to-severe pain3. It is comprised of two
enantiomers, (þ)-tramadol and ()-tramadol, in a race-
mic 1:1 mixture. Tramadol has a number of analgesic
effects in the central nervous system due to three comple-
mentary mechanisms of action. First, (þ)-tramadol and its
major metabolite, (þ)-O-desmethyltramadol (M1), act as
m-opioid receptor agonists in the spinal cord and brain4.
For personal use only.
The (þ)-M1 metabolite has a greater affinity for m-opioid
receptors than (þ)-tramadol, and is primarily responsible
for the opioid action of tramadol5. Secondly, (þ)-tramadol
blocks central pain pathways by inhibiting the reuptake of
serotonin, and thirdly, ()-tramadol inhibits the reuptake
of norepinephrine4.
Paracetamol is an analgesic and antipyretic drug with
weak anti-inflammatory properties. Its mechanism of
action is suggested to be both central and peripheral.
Proposed mechanisms include cyclooxygenase inhibition,
nitric oxide synthesis blockade, and effects on several neu-
rotransmitter systems, in particular the serotonergic
system. Thus, paracetamol has been proposed to affect
opioidergic, noradrenergic, serotonergic, and cholinergic
systems6,7.
Co-administering paracetamol with tramadol results in
synergistic analgesia in both animal and human pain
models1,8. Furthermore, clinical studies have demon-
strated the efficacy and tolerability of immediate-release
(IR) tramadol/paracetamol (37.5 mg/325 mg) for a variety
of pain models, including acute nociceptive pain associ-
ated with orthopedic surgery, osteoarthritis flare, and oral
surgery9–13. IR tramadol/paracetamol combinations are
marketed worldwide with a variety of indications in the
treatment of moderate-to-severe pain14–16.
A twice-a-day tramadol/paracetamol formulation
would be more convenient for patients than currently mar-
keted IR formulations, which must be taken up to 4 times a
day. DDS-06C is an extended-release, twice-daily fixed-
combination formulation of 75 mg tramadol hydrochloride
and 650 mg paracetamol developed by Labopharm Inc
848 Extended-release tramadol/paracetamol for acute low back pain Lasko et al.
May 2012
(Laval, QC, Canada). This formulation was designed to
provide effective analgesia for a full 12-h period. It was
developed using hydroxypropyl distarch phosphate
(ContramidÕ , Labopharm, Laval, Québec, Canada), a
cross-linked high amylose starch matrix that provides con-
trolled release of the active ingredients over an extended
period17. In a multiple-dose comparative bioavailability
study, equivalent total systemic exposure (based on area
under the plasma time–concentration curve [AUC]) at
steady state was demonstrated for both active components
of DDS-06C (2  75 mg tramadol/650 mg paracetamol
controlled-release tablets administered every 12 h) versus
IR tramadol/paracetamol (2  37.5 mg tramadol/325 mg
paracetamol IR tablets administered every 6 h)18.
The objective of this randomized, double-blind, phase
III study was to demonstrate the efficacy and safety of
DDS-06C versus placebo for the treatment of moderate-
to-severe pain, using acute low back pain as a pain model.
This condition is particularly complex and often presents
with intractable pain, so there is a therapeutic need for
effective and long-lasting treatment of pain in this state.
Patients and methods
Patient selection
Patients included in this study were selected from 31 active
centers: 14 from the USA and 17 from Canada. The cen-
ters were comprised of walk-in clinics, clinical research
centers (that received patients referred from pharmacies),
and hospital emergency rooms. Patients included in the
study were males or females in generally good health,
18–80 years of age, with moderate-to-severe acute low
back pain. At baseline, included patients had a rating of
at least 2 on a 4-point categorical pain intensity rating
scale (0 ¼ none, 1 ¼ mild, 2 ¼ moderate, 3 ¼ severe), and
a rating of at least 4 on the 11-point pain intensity numer-
ical rating scale (PI-NRS) (ranges from 0 [no pain] to 10
[worst pain]). The onset of the current acute low back pain
episode was within 48 h prior to dosing.
Patients with a known history or symptoms suspicious
for spinal fracture, cancer (i.e., constitutional symptoms
such as recent unexplained chills or weight loss), or
spinal infection (e.g., IV drug abuse, immunosuppression)
were excluded from the study. Also excluded were patients
with cauda equina syndrome, spina bifida, neurological
deficit (e.g., foot drop), spinal surgery within 1 year of
study entry, chronic low back pain, back pain radiating
below the knee, or more severe pain in a region other
than the lower back. Other exclusion criteria were: treat-
ment with non-pharmacological therapy (e.g., chiroprac-
tic adjustment) within 3 weeks of entry to the study, use of
any sedative hypnotics, topical preparations/medications
and anesthetics or muscle relaxants within 4 h prior to
www.cmrojournal.com ! 2012 Informa UK Ltd

study entry, use of short-acting analgesics (e.g., paraceta-
mol) within 4 h prior to study entry or use of other anal-
gesics within 5 half lives prior to study entry, use of an
opioid within the 14 days preceding randomization, treat-
ment within the last 3 weeks with a drug that reduces sei-
zure threshold, a chronic or acute painful condition other
than the study indication which could have interfered with
the assessment of the efficacy of the study medication or
any other condition that, in the opinion of the investiga-
tor, could have adversely affected the patient’s ability to
complete the study or its measures, patients who had a
history of seizure disorder (other than infantile febrile sei-
zures), bowel disease or postsurgical condition causing mal-
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absorption, significant renal or hepatic disease, or patients
who had ongoing or prior substance abuse or dependence
(other than nicotine).
Study design
This double-blind, randomized, placebo-controlled, two-
arm, multicenter study (Labopharm protocol 06CCL3-
001) evaluated the efficacy and safety of DDS-06C
versus placebo for the treatment of acute low back pain.
For personal use only.
The study was conducted from March 2008 to January
2009. The protocol complied with the 1996
International Conference on Harmonisation – Good
Clinical Practice (ICH-GCP) guidelines and was con-
ducted in compliance with the 2004 revision of the
Declaration of Helsinki (Tokyo). The trial was registered
on clinicaltrials.gov (Identifier: NCT00643383) on March
20, 2008.
During the screening/baseline visit, patients provided
informed consent and underwent an initial screening for
inclusion/exclusion. Laboratory evaluations, physical
examination, medical history and vital signs (including
height and weight) were performed. At the beginning of
the double-blind phase, patients were randomized to DDS-
06C or placebo. To maintain blinding, the active drug and
placebo were identical in appearance and taste. As a gen-
eral rule, the patient received two tablets of DDS-06C or
placebo every 10–12 h without regard to meals. However,
at the investigator’s discretion, he/she may have decided to
initiate treatment with one tablet of the study medication
based on various clinical factors (e.g., level of pain, age,
BMI, etc.). It was also possible to reduce the dose from two
to one tablet, and subsequently go back to two tablets,
based on an individual patient’s tolerability and level of
pain relief.
Patients were required to remain in the study facility for
the first 4 h following the first dose of the study medication
(on-site period). They were asked to maintain a standard-
ized level of activity during the on-site period: standing
and/or sitting (walking to the bathroom was permitted).
After 4 h, patients left the clinic but were required to
! 2012 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 28, Number 5 May 2012
perform the pain intensity and pain relief evaluations as
detailed below. Patients were informed of the importance
of closely adhering to the evaluation schedule and
reminded that if treatment was stopped early, they must
return to the clinic for a discontinuation visit as soon as
possible and no later than 48 h after the last dose of study
medication. Patients were also advised to minimize their
level of physical activity (e.g., walking for a short distance,
sitting, standing). Any intensive physical activity (e.g.,
lifting or pushing weights exceeding 3 kg (6 lbs), jumping,
jogging, gardening, shoveling, etc.) was prohibited for the
duration of the double-blind phase.
The double-blind phase lasted for 2.5 days, with admin-
istration of one to two tablets of DDS-06C or placebo
occurring every 10–12 h. Remedication was only allowed
on day 1, and consisted of one tablet of study medication
which could be taken at any time within 4–10 h after the
initial dose. No other rescue medication was allowed at
any time during the study. The last visit of the double-
blind phase was on day 3. Patients who required further
analgesia could continue into the open-label phase. For
those patients who did not require further analgesia or
were not willing to continue participation in the study,
day 3 was the patient’s final study visit. Patients that
agreed to continue to the open-label phase of the study
received one to two tablets of DDS-06C every 10–12 h for
an additional 2.5 days. The last study visit for these
patients was on day 6.
Study assessments
The primary end point was the sum of pain intensity dif-
ferences over the 50-hour observation (SPID50).
Secondary end points consisted of 9 measures: total pain
relief score over the 50-hour observation (TOTPAR50),
the sum of pain intensity differences over the first 4 h of
observation (on-site period) (SPID4), the patient’s global
impression of study medication, time to onset of meaning-
ful pain relief, time to onset of perceptible pain relief, time
to remedication, weighted SPID50 (SPIDW50), weighted
TOTPAR50 (TOTPARW50), and the change from base-
line in pain intensity at the end of the open-label phase.
During the screening/baseline visit, patients rated their
pain intensity on a 4-point categorical scale (0 ¼ none,
1 ¼ mild, 2 ¼ moderate, 3 ¼ severe). Randomized patients
subsequently rated their pain intensity (using the 4-point
scale) and pain relief (using a 5-point categorical scale:
0 ¼ none [no relief], 1 ¼ a little, 2 ¼ moderate, 3 ¼ a lot,
4 ¼ complete) at the following 10 time points (relative to
the first dose): 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h (30 min),
26 h (30 min), 30 h (30 min), 34 h (30 min), and
50 h (30 min). SPID50 and TOTPAR50 were computed
as the sum of the differences between each post-baseline
pain intensity and pain relief score, respectively, and the
Extended-release tramadol/paracetamol for acute low back pain Lasko et al. 849
 Current Medical Research & Opinion Volume 28, Number 5 May 2012
baseline score. SPIDW50 and TOTPARW50 were calcu-
lated by multiplying these differences by the corresponding
time interval since the previous observation (adjusted at
each daily dosing), and summing these weighted values up
to hour 50. SPID4 was computed as the sum of the differ-
ences between each post-baseline pain intensity score
during the 4 h on-site period and the baseline score.
The patient’s global impression of study medication was
assessed at the end of the double-blind phase (or at study
discontinuation) using a 4-point categorical scale
(1 ¼ very effective, 2 ¼ effective, 3 ¼ somewhat effective,
4 ¼ ineffective).
Time to onset of meaningful pain relief and time to
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onset of perceptible pain were measured on day 1 using
the double stop-watch method. Perceptible pain relief
was defined as the point at which the patient began to
experience any pain relief even though the pain was not
completely relieved, and meaningful pain relief was
defined as the point at which the patient felt a significant
pain relief even though the pain may not have been com-
pletely relieved. Time to remedication was defined as the
time of the rescue medication dose (which was only
allowed 4–10 h post-initial dose) minus the time of the
For personal use only.
initial dose.
Safety data collected consisted of AEs, laboratory eval-
uations (biochemistry, hematology, urinalysis), physical
examination findings, vital signs (blood pressure, heart
rate, respiratory rate and body temperature), and concom-
itant medications. AEs were monitored from the time of
the first study medication dose until the end of the study or
until discontinuation. AEs were recorded as serious AEs
(SAEs) if they met applicable criteria (based on ICH-GCP
guidelines). All SAEs that occurred during the study and
for 30 days after the patient’s last dose of study medication
were documented. All AEs and SAEs were followed to
resolution, until the condition stabilized, or until the
patient was lost to follow-up
Statistical analyses
The primary population for efficacy analyses was the
intent-to-treat (ITT) population, which was defined as
all randomized patients who received at least one dose of
the double-blinded study medication (during the double-
blind phase), regardless of the status of the post-dosing
assessment. In the sensitivity analysis, efficacy parameters
were also analyzed for the per protocol (PP) population,
which was defined as all randomized patients who com-
pleted the double-blind phase of the study without major
protocol deviations. Safety analyses were performed on the
safety population, which was defined as all patients who
received at least one dose of the study medication (double-
blind and/or open-label phase).
850 Extended-release tramadol/paracetamol for acute low back pain Lasko et al.
For the efficacy analyses, missing data during the
double-blind phase of the study were handled using the
baseline observation carried forward (BOCF)/last observa-
tion carried forward (LOCF) method of imputation as
follows: (1) for patients who discontinued during the
double-blind phase due to AEs, BOCF was used (the base-
line value for the pain intensity parameter was substituted,
and the rating of 0 ¼ none was substituted for the pain
relief parameter); (2) for patients who discontinued
during the double-blind phase due to reasons other than
AEs, LOCF was used (the last post-baseline value of the
respective efficacy parameter was substituted); (3) for
patients who completed the double-blind phase but were
missing data values due to missed visits or windowing,
LOCF was used (in cases where no post-baseline data was
available, BOCF was used). Exploratory supportive efficacy
analyses were performed using LOCF as the method of
imputation for all patients. For all missing data during
the open-label phase of the study, LOCF was used.
To achieve 90% power to detect an effect size of 0.45 for
the primary end point (SPID50), a sample size of 105
patients in each treatment group was needed to complete
the study; this assumed a 1:1 randomization ratio and a
two-group two-tailed t-test with significance set at
a ¼ 0.05. Assuming a discontinuation rate of 30%, an
enrollment of 135 patients in each treatment group was
required.
For the analysis of SPID50, residual diagnostics (nor-
mality and homogeneity of variance assessments) were
performed to verify if an analysis of covariance
(ANCOVA) could be considered robust. The normality
of the residuals from the ANCOVA model were tested and
found to be non-normally distributed using Shapiro-Wilk
(and confirmed with a variety of other statistical tests).
Furthermore, the distribution of SPID50 values using
BOCF/LOCF as the method of imputation is both bimodal
and highly skewed (Figure 1), rendering methodology
based on a normal distribution (ANCOVA) inappropri-
ate. Therefore, a non-parametric approach (Wilcoxon
rank-sum test) was used as the primary basis for comparison
of the two treatment groups.
To be consistent with the primary end-point analysis,
the normality of the residuals from the ANCOVA model
for TOTPAR50, SPID4, SPIDW50, and TOTPARW50
were tested and found to be non-normally distributed.
Therefore, analysis of these end points was performed
using a non-parametric method (Wilcoxon rank-sum
test). For the patient’s global impression of study medica-
tion, frequency counts were compared based on the
Cochran–Mantel–Haenszel (CMH) mean score statistic
using modified ridit scores, stratified by pooled center.
Time to onset of meaningful pain relief, time to onset of
perceptible pain relief, and time to remedication were
summarized using Kaplan–Meier curves, and a Cox pro-
portional hazards regression model stratified by
www.cmrojournal.com ! 2012 Informa UK Ltd

60
50
Number of patients
40
30
20
10
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 03/11/13
0
-20
Figure 1. Distribution of SPID50 values. Histogram of the distribution of SPID50 values for the 277 patients in the ITT population (method of imputation:
BOCF/LOCF).
investigative site was used to compare between treatment
groups. Pain intensity at the end of the open-label phase
was analyzed using descriptive statistical methods.
For personal use only.
Safety data were analyzed using descriptive statistics on
AEs, concomitant medications, physical examination, lab-
oratory evaluations, and vital signs.
Results
Patient characteristics
In this study, 277 patients met the eligibility criteria and
were randomized to receive either DDS-06C (n ¼ 141) or
placebo (n ¼ 136). As seen in Figure 2, 26 of 277 patients
(9.4%; DDS-06C, n ¼ 19; placebo, n ¼ 7) prematurely dis-
continued the study during the double-blind phase. The
most frequently indicated reason for discontinuation,
regardless of treatment group, was AEs (DDS-06C,
n ¼ 17; placebo, n ¼ 3). A total of 219 patients entered
the open-label phase (109 patients from the DDS-06C
group continued on active treatment and 110 patients
from the placebo group switched to DDS-06C treatment).
There were ten patients (4.6%) that discontinued during
the open-label phase; all ten patients were randomized to
placebo during the double-blind phase. The most fre-
quently indicated reason for discontinuation during the
open-label phase was AEs (n ¼ 7). The ITT population
contained all 277 patients that comprised the safety pop-
ulation. The PP population contained a total of 226
patients (DDS-06C, n ¼ 111; placebo, n ¼ 115).
Baseline characteristics are presented in Table 1. The
mean age of the ITT population was 42.2 (SD: 13.0) years;
145 of 277 (52.3%) were female, and 156 of 277 (56.3%)
were Caucasian. There were no statistically significant
! 2012 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 28, Number 5 May 2012
-15 -10 -5 0 5 10
SPID50 BOCF/LOCF score
differences between treatment groups with regard to age,
gender, or race. At baseline, the mean patient rating of
pain intensity score was 2.3 for the DDS-06C group, and
2.2 for the placebo group (difference between groups was
not statistically significant; p ¼ 0.0701). The majority of
the patients in both treatment groups (66.0% in the DDS-
06C group and 75.7% in the placebo group) had a score of
2 (moderate pain). As seen in Table 2, there was no sta-
tistically significant difference between groups with regard
to acute low back pain history. The majority of patients
(54.9%) had an onset of pain 2 days prior to
randomization.
The treatment groups were comparable with regard to
past and current medical conditions, and prior and con-
comitant medications. Overall, 110 of the 277 randomized
patients (39.7%) reported use of medications within the 30
days prior to taking the study medication that were dis-
continued before study initiation, and 114 patients
(41.2%) took medications concomitantly with the study
medication. The most commonly used class of medications
that were discontinued before study initiation were other
analgesics and antipyretics (51/277 patients, 18.4%), and
the most commonly used class of concomitant medications
were lipid modifying agents (19 patients; 6.9%).
Dosing and exposure
Overall, 251 patients were exposed to DDS-06C during
this study (141 patients treated with DDS-06C during
the double-blind phase, and 110 patients treated with pla-
cebo during the double-blind phase who were switched to
DDS-06C during the open-label phase). The median
number of days of therapy for all patients exposed to
DDS-06C was 3 days.
Extended-release tramadol/paracetamol for acute low back pain Lasko et al. 851
 Current Medical Research & Opinion Volume 28, Number 5 May 2012

Assessed for eligibility

n = 325
Excluded
n = 48
Randomized
n = 277

Double-blind phase DDS-06C Placebo

Allocated to intervention: 141 Allocated to intervention: 136
Received allocated intervention: 141 Received allocated intervention: 136

Discontinued intervention:
Discontinued intervention:
n=7
n = 19
• Adverse events: 3
• Adverse events: 17
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 03/11/13

• Lack of efficacy: 2
• Lack of efficacy: 2
• Patient request*: 2

Completers Completers
n = 122 n = 129

Continued into open-label phase Continued into open-label phase

n = 109 n = 110

Entered open-label phase

For personal use only.

Open-label phase

n = 219

Discontinued intervention:
n = 10
• Adverse events: 7
• Patient request*: 3

Completers
n = 209

Figure 2. Study flowchart. Disposition of the 277 patients that met the eligibility criteria for this study. Eligible patients were randomized to receive either
DDS-06C (n ¼ 141) or placebo (n ¼ 136). *Patient requests included reasons for discontinuation other than adverse events or lack of efficacy.

During the double-blind phase, 27.7% of patients in the
DDS-06C group always took one tablet of study medica-
tion, 44.0% of patients always took two tablets, and 28.4%
of patients switched between one or two tablets. In the
placebo group, 19.9% of patients always took one tablet,
47.1% of patients always took two tablets, and 33.1% of
patients switched between one or two tablets. Dosing
during the open-label phase was similar to the double-
blind phase: 31.1% of patients always took one tablet,
48.6% of patients always took two tablets, and 20.3% of
patients switched between one or two tablets.
Analgesic efficacy
Results from the primary and secondary efficacy end points
are summarized in Table 3. For the primary end point
(SPID50), using BOCF/LOCF as the method of
imputation, a greater reduction in pain intensity was
observed in the DDS-06C group (median score: 6.0)
compared to the placebo group (median score: 4.0).
This difference was found to be statistically significant
using the Wilcoxon rank-sum z-test (p ¼ 0.038). A statis-
tically significant difference in favor of the DDS-06C
group was confirmed using two other nonparametric anal-
yses: the Wilcoxon rank-sum t-test (p ¼ 0.039) and the
Kruskal–Wallis test (p ¼ 0.038). An exploratory analysis
using a less conservative method of imputation (LOCF for
all patients) also demonstrated a statistically significant
difference in favor of the DDS-06C group (6.0 vs.
4.0, p ¼ 0.012).
Greater pain relief was also observed in patients ran-
domized to DDS-06C compared with those randomized to
placebo: the median TOTPAR50 score was 13.0 for the
DDS-06C group and 11.0 for the placebo group. This
difference was statistically significant (p ¼ 0.026).

852 Extended-release tramadol/paracetamol for acute low back pain Lasko et al. www.cmrojournal.com ! 2012 Informa UK Ltd
 Current Medical Research & Opinion Volume 28, Number 5 May 2012

Table 1. Baseline characteristics of randomized patients (ITT population).

DDS-06C Placebo Overall p-value

(n ¼ 141) (n ¼ 136) (n ¼ 277)

Demographics
Gender [n (%)] 0.1350
Male 61 (43.3%) 71 (52.2%) 132 (47.7%)
Female 80 (56.7%) 65 (47.8%) 145 (52.3%)
Age (years) 0.9910
Mean (SD) 42.2 (12.0) 42.2 (14.0) 42.2 (13.0)
Ethnic origin [n (%)] 0.2943
Caucasian 81 (57.4%) 75 (55.1%) 156 (56.3%)
Black 29 (20.6%) 30 (22.1%) 59 (21.3%)
Hispanic 22 (15.6%) 20 (14.7%) 42 (15.2%)
Asian 2 (1.4%) 5 (3.7%) 7 (2.5%)
Other 7 (5.0%) 6 (4.4%) 13 (4.7%)
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Body mass index (kg/m2) 0.1017

Mean (SD) 29.1 (5.2) 28.1 (5.0) 28.6 (5.1)
Clinical characteristics
PI-NRS* score 0.0054
Mean (SD) 7.2 (1.6) 6.7 (1.4) 6.9 (1.5)
Pain intensity ratingy score 0.0701
Mean (SD) 2.3 (0.5) 2.2 (0.4) 2.3 (0.5)
Distribution [n (%)] Moderate: 93 (66.0%) Moderate: 103 (75.7%) Moderate: 196 (70.8%)
Severe: 48 (34.0%) Severe: 33 (24.3%) Severe: 81 (29.2%)

*Pain intensity numeric rating scale: ranges from 0 (no pain) to 10 (worst pain) (randomized patients had to have a score of at least 4).
yPain intensity scale: none ¼ 0; mild ¼ 1; moderate ¼ 2; severe ¼ 3 (randomized patients had to have a score of at least 2).
For personal use only.

Table 2. Onset of the current episode of acute low back pain (ITT population).

Number of patients (%) DDS-06C Placebo Overall

n ¼ 141 n ¼ 136 n ¼ 277

Onset on the day of randomization 6 (4.3%) 4 (2.9%) 10 (3.6%)

Onset of 1 day prior to the randomization date 51 (36.2%) 57 (41.9%) 108 (39.0%)
Onset of 2 days prior to the randomization date 80 (56.7%) 72 (52.9%) 152 (54.9%)
Onset of 3 days prior to the randomization date 4 (2.8%) 3 (2.2%) 7 (2.5%)

A statistically significant difference in TOTPAR50 was
also demonstrated using LOCF as the method of imputa-
tion (p ¼ 0.008).
The median SPID4 score was 2.0 for the DDS-06C
group and 1.0 for the placebo group. Consistent with the
SPID50 results, this difference was statistically significant
(p ¼ 0.024). Since only one patient (randomized to pla-
cebo) had data imputed using BOCF during the first 4 h, an
exploratory analysis using LOCF as the method of impu-
tation yielded identical results (p ¼ 0.024).
For the patient’s global impression of study medication,
there was a statistically significant difference between
treatment groups in favor of DDS-06C (p ¼ 0.005).
There were 120 patients (86.3%) in the DDS-06C group
who reported effectiveness (somewhat effective, effective,
or very effective) versus 94 patients (69.6%) randomized to
placebo. Conversely, 30.4% of patients in the placebo
group reported that the drug was ineffective, compared
to only 13.7% of patients in the DDS-06C group.
Regarding time to onset of meaningful pain relief, there
was a significant difference between treatment groups in
favor of DDS-06C (hazard ratio: 1.565, p ¼ 0.027).
Furthermore, there were significantly more patients that
reached meaningful pain relief within the first 4 h post-
dosing in the DDS-06C group than in the placebo group
(43.3% vs. 31.1%, p ¼ 0.019).
Regarding time to onset of perceptible pain relief, the
results favored a faster onset of DDS-06C versus placebo
(hazard ratio: 1.219); however, the difference was not sta-
tistically significant (p ¼ 0.166). There were 108 patients
in the DDS-06C (76.6%) and 95 patients in the placebo
group (70.4%) who reached perceptible pain relief within
the first 4 h post-dosing (p ¼ 0.170).
Although patients were allowed to remedicate with the
study medication once on day 1 (between 4 and 10 h after
the initial dose), there were very few patients who reme-
dicated: 18 patients (12.8%) in the DDS-06C group and 17
patients (12.5%) in the placebo group (p ¼ 0.959).
Overall, there was no significant difference between
groups (hazard ratio: 0.93, p ¼ 0.828).
The median SPIDW50 score was 20.0 for the
DDS-06C group and 15.3 for the placebo group.

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 Current Medical Research & Opinion Volume 28, Number 5 May 2012

Table 3. Summary of efficacy results – ITT population (n ¼ 277).

DDS-06C (n ¼ 141) Placebo (n ¼ 136) p-value

Primary end point

SPID50 [median (min/max)]
BOCF/LOCF 6.0 (22/3) 4.0 (23/10) 0.0381
LOCF* 6.0 (22/3) 4.0 (23/10) 0.0121
Secondary end points
TOTPAR50 [median (min/max)]
BOCF/LOCF 13.0 (0/32) 11.0 (0/40) 0.0261
LOCF* 14.0 (0/32) 11.0 (0/40) 0.0081
SPID4 [median (min/max)]
BOCF/LOCF 2.0 (15/5) 1.0 (10/5) 0.0241
LOCF* 2.0 (15/5) 1.0 (10/5) 0.0241
Patient’s global impression of study medication [% of Very effective: 19.4% Very effective: 13.3% 0.0052
patients with non-missing values; n ¼ 139 in the Effective: 26.6% Effective: 22.2%
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 03/11/13

DDS-06C group and n ¼ 135 in the placebo group] Somewhat effective: 40.3% Somewhat effective: 34.1%
Ineffective: 13.7% Ineffective: 30.4%
Time to onset of perceptible pain relief [hazard ratio for 1.22 (0.92, 1.61) 0.1663
treatment (95% CI)]
Time to onset of meaningful pain relief [hazard ratio for 1.57 (1.05, 2.33) 0.0273
treatment (95% CI)]
Time to remedication [hazard ratio for treatment (95% CI)] 0.93 (0.47, 1.84) 0.8283
SPIDW50 [median (min/max)]
BOCF/LOCF 20.0 (67/18) 15.3 (69/26) 0.1621
LOCF* 22.0 (67/18) 17.3 (69/26) 0.0241
TOTPARW50 [median (min/max)]
BOCF/LOCF 43.0 (0/97) 30.5 (0/104) 0.0661
LOCF* 46.5 (0/100) 31.8 (0/104) 0.0071
Change in pain intensity from baseline to the end of the 1.3 (0.8) –
For personal use only.

open-label phase (n ¼ 219) [mean (standard deviation)]

*Performed as supportive efficacy analyses.

BOCF, baseline observation carried forward; LOCF, last observation carried forward.
1
Wilcoxon rank-sum; 2Cochran–Mantel–Haenszel; 3Cox proportional hazards regression.

This difference was not found to be statistically significant
(p ¼ 0.162). However, an exploratory analysis using LOCF
as the method of imputation demonstrated a statistically
significant difference in favor of the DDS-06C group
(22.0 vs. 17.3, p ¼ 0.024).
The median TOTPARW50 score was 43.0 for the
DDS-06C group and 30.5 for the placebo group. This dif-
ference was not statistically significant (p ¼ 0.066).
However, an exploratory analysis using LOCF as the
method of imputation demonstrated a statistically signifi-
cant difference in favor of the DDS-06C group (46.5 vs.
31.8, p ¼ 0.007).
The mean change from baseline in pain intensity for all
patients who had a pain intensity measurement on the day
5 visit (211 patients) was 1.3  0.8. This represents a
60% decrease in the pain intensity rating from baseline.
Safety and tolerability
As seen in Figure 2, the primary reason for discontinuation
in patients receiving active treatment was AEs: there were
17 of 141 patients (12.1%) in the DDS-06C group and
three of 136 patients (2.2%) in the placebo group who
discontinued due to AEs during the double-blind phase
(Figure 2). The most commonly reported reason for
discontinuation due to AEs in the DDS-06C group was
vomiting (nine patients). There were seven of 219 patients
(3.2%) who discontinued due to AEs during the open-
label phase (Figure 2). The most commonly reported
reason was dizziness (five patients).
Overall, 95 of the 251 patients exposed to DDS-06C
(37.8%) experienced at least one AE while being treated
with active drug. The intensity was mild-to-moderate in
the majority (77 of 95; 81.0%) of cases. During the double-
blind phase, 59 of 141 patients in the DDS-06C group
(41.8%) and 17 of 126 patients in the placebo group
(12.5%) reported at least one AE. During the open-label
phase, 48 of 219 patients (21.9%) reported at least one AE.
The most common AEs (reported by 45% of patients
treated with DDS-06C) during the double-blind and open-
label phases are presented in Table 4. Overall, the most
commonly reported AEs were nausea, dizziness, vomiting,
and somnolence. With the exception of one case of vom-
iting during the double-blind phase (experienced by a
patient in DDS-06C group), all incidences of the most
commonly occurring AEs were considered at least possibly
related to treatment. During the double-blind phase, the
mean time to onset of the most common AEs in patients
treated with DDS-06C was between 1.3 and 1.4 days (sim-
ilar time to onset in the placebo group), and mean

854 Extended-release tramadol/paracetamol for acute low back pain Lasko et al. www.cmrojournal.com ! 2012 Informa UK Ltd
 Current Medical Research & Opinion Volume 28, Number 5 May 2012

Table 4. Incidence of treatment emergent adverse events reported by45% Table 5. Percentage of patients with a clinically significant SPID50 or
of patients treated with DDS-06C [n (%)]. TOTPAR50 score – ITT population.

(a) Double-blind phase DDS-06C Placebo Absolute difference

(n ¼ 141) (n ¼ 136) between groups
Preferred term DDS-06C Placebo
(n ¼ 141) (n ¼ 136) Number of patients with SPID50 score of 10 or less, n (%)
BOCF/LOCF 39 (27.7%) 27 (19.9%) 7.8%
Nausea 34 (24.1%) 3 (2.2%) LOCF 44 (31.2%) 27 (19.9%) 11.3%
Dizziness 21 (14.9%) 2 (1.5%) Number of patients with TOTPAR50 score of 13 or more, n (%)
Vomiting 21 (14.9%) – BOCF/LOCF 78 (55.3%) 60 (44.1%) 11.2%
Somnolence 13 (9.2%) 5 (3.7%) LOCF 81 (57.4%) 61 (44.9%) 12.5%

(b) Open-label phase

Medical Database). Furthermore, low back pain affects

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Preferred term DDS-06C

(n ¼ 219) more than 80% of the population worldwide at some
Nausea 20 (9.1%) point in their lifespan19, and is difficult to treat20.
Dizziness 14 (6.4%) Another limitation of this study is that due to the
allowance for dosing with one or two tablets, patients
(c) Overall (double-blind phase and open-label phase combined)
will have variations in exposure to the drug. Although
Preferred term DDS-06C this dosing regimen considers an individual’s clinical
(n ¼ 251) needs, it does not allow for any conclusions to be
Nausea 53 (21.1%) drawn regarding dose-dependent effects of DDS-06C.
Dizziness 35 (13.9%) In this study, the superior analgesic efficacy of DDS-
Vomiting 28 (11.2%) 06C versus placebo was confirmed for the primary efficacy
Somnolence 22 (8.8%)
end point of SPID50, using both BOCF/LOCF and LOCF
For personal use only.

as the method of imputation. Although SPID has been

durations ranged from 1.1 days (vomiting) to 2.9 days
(somnolence). During the open-label phase, mean dura-
tions of the most common AEs were 2.0 days for dizziness
and 2.3 days for nausea. There were no notable changes in
vital signs (blood pressure, heart rate, respiratory rate, and
body temperature) for any patient during the double-blind
phase or open-label phase.
Only one SAE occurred during the study: a patient in
the DDS-06C group experienced exacerbation of back
pain requiring hospitalization during the double-blind
phase. The SAE was considered severe and not related to
the study medication. The patient completely recovered.
Discussion
This randomized, multicenter, placebo-controlled study
demonstrates the efficacy and safety of DDS-06C
versus placebo for the treatment of moderate-to-
severe pain, using acute low back pain as a pain
model. To date, this is the only phase III study that
has been conducted with DDS-06C. One of the lim-
itations of this study is that low back pain is a model
with a high degree of heterogeneity and intrinsic var-
iability. However, this model is representative of the
patient population which currently uses immediate-
release combination treatment with tramadol and para-
cetamol (27% of prescriptions for branded tramadol/
paracetamol combination products in Europe are for
low back pain; 2008 IMS MIDAS Prescribing Insight
used as an end point in various pain studies, there is only
one published back pain study which used SPID, and it was
calculated after 3 and 6 hours of treatment21. Therefore,
this study is the first to use SPID as an end point over
several days of treatment for back pain. DDS-06C also
demonstrated a statistically significant difference from pla-
cebo on the following secondary end points: TOTPAR50,
SPID4, patient’s global impression of study medication,
and time to onset of meaningful pain relief.
In terms of the clinical significance of these results,
Farrar et al. have suggested that a 33% reduction from
baseline in percent SPID (SPID/maximum possible
SPID) or percent TOTPAR (TOTPAR/maximum pos-
sible TOTPAR) represents a clinically relevant
response22. This classification was based on clinical
data using LOCF as the method of imputation23.
Examining the SPID results from the current study,
39 patients (27.7%) in the DDS-06C group and 27
patients (19.9%) in the placebo group experienced a
clinically significant response when using BOCF/LOCF
as the method of imputation (7.8% absolute difference
between groups) (Table 5). The difference between
groups is even more apparent when using LOCF (44
patients [31.2%] in the DDS-06C group vs. 27 patients
[19.9%] in the placebo group; absolute difference:
11.3%). Examining TOTPAR, 78 patients (55.3%) in
the DDS-06C group and 60 patients (44.1%) in the
placebo group experienced a clinically significant
response using BOCF/LOCF (11.2% absolute difference
between groups) (Table 5). The difference between

! 2012 Informa UK Ltd www.cmrojournal.com Extended-release tramadol/paracetamol for acute low back pain Lasko et al. 855
 Current Medical Research & Opinion Volume 28, Number 5 May 2012
groups is also more apparent when using LOCF (81
patients [57.4%] in the DDS-06C group vs. 61 patients
[44.9%] in the placebo group; absolute difference:
12.5%).
The fact that more patients experienced clinically sig-
nificant pain relief than a decrease in pain intensity is
expected, since pain relief scales are perceived as more
sensitive than pain intensity scales24. This may be due to
the fact that all patients begin with the same baseline pain
relief (that of no relief), while patients start with different
levels of pain intensity. The relatively high response
observed in the placebo group for both SPID and
TOTPAR is consistent with the well-characterized ‘pla-
Curr Med Res Opin Downloaded from informahealthcare.com by University of Melbourne on 03/11/13
cebo response’ observed in other pain studies25–27. It is well
recognized that there are neuro-psychological components
to the placebo response25–27, and these would appear to be
prominent in this study.
This study clearly demonstrated the safety and tol-
erability of DDS-06C. The majority of AEs reported
by patients treated with DDS-06C were mild-to-mod-
erate in intensity, and there was a low rate of discon-
tinuation due to AEs in DDS-06C-treated patients in
both the double-blind and open-label phases (12% and
3%, respectively). The most commonly reported AEs
For personal use only.
(reported by 45% of patients receiving DDS-06C)
were nausea, dizziness, vomiting, and somnolence
during the double-blind phase, and nausea and dizzi-
ness during the open-label phase. Based on the well-
known safety profile of the two active components
(both separately and in combination), these AEs
were expected, and are typical of other tramadol/para-
cetamol formulations14–16. Furthermore, treatment with
DDS-06C did not result in any SAEs that were con-
sidered related to treatment.
Conclusion
DDS-06C is a twice-a-day tramadol/paracetamol formu-
lation which has been previously demonstrated to have
equivalent systemic exposure to IR tramadol/paraceta-
mol tablets administered every 6 h18. In this study with
patients with acute low back pain, a model which is
representative of the patient population that currently
uses IR tramadol/paracetamol, the superior analgesic
efficacy of DDS-06C versus placebo was confirmed
for the primary end point (SPID50). Results from sec-
ondary end points provided additional confirmation
regarding the efficacy of DDS-06C. Furthermore,
DDS-06C was well-tolerated; the most common AEs
were typical of other tramadol/paracetamol formula-
tions, and tramadol and paracetamol used separately.
Therefore, this twice-daily formulation of tramadol/
paracetamol offers a convenient therapeutic option
for patients with moderate-to-severe pain.
856 Extended-release tramadol/paracetamol for acute low back pain Lasko et al.
Transparency
Declaration of funding
This study was supported by Labopharm Inc.
Declaration of financial/other relationships
B.L. was an investigator for this study. R.J.L. is an employee of
Labopharm Inc. K.D.R. was a consultant for Labopharm Inc.
S.B. is a former employee of Labopharm Inc. and consultant on
this study. A.R. and S.R. were employees at Labopharm Inc. at
the time that this study was conducted.
CMRO peer reviewers may have received honoraria for their
review work. The peer reviewers on this manuscript have dis-
closed that they have no relevant financial relationships.
Acknowledgments
The authors wish to convey our deepest thanks to the patients
who participated in this clinical study. We also thank INC
Research, Inc. for their implementation of the study protocol
and Peter Treasure, PhD, CStat (Peter Treasure Statistical
Services Ltd, King’s Lynn, UK) for his statistical expertise.
Thanks also to Nancy Vermette for her assistance in creating
tables and figures for this publication.
We are grateful for the hard work and dedication of the fol-
lowing principal investigators and their staff: Pierre Arsenault,
MD; Armen Arslanian, MD; Richard L. Beasley, MD; Stephanie
Berg, MD; Guy Chouinard, MD; Shane Christensen, MD; Lisa
Cohen, DO; David Damian, MD; Pierre Dauth, MD; Waymon
Drummond, MD; Didier Fay, MD; Benoit Gervais, MD; Anil
Gupta, MD; Sam Henein, MD; Dan C. Henry, MD; Louise
Laberge, MD; Ken Lai, MD; Ben Lasko, MD; Vaughn H.
Mancha, MD; Pierre Martin, MD; Giuseppe Mazza, MD; James
Miner, MD; Dennis O’Keefe, MD; Michael O’Mahony, MD;
Armando Perez, MD; Alan Reichman, MD; Paul Rheault, MD;
John Sutherland, MD; Guy Tellier, MD; Anthony Wade,
MD; Daniel Whittington, MD.
This article was previously presented as a poster at the 13th
World Congress on Pain (Montreal, Canada; August 29 –
September 2, 2010).
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