C L I N I C A L F E AT U R E S
Lower-Dose Diclofenac Submicron Particle
Capsules Provide Early and Sustained Acute
Patient Pain Relief in a Phase 3 Study
Allan Gibofsky, MD, FACP, JD1
Stephen Silberstein, MD 2
Charles Argoff, MD 3
Stephen Daniels, DO 4
Steve Jensen 5
Clarence L. Young, MD 6
1
Professor of Medicine and Public
Health, Weill Medical College
of Cornell University, Attending
Rheumatologist, Hospital for Special
Surgery, New York, NY; 2Director,
Jefferson Headache Center, Thomas
Jefferson University Hospital,
Philadelphia, PA; 3Pain Medicine
Specialist, Albany Medical Center;
AMC Neurology Group, Albany,
NY; 4Premier Research Group
Limited, Philadelphia, PA; 5Senior
Vice President, Regulatory Affairs
and Quality, Iroko Pharmaceuticals,
Philadelphia, PA; 6Chief Medical
Officer, Iroko Pharmaceuticals,
Philadelphia, PA
Correspondence: Clarence L.Young, MD
Iroko Pharmaceuticals,
One Kew Place,
150 Rouse Boulevard,
Philadelphia, PA 19112.
Phone: 267-546-3048
Fax: 267-546-3148
Email: cyoung@iroko.com
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DOI:
Background: Non-steroidal anti-inflammatory drugs are prescribed for the treatment of
patients with acute pain but use of such analgesics is associated with dose-dependent adverse
events (AEs). Diclofenac submicron particle capsules have been developed using SoluMatrix
technology to provide analgesia at lower doses than available solid oral dosing forms. Our
study evaluated the analgesic efficacy and safety of lower-dose diclofenac submicron particle
capsules in patients with acute pain following elective surgery. Methods: A phase 3, multi-
center, double-blind study enrolled 428 patients, aged 18 to 65 years, with moderate-to-severe
pain following bunionectomy under regional anesthesia. Patients experiencing a pain intensity
rating of $ 40 mm on a 100-mm Visual Analog Scale were randomized to receive lower-dose
diclofenac submicron particle capsules (35 or 18 mg, 3 times daily [TID]), celecoxib (200 mg,
twice daily [BID], 400-mg loading dose), or placebo. The primary efficacy parameter was the
overall (summed) pain intensity difference measured over 0 to 48 hours (SPID-48). Second-
ary efficacy parameters included pain intensity difference (PID) at scheduled assessments.
Results: Lower-dose diclofenac submicron particle capsules 35 mg TID (524.05; P , 0.001),
18 mg TID (393.25; P = 0.010), and celecoxib 200 mg BID (390.22; P = 0.011) demonstrated
significant pain control compared with placebo (77.10) for the primary efficacy parameter,
mean SPID48. Diclofenac submicron particle capsules 35 mg TID (4.52) provided some pain
control (higher mean PID) at 30 minutes following administration, in contrast to celecoxib
200 mg BID (0.80), diclofenac submicron particle capsules 18 mg TID (0.31), and placebo
(0.12). Better pain control (PID) was noted across all active treatment groups at 5 hours com-
pared with placebo (P # 0.03), and patient pain relief was sustained throughout the treatment
period. The most frequent non-procedure–related AEs were nausea, headache, dizziness, and
vomiting. Conclusion: Lower-dose diclofenac submicron particle capsules provided effec-
tive analgesia in this phase-3 clinical study in patients with acute pain and are a potentially
promising option for the treatment of patients with acute pain.
Keywords: non-steroidal anti-inflammatory drugs; diclofenac submicron particle capsules;
bunionectomy; acute pain; Solumatrix
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are often used to treat various forms
of acute patient pain, including musculoskeletal pain, headache, and dysmenorrhea.1
Despite their widespread use, NSAIDs are associated with the potential for dose-
related gastrointestinal (GI), cardiovascular, and renal adverse events (AEs).2–5 The
AEs are potentially serious and include upper GI bleeding, acute liver injury, acute
renal injury, myocardial infarction, and heart failure exacerbation.2–5 Increased risk for
selected AEs (death after myocardial infarction, onset of upper-GI bleed, and onset of
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Gibofsky et al
acute renal failure) is not limited to chronic use; the higher
risk of NSAID-induced AEs can be observed within the first
week of patient use.6–8
Following a review of these potentially serious AEs, the US
Food and Drug Administration (FDA) issued a Public Health
Advisory recommending that NSAIDs be used at “the lowest
effective dose for the shortest duration consistent with individ-
ual patient treatment goals.”9 However, merely using a lower
dose of existing NSAIDs to reduce the risk of AEs presents a
challenge, as lower doses could result in lower patient peak
plasma levels and may lead to a poor efficacy response.10
To overcome these challenges, SoluMatrix technology has
been used to develop a new lower-dose submicron particle
diclofenac drug product with enhanced dissolution properties,
leading to more rapid absorption.
Treatment with diclofenac submicron particle capsules
35  mg achieved similar peak plasma levels and lower
overall systemic drug exposure compared with diclofenac
potassium immediate-release tablets 50  mg in a phase
1 study.10 In a phase 2 study in patients with mild-to-mod-
erate pain following extraction of multiple impacted third
molars, diclofenac submicron particle capsules (18 and
35 mg) provided effective analgesia and were generally well
tolerated.11 The primary objective of our phase 3 study was to
evaluate the analgesic efficacy and safety of investigational,
lower-dose diclofenac submicron particle capsules and cele-
coxib compared with placebo in patients experiencing pain
following elective surgery.
Materials and Methods
Participants
Male and female patients, aged 18 to 65 years, scheduled for
elective bunionectomy surgery with a body weight $ 45 kg
and a body mass index # 40 kg/m2, were included in the
study. Women patients of childbearing potential were either
using a medically acceptable method of birth control or not
lactating. All patients provided written informed consent and
the study was approved by an institutional review board and
conducted in accordance with the standards of the Declaration
of Helsinki.12 Patients were excluded from the study if
they had a known history of allergic reaction or clinically
significant intolerance to any drugs used in the study, any
clinically significant conditions that would preclude their
participation in the study, a history of alcoholism or drug
abuse or misuse within 2 years of screening, a history of
a clinically significant GI event within 6  months before
screening, or a history of peptic or gastric ulcers or GI
bleeding. Patients were also excluded if they had previously
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participated in an investigational drug or device study within
30 days of our study, or if they had previously participated in
a clinical study of diclofenac submicron particle capsules.
Overall, 428 patients were enrolled, with similar numbers
of patients completing the study across treatment groups
(Figure 1). Most patients were women (371/428, 87%) and
white (329/428, 77%). Baseline demographic characteristics
were similar across all treatment groups (Table 1).
Study Design and Procedure
The phase 3, randomized, double-blind, multiple-dose,
parallel-group, active- and placebo-controlled study (Clini-
calTrials.gov registered study number NCT01462435) was
conducted at 4 investigational sites, some of which provide
non-investigational outpatient surgical care. Patients were
admitted to the study site on day 0, remained until day 3,
and returned for follow-up 5 to 9 days after surgery. On day
0, patients underwent primary, unilateral, first-metatarsal
bunionectomy with osteotomy and internal fixation under
regional anesthesia. Patients received midazolam and/or
propofol for initial sedation pre-surgically with continu-
ous propofol infusion during the surgical procedure. After
adequate sedation was achieved, patients received regional
anesthesia via popliteal sciatic nerve block, followed by
continuous regional infusion for immediate postoperative
pain control. On day 1, the regional anesthetic infusion was
discontinued. During the 9-hour period after discontinu-
ation of the anesthetic block, patients recorded perceived
pain intensity using a Visual Analog Scale (100-mm hori-
zontal line with 0 mm representing “No Pain” and 100 mm
representing “Worst Possible Pain”). Patients experienc-
ing a pain intensity rating of $ 40 mm were eligible for
enrollment.
Eligible patients were randomized using a computer-
generated schedule to 1 of 4 treatment groups at a 1:1:1:1
ratio in the chronological order in which they were enrolled.
Treatment groups included diclofenac submicron particle
capsules 35  mg three times daily (TID), diclofenac sub-
micron particle capsules 18  mg TID, celecoxib capsules
200 mg twice daily (BID) following a 400-mg loading dose,
or placebo. Study drugs were administered 4 times daily
(dummy and active doses) by an unblinded third party who
did not conduct any efficacy or safety assessments. The
patient, investigator, and all other study staff were blinded
as to trial drug administered and patients were blindfolded
during dosing (color differed by study drug). The intent-
to-treat (ITT) population consisted of all patients who
received at least 1 dose of study drug. If additional pain
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Figure 1.  Patient disposition.
Abbreviations: BID, twice daily; TID, three times daily.
control was required following anesthetic discontinuation
or following administration of study drug, a single dose of
hydrocodone/acetaminophen 10 mg/325 mg was permitted
as rescue medication every 4 to 6 hours as needed (daily
maximum 6 tablets).
Patient pain intensity was assessed before the initial
dose of study medication, at 15, 30, and 45 minutes and 1,
1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 32, 40, and 48 hours
after the first dose of study medication, and immediately
before the first dose of rescue medication if it was taken
before the 8-hour time point.
Time to onset of analgesia was assessed using the
2-stopwatch method. Two stopwatches were started imme-
diately after patients were administered their initial dose
of study medication. Patients were instructed to stop the
first stopwatch when pain relief was first perceptible and
the second when pain relief was first deemed meaningful;
if both watches were stopped before 8 hours after the first
dose of study medication or before use of rescue medica-
tion, the time to onset of analgesia was the time recorded
by the first watch.
For the patient’s global evaluation of study drug, the
patient was asked, “How effective do you think the study
drug is as a treatment for pain?” with response choices
of 0 = “poor,” 1 = “fair,” 2 = “good,” 3 = “very good,” or
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Lower-Dose Diclofenac Submicron Particle Capsules for Acute Pain
4 = “excellent.” Patients completed the global evaluation of
study drug at the end of the treatment period (day 3 prior to
discharge from the study site or immediately before the first
dose of rescue medication, whichever occurred first).
Efficacy Assessments
The primary efficacy parameter was the overall (summed)
pain intensity difference over 0 to 48 hours after initial dose
of study drug. Overall (summed) pain intensity difference was
calculated as a time-weighted sum of the change in patient
pain intensity from baseline and each period of assessment
after study entry. Secondary efficacy parameters reported
are overall (summed) patient pain intensity difference over
0 to 4 hours, 0 to 8 hours, and 0 to 24 hours after initial dose
of study drug; pain intensity difference at scheduled assess-
ments; time to onset of analgesia; proportion of patients
using rescue medication; and patient’s global evaluation of
study drug.
Safety and Tolerability Assessments
Safety was evaluated by the incidence of AEs and changes in
patient vital sign measurements through follow-up or early
termination visit, whichever occurred first. The Medical Dic-
tionary for Regulatory Activities was used to classify all AEs
with respect to system organ class and preferred term.
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Gibofsky et al

Table 1.  Patient Demographics and Baseline Characteristics (N = 428)

Patient Submicron Diclofenac Submicron Diclofenac Celecoxib 200 mg BID, Placebo
Demographics 35 mg TID (n = 107) 18 mg TID (n = 109) 400-mg Loading Dose (n = 106) (n = 106)
Sex, n (%)
Male 18 (16.8) 15 (13.8) 10 (9.4) 14 (13.2)
Female 89 (83.2) 94 (86.2) 96 (90.6) 92 (86.8)
Race, n (%) American Indian
Asian 3 (2.8) 1 (0.9) 5 (4.7) 1 (0.9)
Black or African American 1 (0.9) 0 (0.0) 4 (3.8) 5 (4.7)
Native Hawaiian 19 (17.8) 20 (18.3) 23 (21.7) 20 (18.9)
White 1 (0.9) 3 (2.8) 2 (1.9) 2 (1.9)
86 (80.4) 87 (79.8) 75 (70.8) 81 (76.4)
Age, y
Mean ± SD 39.3 ± 11.8 39.4 ± 11.7 40.3 ± 11.9 39.9 ± 12.6
Median 39.0 37.0 39.0 41.0
Range 18–65 19–62 19–64 19–64
Weight, kg
Mean ± SD 76.9 ± 18.7 74.7 ± 16.8 72.4 ± 15.6 72.7 ± 14.0
Median 72.7 72.7 69.8 71.1
Range 48.6–130.2 48.2–127.3 46.4–112.5 46.4–122.9
Height, cm
Mean ± SD 166.6 ± 9.1 166.9 ± 8.9 165.1 ± 7.5 166.7 ± 7.7
Median 165.1 165.1 163.4 165.7
Range 148.6–188.0 149.9–190.5 144.8–198.1 147.3–182.9
BMI, kg/m2
Mean ± SD 27.5 ± 5.7 26.6 ± 4.9 26.4 ± 5.2 26.0 ± 4.6
Median 26.0 27.0 26.0 25.0
Range 19–40 18–39 18–39 17–40
Abbreviations: BID, twice daily; BMI, body mass index; SD, standard deviation;  TID, three times daily.

Statistical Analyses (393.25 ± 85.45; P = 0.010) treatment groups experienced

The ITT population served as the primary population for the
efficacy analysis using the analysis of covariance model.
A sample size of 106 patients per treatment group provided
$ 90% power to detect a minimal difference of 535 in overall
(summed) pain intensity difference over 0 to 48 hours after
study entry between each individual treatment arm and placebo
using a 2‑sample t test at a 0.05 two-sided significance level.
For the secondary efficacy parameter, time to onset of analgesia,
Cox proportional hazards modeling was used to compare the
diclofenac submicron particle capsules treatment groups to the
celecoxib treatment group and placebo. For all other secondary
efficacy parameters, nominal P values with placebo as a com-
parator were calculated; no formal statistical inferences were
drawn on the basis of these tests. For pain intensity, missing
observations were imputed using baseline-observation-carried-
forward or last-observation-carried-forward for patients who
withdrew from the study prior to completion.
Results
Primary Efficacy Parameter
Patients in the diclofenac submicron particle capsules
35 mg TID (524.05 ± 86.23; P , 0.001) and 18 mg TID
greater overall reductions in pain intensity over 48 hours as
measured by mean overall (summed) pain intensity differ-
ence over 0 to 48 hours ± SE (77.10 ± 86.62) compared with
placebo (Figure 2). There was a significantly greater overall
decrease in pain intensity based on mean overall (summed)
pain intensity difference over 0 to 48 hours ± SE for patients
in the celecoxib 200 mg BID (390.22 ± 86.63; P = 0.011)
treatment group compared with placebo.
Overall Analgesia Assessments Across
Various Time Periods
Diclofenac submicron particle capsules 35 mg TID-treated
patients reported significant reductions in overall pain inten-
sity as measured by mean overall (summed) pain intensity
difference ± SD (Figure  3) over 0 to 4 (31.57  ±  68.62;
P = 0.04), 0 to 8 (64.69 ± 138.55; P = 0.009), and 0 to 24
(230.71  ±  499.93; P  ,  0.001) hours following the initial
dose. Diclofenac submicron particle capsules 18 mg TID also
provided effective patient pain control as demonstrated by
higher mean overall (summed) pain intensity difference ± SD
compared with placebo over 0 to 8 (56.40 ± 132.63; P = 0.03)
and 0 to 24 (177.10 ± 418.27; P = 0.004) hours following

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Figure 2.  Comparison of mean overall (summed) pain intensity difference over 0 to 48 hours after initial dose of study drug.
Abbreviations: BID, twice daily; SE, standard error; T
  ID, three times daily.
the first dose. Celecoxib 200  mg BID (170.85  ±  392.10;
P = 0.004) produced greater patient pain control based on
higher mean overall (summed) pain intensity difference
± SD compared with placebo over 0 to 24 hours following
first dose (Figure 3).
Individual Analgesia Assessments
at Scheduled Time Points and Time
to Onset of Analgesia
Patients treated with diclofenac submicron particle capsules
35  mg TID (4.52  ±  18.52) experienced some evidence of
pain control (higher mean pain intensity difference ± SD) as
soon as 30 minutes after the first dose, in contrast to patients
treated with celecoxib 200 mg BID (0.80 ± 15.43) and the
placebo group (0.12 ± 17.25; Figure 4). At 4 hours following
the first dose of study medication, mean patient pain inten-
sity difference ± SD for the diclofenac submicron particle
capsules 35 mg TID treatment group (10.15 ± 22.29) was
evident compared with placebo (4.28 ± 15.05; P = 0.025).
At 5 hours, analgesia as demonstrated by higher mean pain
intensity difference was evident across all treatment groups
compared with placebo (P  #  0.03; Figure  4). Diclofenac
submicron particles 35  mg TID (2.2 h  ±  0.14 h; hazard
ratio [HR] 1.2 [95% CI], 0.7–1.9; P = 0.46) and 18 mg TID
(1.8 h ± 0.09 h; HR 0.9 [95% CI], 0.5–1.5; P = 0.64) admin-
istration resulted in a similar mean time to onset of anal-
gesia compared with celecoxib 200 mg BID (1.5 h ± 0.07
h). Patients in the diclofenac submicron particle capsules
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Lower-Dose Diclofenac Submicron Particle Capsules for Acute Pain
35 mg TID treatment group (2.2 h ± 0.14 h; HR 1.8 [95%
CI], 1.1–3.1; P = 0.03) experienced analgesia at a faster rate
than those in the placebo group.
Rescue Medication
Use of protocol-defined rescue medication for pain that
was not controlled by study drugs was observed across all
treatment groups; however, fewer patients required rescue
medication in the diclofenac submicron particle capsules
35 mg TID (88/107, 82%) and 18 mg TID (93/109, 85%)
treatment groups, as well as the celecoxib 200  mg BID
(90/106, 85%) treatment group, compared with placebo
(103/106, 97%; Figure 5).
Global Evaluation of the Study Drug
Overall, diclofenac submicron particle capsules 35 mg TID
(P , 0.001), 18 mg TID (P = 0.012), and celecoxib 200 mg
BID (P = 0.004) appeared to be therapeutically superior in
relieving patient pain when compared to placebo based on
patients’ global evaluation of study drug. A greater propor-
tion of patients in the diclofenac submicron particle capsules
35 mg TID (32/107, 30%) and 18 mg TID (24/109, 22%)
treatment groups evaluated the study drug as “good,” “very
good,” or “excellent,” compared with patients receiving pla-
cebo (14/106, 13%). More patients in the celecoxib 200 mg
BID treatment group (24/106, 23%) evaluated the study
medication as “good,” “very good,” or “excellent” than those
receiving placebo.
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Gibofsky et al

Figure 3.  Mean overall (summed) pain intensity difference (SPID) over 0 to 4 hours (SPID-4); 0 to 8 hours (SPID-8); and 0 to 24 hours (SPID-24), after initial dose of study drug.

Abbreviations: BID, twice daily; T

  ID, three times daily.

Safety
Treatment with diclofenac submicron particle capsules was
generally well tolerated by patients. A summary of the most
common non-procedure-related AEs following the start of
treatment (. 5% in any treatment group) is given in Table 2.
Overall, the most frequent non-procedure-related AEs were
nausea (127/428, 30%), headache (55/428, 13%), and dizzi-
ness (50/428, 12%). One serious AE (deep vein thrombosis)
was reported in a patient in the celecoxib 200 mg BID treat-
ment group.
Discussion
During the last several years, efforts to potentially reduce
the risks of NSAID-associated AEs in patients have included
development of inhibitors of cyclooxygenase-2,13,14 co-
administration of NSAIDs with gastroprotective agents,15–17
and development of topical formulations of NSAIDs.18–20 Our
phase 3 study evaluated the analgesic efficacy, safety, and
tolerability of investigational, lower-dose diclofenac sub-
micron particle capsules in patients experiencing acute pain
following elective surgery. Post-surgical bunionectomy is a

Figure 4.  Mean pain intensity difference at each scheduled time point after initial dose of study drug.

Abbreviations: BID, twice daily; TID, three times daily.

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Figure 5.  Proportion of patients using rescue medication following surgery.
Abbreviations: BID, twice daily; T
  ID, three times daily.
well-documented and accepted model of moderate-to-severe
pain which has been widely used to quantify the analgesic
efficacy of investigational analgesics for the treatment of
patients with acute pain.21–24 The model has the appropriate
characteristics to determine acute analgesic efficacy: it is
easily reproducible, it consistently results in moderate-to-
severe pain intensity, patients are generally characterized
as being in good health, and the model allows for both
single and multiple doses.22,25 Evidence of analgesia in these
patients is considered to provide support for monotherapy
in the treatment of less severe forms of acute pain of mild-
to-moderate intensity.
Using the bunionectomy model, diclofenac submicron
particle capsules (35 and 18  mg TID) provided greater
reductions in overall patient pain intensity over 0 to
48 hours compared with placebo. Moreover, fewer patients
in the diclofenac submicron particle capsule (35 and 18 mg)
treatment groups required rescue analgesic medication and a
greater proportion of diclofenac submicron particle capsules-
treated patients evaluated their treatment agent positively
compared with placebo.
Rapid onset of analgesia is a desirable attribute for
medications used to relieve acute patient pain.24,25 In an
analysis that permitted a precise characterization of the onset
of analgesia, diclofenac submicron particle capsules 35 mg
provided early patient pain control, based on pain intensity
difference data collected at each individually scheduled
patient assessment. Time to onset of analgesia was similar for
diclofenac submicron particle capsules (35 and 18 mg) and
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Lower-Dose Diclofenac Submicron Particle Capsules for Acute Pain
celecoxib 200 mg. Although the time to onset of analgesia
was the only efficacy parameter for which a prospectively
defined comparison was made between the active treatment
groups, diclofenac submicron particle capsules 35 mg dem-
onstrated numerically higher values than celecoxib for most
efficacy parameters. Although not formally compared, the
numerical values for several study efficacy parameters were
not formally compared between patients treated with diclof-
enac submicron particle capsules 18 mg and patients treated
with celecoxib 200  mg; however, values were generally
similar for the 2 agents. Our phase 3  study was designed
to compare the active treatment groups to placebo for the
primary efficacy parameter, so no formal inferences can be
made between diclofenac submicron particle capsules and the
active comparator, celecoxib. As is common in study popula-
tions following bunionectomy, the use of rescue medication
was noted across all treatment groups.26
Results of our study confirm and expand on the results
of a single-dose, phase 2  study that evaluated diclofenac
submicron particle capsules (35 and 18 mg) in patients with
pain following extraction of impacted third molars. In that
study, diclofenac submicron particle capsules, at both the
35-mg and 18-mg doses, demonstrated effective patient
pain relief and earlier onset of analgesia compared with
placebo.27
Safety is a priority in the development of new NSAIDs
because of associated severe patient AEs. The use of
regularly prescribed NSAID doses has been associated
with greater patient risk of GI (# 8-fold),28 cardiovascular
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Gibofsky et al

Table 2.  Most Frequent Non-Procedure–Related Adverse Eventsa Mezzacappa, PhD, of AlphaBioCom LLC (King of Prussia,
in Study Patients (N = 428) PA), provided editorial support. Funding for editorial support
Adverse Diclofenac Diclofenac Celecoxib Placebo was provided by Iroko Pharmaceuticals, LLC.
Event Submicron Submicron 200 mg BID, (n = 106)
35 mg TID 18 mg TID 400-mg n (%)
(n = 107) (n = 109) Loading Dose Conflict of Interest Statement
n (%) n (%) (n = 106) Allan Gibofsky, MD, FACP, JD, is a member of the
n (%) speakers bureau, on the advisory committee/board, and
Nausea 25 (23.4) 34 (31.2) 29 (27.4) 39 (36.8) stock shareholder of Abbott Laboratories, Amgen, Inc,
Dizziness 5 (4.7) 17 (15.6) 11 (10.4) 17 (16.0)
Genentech, Inc, and Pfizer Inc. Dr Gibofsky is also a stock
Headache 11 (10.3) 17 (15.6) 11 (10.4) 16 (15.1)
Vomiting 7 (6.5) 13 (11.9) 15 (14.2) 13 (12.3) shareholder of GlaxoSmithKline plc, Bristol-Myers Squibb,
Constipation 6 (5.6) 12 (11.0) 9 (8.5) 4 (3.8) and Johnson and Johnson, and serves as a consultant for
Pruritis 6 (5.6) 4 (3.7) 4 (3.8) 4 (3.8) Takeda. Stephen Silberstein, MD, is a consultant for Alderbio,
Paresthesia 2 (1.9) 2 (1.8) 8 (7.5) 3 (2.8)
Amgen, Electrocore, Opti-Nose, and Zogenix. Dr Silberstein
a
. 5% in any treatment group.
Abbreviations: BID, twice daily;  TID, three times daily.
is a member of the advisory committee/board of Allergan,
Capnia, Eli Lilly and Co., Inc, MAP, Medtronic, Neuralieve,
(. 1- to 2-fold),29–32 and renal (3-fold) events in NSAID NINDS, NuPathe, Pfizer Inc, and St Jude Medical. Charles
users versus non-users.33 Additionally, the increased risk of Argoff, MD, is a consultant, member of the speakers bureau,
NSAID-associated AEs is dose-dependent and evident from and receives research funding from Endo, Eli Lilly, and
the initiation of therapy.34–36 Throughout our phase 3 study, Forrest Laboratories. Dr Argoff is a consultant and member
treatment of patients with diclofenac submicron particle of the speakers bureau for Janssen, Depomed, Quest, and
capsules (18 and 35 mg) was generally well tolerated. Patients Millenium Laboratories; is a consultant for Pfizer, Zogenix,
experienced no serious GI AEs, such as GI ulcers, bleeding, Iroko Pharmaceuticals, LLC, Covidien, Ameritox, Merz
or perforation, and no serious cardiovascular, renal, or hepatic Pharmaceuticals, Daiichi Sankyo, Inc, QRX Pharma, Nektar
events occurred. Therapeutics, Xenoport, and Collegium; and a member of
Lower-dose NSAID drug products may aid in address- the speakers bureau for Allergan Pharmaceuticals. Stephen
ing the safety and tolerability concerns associated with Daniels, DO, is an employee of Premier Research Group.
NSAID use by permitting effective treatment with lower Clarence L. Young, MD, and Steve Jensen are employees
overall systemic drug exposure to patients. The performance of Iroko Pharmaceuticals, LLC.
of diclofenac submicron particle capsules with enhanced
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