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RES E AR C H A R T I C L E Open Access
Efficacy and safety of diclofenac diethylamine
1.16% gel in acute neck pain: a randomized,
double-blind, placebo-controlled study
Hans-Georg Predel
1*†
, Bruno Giannetti
2†
, Helmut Pabst
3
, Axel Schaefer
4
, Agnes M Hug
5
and Ian Burnett
6†
Abstract
Background: Neck pain (NP) is a common musculoskeletal disorder in primary care that frequently causes
discomfort. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce neck pain and associated
inflammation and facilitate earlier recovery. Topical diclofenac diethylamine (DDEA) 1.16% gel is clinically proven to
be effective and well tolerated in acute and chronic musculoskeletal conditions, but until now no clinical data
existed for its use in acute NP. The aim of this study was to assess the efficacy and safety of DDEA 1.16% gel
compared with placebo gel in acute NP.
Methods: In a randomized, double-blind, placebo-controlled study, patients with acute NP (n = 72) were treated
with DDEA 1.16% gel (2 g, 4x/day, for 5 days) or placebo. Efficacy assessments included pain-on-movement (POM),
pain-at-rest (PAR), functional neck disability index (NDI) and response to treatment (decrease in POM by 50% after
48 h). Adverse events (AEs) were recorded throughout the study.
Results: The primary outcome, POM at 48 h, was statistically significantly lower with DDEA gel (19.5 mm)
vs. placebo (56.9 mm) (p < 0.0001), r epresenting a clinically relevant decrease from baseline (75% vs. 23% ,
respectively). All POM scores were significantly lower with DDEA gel vs. placebo from 1 h, as were PAR
and NDI scores from first assessment (24 h) onwards (all p < 0.0001). Response to treatment was
significantly higher with DDEA gel (94.4%) vs. placebo (8.3% ) (p < 0.0001). There were no AEs with
DDEA gel.
Conclusions: DDEA 1.16% gel, which is available over-the-counter, was effective and well tolerated in the
treatment of acute neck pain. The tools used to assess efficacy suggest that it quickly reduced neck pain and
improved neck function . However, questions re main regarding the comparab ility and validity of such t ools.
Further studies will help ascertain whether DDEA 1.16% gel o ffers an alternative treatment option in this
common, often debilitating condition.
Trial registration: ClinicalTrials.gov identifier: NCT01335724
Keywords: Acute neck pain, Diclofenac diethylamine gel, Neck function, Pain relief, Safety
* Correspondence: predel@dshs-koeln.de
†
Equal contributors
1
Deutsche Sporthoschschule Köln, Köln, Germany
Full list of author information is available at the end of the article
© 2013 Predel et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Predel et al. BMC Musculoskeletal Disorders 2013, 14:250
http://www.biomedcentral.com/1471-2474/14/250
Background
Neck pain (NP), specifically uncomplicated neck pain (i.e.
absence of fracture, no concurrent shoulder pain or nerve
root symptoms, etc.), is a common, mostly musculoskel-
etal disorder in primary care [1]. Estimates of annual
prevalence in adults range between 30–50%, with some re-
ports indicating a prevalence as high as 71% [2,3]. It ap-
pears to affect women more than men, and prevalence
increases with age [1]. Neck pain is a frequent cause of
discomfort and functional impairment, and can thus limit
social activities and the ability to work [4]; in fact, NP
causes health-related absence from work at levels compar-
able to low back pain [5,6], resulting in considerable
healthcare costs [7,8].
Characteristically, acute neck pain is felt as stiffness
and/or pain in the cervical region of the spine and is
usually associated with some of the classical symptoms
of inflammation (e.g. redness, tenderness, warmth, stiff-
ness) [9]. Acute neck pain most commonly results from
injury to the muscle, disk, nerve, ligament or facet joints
with subsequent inflammation and spa sm [9,10]. How-
ever, no data exist on the actual cause of common, un-
complicated neck pain [10]. In acute neck pain, damage
to the neck structures as a result of injury, for example,
releases biochemical mediators of inflammation such as
prostaglandins [9], which stimulate the nociceptors and
mediate pain and inflammation [11]. One of the goals of
treating any acute pain syndrome should be inhibit ion
or suppression of production of these inflammatory me-
diators, and a successful outcome is one that results in
less inflammation and thus less pain [9].
Although neck pain is usually self-limiting, resolving
within days or weeks, it may become chronic in approxi-
mately 10% of patients [12], with symptoms persisting
for more than 12 weeks. Thus, any intervention should
not only aim to aid the recovery from an acute episode
(usually within 4 weeks), but also to help prevent the de-
velopment of long-term symptoms while minimizing the
potential for adverse reactions to treatment [12].
Non-steroidal anti-inflammatory drugs (NSAIDs) are
commonly used to reduce neck pain and inflammation
[12]. However, to date only four trials have evaluated the
efficacy and safety of oral NSAIDs as part of conservative
management of acute NP [13-16], demonstrating unclear
benefits [17]. None has assessed topical NSAIDs in this
condition. Systematic review of the literature confirms
that NSAIDs are effective analgesics and reduce inflamma-
tion in other musculoskeletal conditions [18-22].
Topical diclofenac diethylamine (DDEA) 1.16% gel is an
NSAID that is clinically proven to be effective and well
tolerated in acute and chronic musculoskeletal conditions
[11]. Applied topically, diclofenac penetrates the skin bar-
rier to reach joints, muscles and synovial fluid. It preferen-
tially distributes and persists in the target inflamed tissues
[23], achieving a sufficiently high concentration to exert
local therapeutic activity [24]. Therefore, this randomized,
double-blind, placebo-controlled study aimed to assess its
efficacy and safety in the treatment of acute NP. The pri-
mary objective of the study was to assess the efficacy of
DDEA 1.16% gel compared with placebo gel in the treat-
ment of acute NP in terms of pain-on-movement (POM)
at 48 h (Day 3) from baseline. Secondary objectives in-
cluded the effect of DDEA 1.16% gel on pain-at-rest
(PAR), functional impairment (using the neck disability
index, NDI), patients’ global assessment of treatment effi-
cacy and safety following application for 5 days.
Methods
The clinical study (ClinicalTrials.gov identifier: NCT01335724)
was designed, implemented and reported in accordance
with the International Conference on Harmonization
(ICH) Harmonized Tripartite Guidelines for Good
Clinical Practice (GCP) and with the ethical principles
laid down in the Declaration of Helsinki. The study
protocol (E udraC T number 2010-022794-34), protocol
amendment and assoc iated documents were reviewed
by an Independent Ethics Committee in Germany (Ethik-
Kommission der Ärztekammer Nordrhein, Düsseldorf,
Germany, reference number 2010456). Informed con-
sent wa s obtained from each subje c t in writing bef ore
randomization and the rights of subjects were protected.
Subjects
The study population consisted of male and female sub-
jects, aged 18 years and over with acute NP originating
from cervical joints and accompanying soft tissues. Pain
had be en present for at lea st 12 h and re su lted in POM
≥50 mm on a 100-mm visual a nalogue scale ( VAS).
Exclusion criteria included any neck pain that was at-
tributable to an organic disease (e.g. prolapsed disc,
inflammatory arthritis, neurological disea ses , etc.), as
assessed by the medical history, including previous and
concomitant diseases, and a neck examination and diag-
nosis, any recent strains of the neck muscles, chronic
neck pain defined a s pain for 3 months or longer, and
use of pain medication within the 6 h pre ceding
randomization.
Study design
Eligible subjects with acute NP from three German
(Cologne, Gilching and Essen) sports medicine practice
clinics were randomized in a 1:1 ratio to treatment
with DDEA 1.16% gel or placebo gel in a double-blind,
placebo-controlled, multicenter, parallel group study.
Novartis Pharmaceuticals Drug Supply Management pro-
duced the randomization list, using a system that auto-
mated the random assignment of treatment groups to
randomization numbers. At Visit 1 (baseline), each subject
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underwent clinical evaluation and anamnesis, including
previous and concomitant diseases, neck examination and
diagnosis to ensure that neck pain could not be attributed
to an organic disease. If all of the inclusion and none of
the exclusion criteria were fulfilled, the subject was given
the lowest available number on the randomization list by
the investigator. Subjects, investigator staff, persons
performing all assessments, monitors and data analysts
remained blinded to the identity of the treatment from the
time of randomization until database lock, using the fol-
lowing methods: (1) randomization data were kept strictly
confidential until the time of unblinding and were not ac-
cessible by anyone involved in the study, (2) the identity of
the treatments was concealed by the use of study drugs
that were all identical in packaging, labeling, schedule of
administration, appearance and odor. Unblinding only oc-
curred in the case of subject emergencies and at the con-
clusion of the study.
Subjects applied the study medication for 5 days. Study
visits occurred as follows: Day 1 (baseline and 1 h after
first application of study drug); Day 2 (24 h ± 4 h after first
application of study drug), Day 3 (48 h ± 4 h after first ap-
plication of study drug) and Day 5 (study end, 96 h + 24 h
after first application of study drug). Efficacy was assessed
at each visit. Additional examinations included measure-
ment of vital signs (blood pressure, pulse) by the investiga-
tor on Days 1 and 5. Adverse events (AEs) were recorded
at every visit.
Treatment regimen
Subjects were randomized to topical treatment with
DDEA 1.16% gel (Voltaren® Schmerzgel® (German trade
name), Voltaren® Emulgel® (European trade name),
Novartis Consumer Health) or placebo gel (the same ve-
hicle as for DDEA 1.16% gel without diclofenac). A dose
of 2 g gel was applied topically with the fingertips on the
affected area and massaged into the skin for around
1 min. The gel was applied 4 times a day for 5 days. Res-
cue medication (paracetamol, up to 2,000 mg daily) was
allowed during the study, except for 6 h prior to each
study visit. Non-analgesic topical treatments could be
applied to other parts of the body but no other concomi-
tant therapies were allowed.
Study assessments
POM was assessed at all visits using a 100-mm VAS (0, no
pain to 100, extreme pain) for each of three muscles
(upper M. trapezius, upper M. erector spinae, M. levator
scapulae); the subject stretched each muscle through a
specific movement of the head, shoulders or arms as
instructed by the investigators and the extent of pain was
evaluated (Table 1). POM was then defined as the average
of the three scores. Pain-at-rest was measured at baseline
and Days 2, 3 and 5 using a 100-mm VAS (0, no pain to
100, extreme pain); the subject stood in upright position
for one minute relatively motionless and the extent of pain
was recorded. Functional impairment was evaluated at
baseline and Days 2, 3 and 5, using the NDI [25,26]
consisting of a series of questions each relating to an as-
pect of neck pain; the NDI score was the sum of scores for
all answers given by the subject, ranging from 0 (best out-
come) to 50 (worst outcome). The assessments were
conducted in the following sequence: PAR, followed by
POM and finally the NDI. The global assessment of treat-
ment efficacy was recorded at Days 3 and 5 as the re-
sponse to the question, “Considering how your neck pain
has affected you, how would you assess the effect of treat-
ment today?” and rated on a scale from 0 = poor to 4 = ex-
cellent. The investigator was present at all assessments,
but actively participated in the POM measurement only.
The primary efficacy variable was POM after 48 h. Sec-
ondary efficacy variables included POM at all other visits,
PAR and NDI score at Days 2, 3 and 5, response to treat-
ment (decrease in POM by 50% after 48 h), early response
to treatment (decrease in POM by 10 mm at 1 h), global
assessment of treatment efficacy at Days 3 and 5 and use
of rescue medication.
Safety
Adverse events, their severity and relationship to study
drug were recorded at every visit. Vital signs (blood
pressure and pulse rate) were assessed at the beginning
and end of the study.
Statistical analysis
The planned sample size of 72 (36 per group) was based
on the primary efficacy variable, POM on VAS 48 h after
baseline, assuming a two-sided t-test with α = 5% and a
standard deviation (SD) of 18 mm on the VAS. Then a
sample size of 36 subjects per group provides 80% power
to declare statistically significant efficacy if the true dif-
ference between treatments was 12 mm. With an ob-
served SD of 18 mm, an observed difference of 8.5 mm
would be just statistically significant.
Efficacy wa s analyzed in the intent-to-treat (ITT)
population, which included all patients who received at
least one dose of study drug. All statistical test s were
two-sided with significance level α = 0.05. The safety
population consisted of all subjects that received at least
one dose of study drug.
Efficacy was tested with an ANCOVA model, with
treatment and study site as main effects and the baseline
value as a covariate. As a sensitivity analysis of the terms
in the final model, the treatment by study site inter-
action was added to the model. POM at other visits,
PAR and the NDI were analyzed with the ANCOVA
model used to analyze the primary efficacy outcome.
The global assessment of treatment efficacy was tested
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Table 1 Measurement of pain-on-movement and pain-at-rest
Pain-on-movement M. trapezius (upper part):
Position: the subject sat on a chair and the investigator stood behind him/her and fixed his/her shoulders. The investigator
determined which shoulder the subject pulled his/her head towards.
Test: The subject pulled her/his head sideways towards the left or the right shoulder as appropriate without lifting up the shoulder at the same time.
M. erector spinae (upper part):
Position: The subject sat on a chair and the investigator stood behind him/her and fixed his/her shoulders with his hands.
The subject’s back leaned against the back of the chair.
Test: The subject tried to place his/her chin onto the chest without lifting up the shoulders at the same time and without losing
contact with the back of the chair.
M. levator scapulae
Position: The subject sat on a chair with hanging arms and the investigator stood behind and fixed his/her shoulders with his hands.
Test: The subject tried to lift the arms over the side upwards against the gentle resistance of the investigators hands.
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with the Cochran-Mantel-Haenszel (CMH) test of mean
ridits stratified by site. The percentages of subjects
responding to treatment were compared with the CMH
test of gen eral association stratified by site. Because little
rescue medication was used, rescue medication con-
sumption was summarized only as whether any rescue
medication was taken, overall and by day to treat neck
pain, with no statistical testing. There were no missing
efficacy data. Hence, procedures to impute for missing
data were not needed.
Results
Patient characteristics
In total, 72 subjects were randomized to treatment
between April 2011 (first subject in) and July 2011 (last
subject out); 36 to DDEA 1.16% gel and 36 to placebo
gel (Figure 1). All 72 patients completed the study and
were included in the ITT population. The mean age was
33.8 years, with an almost equal number of males and
females, and all subjects were Caucasian. Overall, sub-
jects had neck pain at baseline for about 10 days, an
NDI score (24.5) midway the best and worst outcomes
(0, 50), mild-to-moderate PAR (40.6 mm) and severe
POM (75.5 mm). The treatment groups did not differ
appreciably on any demographic or ba seline neck pain
characteristics (Table 2). In particular, POM in the
DDEA 1.16% gel and placebo groups were comparable
at baseline (77.2 mm vs. 73.8 mm, respectively).
Efficacy
The primary outcome, POM at 48 hours, was almost
three times lower with DDEA 1.16% gel (19.5 mm) com-
pared with placebo (56.9 mm) (p < 0.0001, Table 3).
Change from baseline was 57.7 mm with DDEA 1.16%
gel (75% decrease) compared with 16.9 mm with placebo
(23% decrease).
With regards to the secondary efficacy variables, there
was a significantly greater reduction in POM with DDEA
1.16% gel compared with placebo from the first assess-
ment at 1 h to the final visit at 96 h (p < 0.0001) (Figure 2).
Similarly, PAR was significantly lower with DDEA 1.16%
gel vs. placebo at all post-baseline visits (p < 0.0001)
(Table 4, Figure 3). The NDI score demonstrated that pa-
tients’ function also improved significantly with DDEA
1.16% gel vs. placebo from the first to the last assessment
(p < 0.0001) (Table 4, Figure 4).
Almost all DDEA 1.16% gel patients (94.4%) responded
to treatment (decrease in POM by 50% after 48 h) com-
pared with 8.3% of placebo patients (p < 0.0001). More than
half of DDEA 1.16% gel patients (58.3%) showed an early
response to treatment (decrease in POM by 10 mm at 1 h)
compared with placebo (8.3%), with a mean reduction from
77.2 ± 10.4 to 66.7 ± 10.2 with DDEA 1.16% gel vs. 73.8 ±
9.7 to 72.6 ± 12.3 with placebo (p < 0.0001). At study end,
100% of DDEA 1.16% gel patients rated treatment as “good”
to “ex cellent” compared with just 19.4% of placebo patients
(p < 0.0001). Only one patient used rescue medication once
(in the placebo group, for ankle pain and headache). Effi-
cacy outcomes were consistent across all study sites.
Safety
Only one AE was recorded (moderate headache in the
placebo group), which was not considered by the investi-
gator to be drug related. No serious AEs were reported
and no clinically relevant abnormal vital signs were ob-
served during the study, according to the clinical judg-
ment of the investigators.
Discussion
The present study is the first randomized, controlled
trial to demonstrate the efficacy of a topical NSAID
(DDEA 1.16% gel) in relieving acute NP and helping to
Table 1 Measurement of pain-on-movement and pain-at-rest (Continued)
After each test:
The extent of pain was evaluated in answer to the question:
“How would you describe your neck pain during movement?”
The subject drew a perpendicular line on the 100-mm VAS scale with anchors at 0 = “No pain at all” and 100 = “Extreme pain” to
reflect the pain intensity during movement.
The results were documented directly in the CRF.
Pain-on-movement was defined as the average of the three VAS scores measured with the three muscle tests.
Pain-at-rest The subject stood in an upright position for one minute, relatively motionless.
The extent of pain is evaluated in answer to the question:
“How would you describe your neck pain right now?”
The subject drew a perpendicular line on the 100-mm VAS scale with anchors at 0 = “No pain at all” and 100 = “Extreme pain” to
reflect the pain intensity at rest.
The results were documented directly in the CRF.
CRF = case report form.
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improve neck function. Furthermore, it demonstrates
that the onset of effect of DDEA 1.16% gel is relatively
fast, for a topical agent, a feature that is desirable for the
analgesics aiming to treat acute pain [27]. Within 1 hour
of the first application, a response to treatment (i.e. a de-
crease in POM by 10 mm [28,29]) was dete cted in more
than half of patients; however, the clinical relevance of
these findings should be carefully considered given the
limited number of patients included in the study and the
possible different etiologies of neck pain. The results are
nevertheless encouraging and a good basis for further in-
vestigation. Measurement of POM at 48 h (the primary
efficacy variable) showed that the baseline POM was re-
duced by 75% with DDEA 1.16% gel vs. 23% with pla-
cebo. This reduction can reasonably be considered
clinically relevant. By the end of the study, after 4–5 days
of treatment, almost complete pain relief was achieved
with DDEA 1.16% gel (as a ssessed by POM and PAR)
and almost all patients responded to treatment (94%,
compared with only 8% of placebo patients).
The detected improvement in neck function with
DDEA 1.16% gel was approximately 100% higher than
placebo. Furthermore, patients randomized to DDEA
1.16% gel experienced an approximate 50% reduction in
Assessed for eligibility (n=72)
Excluded (n=0)
Not meeting inclusion criteria (n=0)
Declined to participate (n=0)
Other reasons (n=0)
Analysed (n=36)
Lost to follow-up (give reasons) (n=0)
Discontinued intervention (give reasons) (n=0)
Allocated to dicofenac diethylamine (n=36)
Received allocated intervention (n=36)
Lost to follow-up (give reasons) (n=0)
Discontinued intervention (give reasons) (n=0)
Allocated to placebo (n=36)
Received allocated intervention (n=36)
Analysed (n=36)
Allocation
Analysis
Follow-Up
Randomized (n=72)
Enrollment
♦
♦
♦
♦
♦
Figure 1 Progress of patients throughout the trial.
Table 3 Pain-on-movement at 48 h (primary efficacy
variable)
Mean
(SD) [mm]
LS * mean
(SE) [mm]
LS mean
difference
(SE) 95% CI
p-value
†
DDEA
1.16% gel
(N = 36)
Placebo DDEA
1.16% gel
(N = 36)
Placebo Placebo –
DDEA
1.16% gel
(N = 36) (N = 36)
19.5 (12.9) 56.9 (16.1) 17.8 (2.1) 56.3 (2.4) 38.4 (3.0) p < 0.0001
32.4–44.5
* LS-mean – Least squares mean difference adjusted for effects of site and
baseline POM;
†
ANCOVA – Analysis-of-covariance test with treatment and site
as main effec ts and the baseline POM as a covariate.
DDEA = diclofenac diethylamine; SD = standard deviation; SE = standard error;
CI = confidence interval.
Table 2 Demographic summary by treatment group
(all randomized subjects)
DDEA
1.16% gel
Placebo
(N = 36) (N = 36)
Age (years) – mean ± SD (range) 29.8 ± 10.5
(19–65)
37.8 ± 15.2
(18–74)
Sex (male) – n (%) 19 (52.8) 14 (38.9)
Time from onset of neck pain (hours) –
mean ± SD (range)
246.5 ± 306.5
(23–1491)
248.4 ± 348.3
(22–1691)
Pain-on-movement* (mm) (0 = no pain,
100 = extreme pain) – mean ± SD (range)
77.2 ± 10.5
(57–92)
73.8 ± 9.8
(56–90)
Neck Disability Index score (0 = best
outcome, 50 = worst outcome) – mean ±
SD (range)
25.3 ± 8.4
(7–37)
23.6 ± 7.3
(9–34)
Pain-at-rest (mm) (0 = no pain, 100 =
extreme pain) – mean ± SD (range)
41.1 ± 17.0
(11–79)
40.1 ± 16.9
(5–64)
* Mean score, average of the three VAS scores. DDEA = diclofenac
diethylamine; SD = standard deviation.
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recovery time (defined as a clinically relevant decrease in
pain plus an increase in neck function) compared with
placebo patients. The mean POM and neck disability
scores were achieved at 48 h with DDEA 1.16% gel com-
pared with appr oximately 96 h with placebo.
No adverse effect s were experienced with active treat-
ment. The efficacy and tolerability of DDEA 1.16% gel
led to all patients rating treatment as “good” to “excel-
lent”, whereas only one-fifth of placebo patients rated
treatment similarly; it should be noted that this reflects
the satisfaction of the patients, rather than a difference
in safety between the two treatment groups.
The fact that treatment did not cause any adverse ef-
fect s in this study is an important finding confirming the
good tolerability of DDEA 1.16% gel, which is available
over-the-counter. Thus, DDEA 1.16% gel may be a pref-
erable alternative to oral NSAIDs which, although gener-
ally well tolerated, can cause gastrointestinal adverse
reactions such as bleeding and perforation [30]. The re-
sults of this study in acute NP could be used as
hypothesis to investigate the effects of the treatment in
other pain mod els (e.g. non-specific lower back pain).
The early response to treatment noted in this study
cannot be compared to the literature, in which the earli-
est assessment of neck pain or disability wa s 1 week
[14,31,32]. In fact, the short follow-up period in this
study was a limitation, as it was not long enough to de-
termine the time to resolution in the placebo group. Al-
though extrapolation of the data suggests that resolution
would have been achieved in approximately a week with
placebo, this can only be confirmed with a longer follow-
up period. Other publications have followed patients for
up to 52 weeks [14,31,32], allowing a better reflection of
the efficacy and safety of the active treatment and placebo
over time. In future studies, inclusion of a non-treated
study arm would help to further clarify the efficacy of
DDEA 1.16% gel. Since the study took an assessment ap-
proach based on parameters related to inflammation, and
since psychological factors may play an important role in
neck pain, another important limitation of the study is the
Figure 2 Pain-on-movement (POM) over time (5 days of treatment). There was a significantly greater reduction in POM with DDEA 1.16%
gel compared with placebo from the first assessment at 1 h to the final visit at 96 h (p < 0.0001).
Table 4 Changes in secondary efficacy variables
Time after first application of study drug
24 hours 48 hours 96 hours
Efficacy variable DDEA 1.16%
gel
Placebo DDEA 1.16%
gel
Placebo DDEA 1.16%
gel
Placebo
Pain-at-rest – mean ± SD, mm (% difference from
baseline)
18.5 ± 11.3*
(55.0)
36.3 ± 16.0
(9.5)
6.5 ± 7.6*
(84.2)
29.2 ± 15.7
(27.2)
1.2 ± 2.9*
(97.1)
19.2 ± 11.9
(52.1)
Neck disability index score – mean ± SD (% difference
from baseline)
16.0 ± 7.1*
(36.8)
21.9 ± 7.9
(7.2)
7.8 ± 2.9*
(69.2)
19.9 ± 8.4
(15.7)
2.8 ± 3.0*
(88.9)
14.6 ± 6.8
(38.1)
* ANCOVA (analysis-of-covariance test with treatment and site as main effects and the baseline pain-at-rest value as a covariate): p < 0.0001 versus placebo.
SD = standard deviation.
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lack of validation of the psychometric properties of the
measured parameters (for example, the standard error of
measurement, the smallest detectable change, etc.). This
situation should be addressed in further studies.
As mentioned previously, another limitation of the study
is the relatively small size of the study population. Since
the primary efficacy variable was the most important, the
power calculation was based primarily on this outcome;
therefore, conclusions based on secondary outcomes
should be made with this methodological factor in mind.
It should also be noted that the studies used to determine
a statistically significant early response to treatment (de-
crease in POM by 10 mm at 1 h) [28,29] were performed
in trauma patients; nevertheless, we believe that it is a
suitable parameter to use since the pathophysiological
mechanisms of inflammation underlying both conditions
can be assumed to be similar. As a challenge to the active
treatment, patients showing relatively strong pain symp-
toms (POM ≥ 50 mm) were included – this does not ne-
cessarily mean that similar results will be achieved under
different conditions. Therefore, in further studies the effi-
cacy of topical DDEA 1.16% in treating patients with mild
neck pain should also be investigated, in such cases where
a pharmacological treatment is considered appropriate.
Based on these limitations, it would be desirable to con-
firm our observations around fast relief of pain with DDEA
1.16% gel in a study with a larger cohort, perhaps with less
severe neck pain, and with suitable evaluation of the psy-
chometric properties of the outcome measurements.
In summary, DDE A 1.16% gel patients with acute NP
experienced a statistically significant reduction in pain
from the first dose of treatment (at 1 h), were virtually
Figure 3 Pain-at-rest (PAR) over time (5 days of treatment). PAR was significantly lower with DDEA 1.16% gel vs. placebo at all post-baseline
visits (p < 0.0001).
Figure 4 Functional impairment (Neck Disability Index, NDI) over time (5 days of treatment). The NDI score demonstrated that patients’
function improved significantly with DDEA 1.16% gel vs. placebo from the first to the last assessment (p < 0.0001).
Predel et al. BMC Musculoskeletal Disorders 2013, 14:250 Page 8 of 10
http://www.biomedcentral.com/1471-2474/14/250
pain free with little functional impairment in the neck
96 h after initiating therapy, and all patients were satis-
fied with treatment. In contrast, subjects treated with
placebo still had considerable pain and functional im-
pairment at the end of the study.
Conclusions
The findings of this study suggest that topical DDEA
1.16% gel is fast-acting, effective and well tolerated for the
relief of acute neck pain, helping to improve neck func-
tion. This study demonstrated for the first time the signifi-
cant superiority and clinical relevance of treatment with
DDEA 1.16% gel vs. placebo on all parameters assessed.
Thus DDEA 1.16% gel can be considered a potential treat-
ment for acute neck pain, and could be investigated for
use in other indications with similar pathomechanisms,
such as non-specific lower back pain.
Abbreviations
AE: Adverse event; CMH: Cochran-Mantel-Haenszel; DDEA: Diclofenac
diethylamine; ITT: Intention-to-treat; NDI: Neck disability index; NP: Neck pain;
NSAID: Non-steroidal anti-inflammatory drug; PAR: Pain-at-rest; POM: Pain-on-
movement; SD: Standard deviation; VAS: Visual analogue scale.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
H-GP: principal investigator, patient recruitment, data collection. BG: data
collection, quality assurance of data, final study report. HP & AS:
co-investigators, patient recruitment data collection. AMH: investigator training.
IB: study design, analysis and interpretation of data. All authors discussed the
results and critically reviewed the manuscript. All authors read and approved
the final manuscript.
Acknowledgements
This manuscript was prepared by a professional medical writer, Deborah
Nock (DPP-Cordell Ltd), with full review and approval by all authors. The
authors thank the CRM clinical trials GmbH study personnel for overseeing
this study, Christian Milliet for providing clinical operations support, Morris
Gold for providing statistical support and Jean-Pierre Viaud for providing
data management support on behalf of Novartis Consumer Health SA.
The study was funded by Novartis Consumer Health SA, Nyon, Switzerland.
The medical writer was funded by Novartis Consumer Health SA, Nyon,
Switzerland. The authors Agnes Hug and Ian Burnett are employees of
Novartis Consumer Health.
Author details
1
Deutsche Sporthoschschule Köln, Köln, Germany.
2
CRM clinical trials GmbH,
Rheinbach, Germany.
3
General Practitioner, Sports Medicine Specialist,
Gilching, Germany.
4
Practitioner for Internal Medicine and Sport, Essen,
Germany.
5
Novartis Consumer Health GmbH, Munich, Germany.
6
Novartis
Consumer Health SA, Nyon, Switzerland.
Received: 5 November 2012 Accepted: 30 July 2013
Published: 21 August 2013
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doi:10.1186/1471-2474-14-250
Cite this article as: Predel et al.: Efficacy and safety of diclofenac
diethylamine 1.16% gel in acute neck pain: a randomized, double-blind,
placebo-controlled study. BMC Musculoskeletal Disorders 2013 14:250.
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