A Randomized, Double-Blind, Placebo-Controlled.pdf

1. CLINICAL THERAPEUTICS®/VOL.24, NO. 7, 2002
A Randomized, Double-Blind, Placebo-Controlled
Comparison of the Analgesic Efficacy, Onset of Action,
and Tolerability of Ibuprofen Arginate and Ibuprofen
in Postoperative Dental Pain
Peter Black, MS,1 Mitchell B. Max, MD,2 Paul Desjardins, DMD,1
Thomas Norwood, PhD,3 Alfredo Ardia, PhD 4 and Teresa Pallotta, PhD 4
tScirex Corporation Inc., Austin, Texas,:National Institute of Dental and Craniofacial
Research, National Institutes of Health, Bethesda, Maryland, 3Privatepractice,
Bridgewater, New Jersey, and 4Zambon Group S.pa4.,Bresso, Italy
ABSTRACT
Background: Because of its enhanced pharmacokinetic characteristics, ibuprofen
arginate might be expected to provide faster pain relief than standard ibuprofen formula-
tions in patients experiencing acute pain.
Objective: This study assessed the analgesic efficacy, speed of onset, and tolerability
of ibuprofen arginate compared with a commercially available form of ibuprofen in pa-
tients with postoperative dental pain.
Methods: Patients were randomized to receive ibuprofen arginate 200 or 400 mg, ibu-
profen 200 or 400 rag, or placebo in this multicenter, double-blind, double-dummy,
parallel-group trial. Patients were observed for 6 hours after administration of a single
dose of study medication. A repeated-dose, open-label phase followed. Pain intensity and
pain relief were measured using traditional verbal descriptor scales; onset of analgesia
was assessed using 2 stopwatches to measure the time to achievement of specific pain re-
lief criteria.
Results: A total of 498 patients (219 men, 279 women; mean age, 21.5 years) partici-
pated in this study. Baseline pain was moderate in 388 patients (78%) and severe in 110
patients (22%). Meaningful pain relief was reached after a median of 29 and 28 minutes
with ibuprofen arginate 200 and 400 rag, respectively, and after 52 and 44 minutes with
ibuprofen 200 and 400 mg, respectively (all, P < 0.05). The percentages of patients who
achieved meaningful pain relief within the first hour after treatment were 77.6% and
83.7% for ibuprofen arginate 200 and 400 mg, respectively, 61.0% and 63.0% for ibu-
profen 200 and 400 rag, respectively, and 39.8% for placebo. The differences between
ibuprofen arginate and ibuprofen were statistically significant (both doses, P < 0.05). Sig-
nificantly greater numbers of patients achieved meaningful pain relief with ibuprofen
Accepted for publication April 16, 2002.
Printed in the USA. Reproduction in whole or part is not permitted.
1072 0149-2918/02/$19.00

2. E BLACK ET AL.
arginate 400 mg compared with placebo
from 20 minutes through 6 hours and with
ibuprofen arginate 200 mg from 30 min-
utes through 6 hours (P < 0.05). Com-
pared with placebo, a greater number of
patients achieved meaningful pain re-
lief with ibuprofen 400 mg from 45 min-
utes through 6 hours; with ibuprofen 200
mg, the corresponding interval was from
1 through 6 hours. After the first hour,
pain reduction was similar for the similar
doses of the 2 ibuprofen preparations. Me-
dian remedication times with both doses
of ibuprofen arginate were similar to those
with both doses of ibuprofen, ranging
from 4.0 to 5.2 hours. Adverse-event pro-
files were similar between the 2 active
medications.
Conclusions: Ibuprofen arginate was
effective in this population of patients ex-
periencing moderate to severe pain after
surgical extraction of 2l impacted third
molar, with 16 to 24 minutes' faster time
to meaningful pain relief than with ibu-
profen. The 2 formulations had similar
tolerability profiles.
Key words: dental pain, pain manage-
ment, ibuprofen, onset, clinical trial. (Clin
Ther. 2002;24:1072-1089)
INTRODUCTION
Ibuprofen is a well-accepted treatment for
postoperative pain, arthritis, injuries, and
the aches and pains of febrile illnesses
and is among the safest of the nonsteroidal
anti-inflammatory drugs (NSAIDs); how-
ever, some solid dose formulations have a
relatively slow absorption rate and onset
of action,t-9 The highly soluble L-arginine
salt of ibuprofen (ibuprofen arginate) is
formed by combining racemic ibuprofen
with the naturally occurring amino acid
L-arginine. L-arginine renders ibuprofen
more soluble in water and facilitates its
rapid absorption across the gastric and en-
teric mucosa. Combining ibuprofen with
L-arginine has the potential to deliver the
analgesic effect of ibuprofen more rapidly.
Physicochemical characterization of ibu-
profen arginate indicates that ibuprofen
and L-arginine are released from the salt
and that the dissolved ibuprofen behaves
in the same way as the ibuprofen from the
free acid.~°Each ibuprofen arginate tablet
delivers the equivalent of 200 mg of ibu-
profen and 185 mg of arginine.
Oral formulations of ibuprofen arginate
produce peak plasma levels that are signif-
icantly higher (P < 0.01) than those pro-
duced by standard solid dose formulations
of ibuprofen.1~ Peak concentrations are
reached 15 to 30 minutes after administra-
tion, compared with 1 to 2 hours after ad-
ministration with commercially available
oral ibuprofen products. The relative bio-
availability of the 2 preparations is simi-
lar,II as are the mean elimination half-life,
total area under the concentration-time
curve, apparent volume of distribution, and
apparent clearance.~2
Motrin®IB (McNeil Consumer Health-
care, Fort Washington, Pa.), like other
commercially available ibuprofen prepa-
rations, is a racemic mixture of 2 optical
isomers. The results of in vivo and in vitro
studies 13 indicate that only the S-isomer
of ibuprofen has clinical activity. The
R-isomer, which is considered clinically
inactive,is slowly and incompletely(~60%)
converted in S-ibuprofen.
Because of its enhanced pharmacoki-
netic characteristics, ibuprofen arginate
might be expected to provide faster pain
relief than ibuprofen in patients with acute
pain. The dental impaction pain model
was selected for the present study because
of its established reliability and sensitiv-
1073

3. CLINICAL THERAPEUTICS®
ity in assessing many different classes of
analgesic compounds. The study com-
pared the effects of ibuprofen arginate
with a prototypic solid dose form of ibu-
profen (Motrin IB 200 mg tablets) in terms
of analgesic efficacy, including onset and
duration of pain relief, peak effect, and
total effect in patients with acute postop-
erative dental pain. A secondary study ob-
jective was to assess the tolerability of the
study medications after repeated doses.
The study was designed in 1991, and
the comparator was chosen with the ex-
pectation that ibuprofen arginate would
eventually be introduced to the US mar-
ket. Although not yet available in the
United States, ibuprofen arginate 400 mg
tablets have recently been introduced in
Europe. Thus, it is now appropriate to
publish the results.
MEASUREMENT OF ANALGESIC
ONSET: METHODOLOGIC
CONSIDERATIONS
Several methods have been suggested for
estimating the time of onset of action of
an analgesic agent. Methodologic issues
include criteria for onset of analgesia, how
and when the patient reports onset, and
statistical handling of the results. The fol-
lowing subsections review considerations
that guided the choice of method when
this study was designed.
Criteriafor Analgesic Onset
Investigators have proposed various def-
initions of analgesic onset as the time the
patient first detects the slightest relief, an
intermediate level of relief (eg, "some"
relief or "pain half gone"), or the higher
standard (as used in headache clinical tri-
als) of "nearly complete relief.''14-16 Pre-
liminary observations suggested that min-
imal criteria like "first perceptible," "any,"
or "slight" relief provide little separation
between analgesics and placebo, because
most patients report such a change quickly
after a dose. On the other hand, stringent
criteria such as "a lot" of relief or "com-
plete" relief appeared inappropriate for
studies in dental surgery, in which barely
50% of patients ever reach "pain half
gone" after 650 mg aspirin. 14-16There-
fore, in designing the present study, we
concurred with Siegel et alIv in viewing
intermediate levels of relief, attainable by
most patients with over-the-counter anal-
gesics, as most fitting. On the most com-
monly used pain relief descriptor scale-
"none," "a little," "some," "a lot," or
"complete" relief--"some" fits this de-
scription, as does the standard question
"Is your pain half gone?"
Laska et a118introduced a method using
a single stopwatch to assess when the pa-
tient first experienced a "meaningful" level
of pain relief. This method allowed patients
to define for themselves a level of pain re-
lief that made a clinical difference. Prelim-
inary observations14suggested that patients
would generally report "meaningful relief"
at a time when pain reliefhad just surpassed
"some relief" or "pain half gone."
Method of Collecting Patients'
Assessments of Onset
Investigators can use the standard pain
relief descriptors collected at regularly
scheduled interviews without any modifi-
cation to traditional study methodology.
However, because these descriptors have
traditionally been collected at 30- to 60-
minute intervals, estimates of analgesic
onset for individual patients become
crude. Patients may be asked to retro-
1074

4. P. BLACK ET AL.
spectively assess the onset time when in-
terviewed, but variability in individuals'
ability to remember pain levels, potential
central nervous system effects of anal-
gesics, and estimation of elapsed time in-
troduce errors. Some investigators w have
added frequent interviews during the first
60 to 90 minutes, but this method often
requires substantial costs for additional
nurse-observers.
Siegel et ally gave patients a stopwatch
to use between scheduled interviews to in-
dicate the exact moment at which a certain
criterion for analgesic onset was reached.
They used the criterion of "meaningful re-
lief" introduced by Laska et alJ 8We chose
to use 2 stopwatches, the first to indicate
when patients detected "first perceptible
pain relief" and the second to indicate when
they achieved their own criterion for "mean-
ingful relief." A 2-stopwatch technique
has come to be accepted as a valid and
reproducible method for assessing onset of
analgesia. 12-I4
Statistical Determination of Onset
Some investigators have proposed that
analgesic onset be defined as the first
scheduled interview point at which the
difference between a treatment and pla-
cebo reaches statistical significance.2° A
weakness of this approach is that the esti-
mated onset time will be altered dramati-
cally by changes in interview frequency
or sample size; for example, a large study
comparing a drug with placebo will show
an earlier onset than a small study of the
same comparators. Given the inherent
weakness of this approach, we decided
not to use differences between mean pain
relief scores or between pain intensity dif-
ference (PID) scores as a primary mea-
sure of analgesic onset.
Inclusion of Patients Who Never Reach
Onset in Calculating Mean or Median
Onset Times
Laska et al ~8 proposed that the median
time of onset in a drug treatment group be
calculated using data only from patients
who achieve analgesic onset at some point
in a trial. However, there are concerns that
this method may produce confusing re-
sults; for example, in the few patients who
experience onset of analgesia with placebo,
the median time of onset is often similar to
or earlier than that for the active drug. For
the purpose of comparing the onset of anal-
gesia of 2 active treatments using the rele-
vant value for all randomized patients, we
chose to consider patients who never reach
onset as having an "onset after the study is
over" (ie, we assigned an onset time equal
to the last hourly pain observation in the
trial and included all patients when calcu-
lating the medians).
PATIENTS AND METHODS
Investigators from 4 institutions (Uni-
versity of Medicine and Dentistry of
New Jersey, Newark; Eastman Dental
Center and Rochester General Hospital,
Rochester, NY; and Recovery Center,
Midvale, Utah) enrolled 498 patients
in this double-blind, double-dummy,
randomized, placebo-controlled, parallel-
group study. The ethics committee at
each institution approved the protocol
and informed consent form. The first pa-
tient was enrolled in May 1994 and
the last patient completed treatment in
April 1995. All patients gave written in-
formed consent before participation in the
study. The study was conducted accord-
ing to the Declaration of Helsinki as
amended by the 41st World Medical As-
1075

5. CLINICALTHERAPEUTICS *
sociation General Assembly in Hong
Kong, September 1989.
Patients underwent surgical removal of
1 to 4 third molars. At least 1 tooth had to
be impacted, requiring extraction using
standardized surgical technique involving
a full-thickness mucoperiosteal flap, re-
moval of alveolar bone, and, if required,
tooth sectioning. Local anesthesia was
supplemented with parenteral conscious
sedation. Local anesthesia was achieved
with lidocaine 2% with epinephrine
1:100,000 or mepivacaine 3% without a
vasoconstrictor. Mandibular anesthesia
was obtained by mandibular block with
supplemental lingual nerve and long buc-
cal nerve infiltration. Maxillary anesthesia
was obtained by local infiltration. Local
anesthesia was supplemented in most pa-
tients with intravenous sedation using mi-
dazolam 1 to 5 mg, or diazepam 5 to 25
mg titrated to standard clinical end points
of ptosis or slurred speech. Nitrous ox-
ide/oxygen was also permitted in doses up
to 50%:50% administered by nasal hood.
Patients could use perioperative antibiotics
if required for local infection or for pro-
phylaxis of endocarditis. Prophylactic use
of antiemetic drugs was not permitted.
Patients were randomly assigned to 1 of
5 treatment groups: (1) ibuprofen arginate
200 mg (n = 100); (2) ibuprofen arginate
400 mg (n = 99); (3) ibuprofen 200 mg
(n = 100); (4) ibuprofen 400 mg (n = 100);
or (5) placebo (n = 99). Ibuprofen arginate
and Motrin® IB (Upjohn Lot # 684KR)
were supplied together with matching
placebo. All patients ingested a total of 4
active and/or placebo tablets according to
a placebo-controlled, double-dummy de-
sign. Study kits were assigned to patients
in numerical order within each site. Pa-
tients were randomized to treatment, with
stratification by baseline severity. Ran-
domization was by center, with treatments
balanced every 10 patients.
All patients had moderate to severe pain
following surgical extraction of ~1 im-
pacted third molar requiring some bony
surgery. Pain intensity was rated as 0 =
none, 1 = mild, 2 = moderate, or 3 =
severe. Patients were not permitted to re-
ceive analgesics, anti-inflammatory drugs,
tranquilizers (other than the aforemen-
tioned intraoperative sedatives), or caffeine-
containing beverages or medications
within 4 hours of surgery. They were not
permitted to use any concomitant medica-
tions, including psychotropics, antide-
pressants, sedative-hypnotics, or NSAIDs
other than ibuprofen that could confound
assessments of pain relief. Ice packs were
not permitted before the 2-hour assess-
ment or within 15 minutes before any
scheduled pain assessment. Patients fasted
for ~8 hours before surgery and remained
fasted for ~2 hours after dosing. Clear flu-
ids were permitted any time after surgery.
Patients were observed at regular inter-
vals for 6 hours after administration of a
single dose of study medication. After
completing the assessment for hour 6,
each patient was discharged from the in-
vestigative site. On discharge, each pa-
tient was briefed on the study procedure
and supplied with 19 doses of open-label
study medication to be taken over the fol-
lowing days, to a maximum of 6 doses/d.
In the repeated-dose phase, which be-
gan when the second dose of medication
was taken, patients randomized to the ibu-
profen arginate or ibuprofen treatment
group in the single-dose phase continued
with the same study medication at the 200-
mg dose. Patients who received placebo
in the single-dose phase were randomized
to ibuprofen arginate or ibuprofen in the
repeated-dose phase.
1076

6. P, BLACK ET AL.
Study Assessments
When local anesthesia dissipated and
the patient's pain was of moderate or se-
vere intensity (grade 2 or 3), this rating
was recorded as the baseline pain inten-
sity on the patient self-assessment ques-
tionnaire. At that time, patients were given
2 stopwatches that were started at the time
of dosing. They were instructed to stop
the first watch when they felt any pain re-
lief whatsoever and to stop the second
watch when meaningful pain relief had
been achieved. If patients had a question
about the definition of "meaningful re-
lief," the instructions were repeated and
patients were instructed to use their own
criteria. Pain intensity and pain relief were
recorded at the time patients stopped each
watch. Pain relief was rated as 0 = none,
1 = a little, 2 = some, 3 = a lot, and 4 =
complete.
Patients recorded their pain intensity
and pain relief on a self-assessment ques-
tionnaire at regularly scheduled intervals
(5, 10, 15, 20, 30, 45, 60, 90, 120, 180,
240, 300, and 360 minutes) after taking
study medication. In addition, at each as-
sessment, the patient was asked to respond
to the question "Is your starting pain at
least half gone at this time?"
Patients also provided a global assess-
ment of study medication using a 5-point
scale (0 = poor, I = fair, 2 --- good, 3 =
very good, and 4 = excellent) at the 360-
minute assessment point or at the time of
the second dose of medication, whichever
came first.
Efficacy was based on measures of
overall pain intensity and pain relief, in-
cluding PID from baseline and summary
of pain intensity differences (SPID) from
baseline, mean hourly pain relief scores,
total pain relief (TOTPAR) from baseline,
peak pain relief, and patients' global as-
sessments. Summary measures for onset of
analgesia included time to any relief (stop-
watch 1 time), time to meaningful relief
(stopwatch 2 time), time to some relief,
time to a little relief, and time to pain half
gone. The 3 latter measures were derived
from the pain assessment diary entries.
Tolerability of ibuprofen arginate was
based on a comparison of the incidence of
spontaneously reported adverse events in
each of the treatment groups, Adverse
events were not recorded separately for
the single-dose and repeated-dose phases,
nor were the numbers or percentages of
patients with an adverse event calculated
based on the time patients reported the
event relative to the time of dosing.
Statistical Analysis
In the initial-dose phase, time to onset
of pain relief and time to remedication
were analyzed using survival data meth-
ods (Wilcoxon test). This analysis in-
cluded all patients, both with and without
onset of analgesia. The proportions of pa-
tients with onset of analgesia and remed-
ication data were analyzed using chi-
square tests.
For all the other first-dose efficacy
variables, comparisons of the active-
treatment groups with placebo were per-
formed using analysis of covariance,
with investigator, treatment, and base-
line pain severity (moderate or severe)
as covariates. Comparisons with placebo
were performed using t tests. A sig-
nificance level of 0.05 was used in all
analyses.
The treatment group sizes were calcu-
lated to detect a 10-minute difference in
onset of analgesia at an ct of 5% with 80%
power.
1077

7. CLINICAL THERAPEUTICS~
RESULTS
Patient Disposition and
Demographic Characteristics
A total of 498 patients (219 men, 279
women; mean age, 21.5 years) were en-
rolled in the trial and randomized to treat-
ment (Table I). There were no statistically
significant differences across treatment
groups with respect to demographic char-
acteristics, baseline pain severity, number
of teeth extracted, bony extractions, or
maximum trauma. Baseline pain was
moderate in 388 patients (78%) and se-
vere in 110 patients (22%) (Table II).
All 498 patients were included in the
safety analysis, and 494 patients were in-
cluded in the efficacy analysis. Of the 4
patients excluded from the efficacy analy-
sis during the single-dose phase, 2 pa-
tients vomited soon after taking study drug
and 2 received medication during surgery
that was not permitted by the protocol.
The 2 patients who vomited had received
ibuprofen arginate; this adverse event was
considered mild and unlikely to be related
to the study drug.
Efficacy
Single-Dose Phase
Mean hourly and summary scores for
the various measures of analgesia are pre-
sented in Tables III, IV, and V and in Fig-
ure 1. PID, SPID, TOTPAR, and peak pain
relief measures were comparable between
comparable doses of ibuprofen arginate
and ibuprofen, although the ibuprofen
arginate groups demonstrated less pain and
some pain relief at earlier time points than
did the ibuprofen groups as a result of the
faster onset of action of ibuprofen arginate.
Statistically significant differences in
PID scores were noted at several time
points (all, P < 0.05). At 15, 20, and 30
minutes, PID scores were significantly
different for ibuprofen arginate 200 mg
compared with ibuprofen 200 and 400 rag.
At 45, 60, and 90 minutes, the difference
was significant between ibuprofen ar-
ginate 200 mg and ibuprofen 200 mg.
Similar findings were seen for PID scores
with ibuprofen arginate 400 mg, which
were significantly different compared
with ibuprofen 200 and 400 mg at 15, 20,
30, 45, and 60 minutes. At 90, 120, and
180 minutes, the difference was signifi-
cant between ibuprofen 400 and 200 mg
(Table III). Both active drugs were supe-
rior to placebo.
Onset of analgesia was significantly
faster with ibuprofen arginate 200 and 400
mg compared with ibuprofen 200 and 400
mg for 3 of the 5 onset measures (P <
0.05): time to meaningful relief, time to
some relief, and time to pain half gone
(Table V).
Table VI and Figure 2 show the pro-
portions of patients reporting meaningful
relief over time. The percentages of pa-
tients who achieved meaningful relief
within the first hour after treatment were
77.6% and 83.7% in the ibuprofen ar-
ginate 200- and 400-mg groups, respec-
tively, compared with 61.0% and 63.0%
in the ibuprofen 200- and 400-mg groups,
respectively, and 39.8% in the placebo
group. Values for ibuprofen arginate were
significantly higher than those for ibupro-
fen (both doses, P < 0.05). Significantly
greater numbers of patients achieved
meaningful pain relief with ibuprofen
arginate 400 mg compared with placebo
from 20 minutes through 6 hours and with
ibuprofen arginate 200 mg from 30 min-
utes through 6 hours (P < 0.05). Com-
pared with placebo, a greater number of
patients achieved meaningful pain relief
1078

8. P. BLACK ET AL.
Table I. Number of patients valid for efficacy and safety assessment in each treatment
group.
lbuprofen Arginate Ibuprofen
Validity Status 200 mg 400 mg 200 mg 400 mg Placebo
Efficacy 98 98 100 100 98
Safety 100 99 100 100 99
Total 100 99 100 100 99
Table II. Demographic characteristics.
Ibuprofen Arginate lbuprofen
200 mg 400 mg 200 mg 400 mg Placebo
(n = 100) (n = 99) (n = 100) (n = 100) (n = 99)
Mean age, y 20.8 21.8 22.3 21.8 20.7
Sex, no.
Male 47 44 44 41 43
Female 53 55 56 59 56
No. of teeth extracted
l 18 16 18 16 15
2 24 29 30 28 30
3 6 8 9 13 6
4 52 43 43 43 46
5 0 3 0 0 2
No. of bony extractions
1 43 46 45 43 43
2 10 5 15 14 10
3 7 II 8 7 11
4 40 35 32 36 35
5 0 2 0 0 0
Maximum trauma,
no. of patients
Mild 2 1 0 2 3
Moderate 65 72 68 69 64
Severe 33 26 32 29 32
Baseline pare seventy,
no. of patients
Moderate 78 79 76 79 76
Severe 22 20 24 21 23
*Scale: 0 = none, 1 = mild, 2 = moderate, and 3 = severe.
1079

9. CLINICAL THERAPEUTICS®
Table III. Mean (SD) pain intensity difference scores.
Ibuprofen Arginate Ibuprofen
200 mg 400 mg 200 mg 400 mg
Time, rain (n = 98) (n = 98) (n = 100) (n = 100)
Placebo
(n = 98)
5 0.1 (0,4) 0.1 (0.5) 0.1 (0.3) 0.0 (0.4)
10 0.4 (0.6) 0.3 (0.6) 0.2 (0,5) 0.2 (0.6)
15 0.7 (0.7) *+~ 0.6 (0.8)*** 0.3 (0,6) 0.4 (0.7)
20 0.9 (0.7) *t* 0.8 (0.8)*** 0.4 (0.7) 0.5 (0.8)
30 1.2 (0.8) *+* 1.2 (0.9)*** 0.6 (0.8) 0.8 (0.9)*
45 1.3 (0.8)** 1.4 (0.9) *+* 0.8 (0.9)* 1.1 (0.9) *t
60 1.4 (0.8)*t 1.5 (0.9)*** 1.0 (0.9)* 1.2 (0.9)*~
90 1.4 (0.9)** 1.5 (0.9) *+ 1.1 (1.0)* 1.3 (1.0) **
120 1.3 (0.9)* 1.5 (0.9)** 1,1 (1.0)* 1.4 (1.0)*t
180 1.1 (1.1)* 1.3 (0.9) *+ 1,1 (l.0)* 1.4 (1.0) *t
240 0.8 (0.8)* 1.1 (1.0) *.~ 1.0 (0.9)* 1.2 (1,0)*§
300 0,7 (0.8)* 0.9 (0.9) *.~ 0.8 (0.9)* 1.0 (1.0) *,~
360 0.6 (0.8)* 0.8 (0.9)* 0.7 (0.9)* 1.0 (1.0)*t~
0.1 (0.4)
0.3 (0.6)
0.4 (0.7)
0.4 (0.7)
0.4 (0,9)
0.4 (1.0)
0.3 (1.1)
0.3 0.1)
0.2 (1.1)
0.2 (1.1)
0.2 (1.0)
O,l (1.o)
o.1 0.o)
*P < 0.05 versus placebo.
*P < 0.05 versus ibuprofen 200 mg.
*P < 0.05 versus ibuprofen 400 mg.
~P < 0.05 versus ibuprofen arginate 200 mg.
Table IV. Summary of analgesic efficacy.
Ibuprofen Arginate lbuprofen
200 mg 400 mg 200 mg 400 mg Placebo
(n = 98) (n = 98) (n = 100) (n = 100) (n = 98)
SPID 5.7" 6.7 *t 5.4* 6.7.I 1.2
TOTPAR 13.1* 15.0*+* 12.6" 14.9*+ 6.9
Peak pain relief 3.2*+ 3.4*t 2.9* 3.2" 2,0
Global assessment 2.2* 2.5*+ 2.1" 2.5*t 1.1
SPID = summary of pain intensity differences from baseline; TOTPAR = total pain relief from baseline.
*P < 0.05 versus placebo.
tp < 0.05 versus ibuprofen 200 mg.
*~P< 0.05 versus ibuprofen arginate 200 mg.
1080

10. E BLACK ET AL.
Table V. Median times to onset of action and remedication.
Ibuprofen Arginate Ibuprofen
200 mg 400 mg 200 mg 400 mg
(n = 98) (n = 98) (n = 100) (n = 100) Placebo
Time to
Any relief,* rain 10 10 12 12 9
A little relief, rain 10 10 15 I0 10
Some relief, rain 15*~ 15~*~ 30 30 53
Meaningful relief,* rain 29t$~ 28 t*~ 52t 44 ~ NC
Pain half gone, rain 20 t~,~ 20tt~ 45 + 30+ NC
Remedication, h 4.0*~ 4.5+ 4.2+ 5.2~ 1.3
NC = not computed (median could not be computed for the placebo group, as only 46% experienced meaning-
ful relief and pain half gone).
*Measured by stopwatch method.
+P < 0.05 versus placebo.
~+P< 0.05 versus ibuprofen 200 rag.
§P < 0.05 versus ibuprofen 400 mg.
-II- Ibuprofenarginate 200 mg
Ibuprofenarginate 400 mg
-0- Ibuprofen200 mg
0- Ibuprofen400 mg
Placebo
3.5--
30
25
20
e.-
~_ 1.5
1.0
°-I I I I I I I [ I I I I I I
5 10 15 20 30 45 60 90 120 180 240 300 360
Time (min)
Figure 1. Mean pain relief over time. Pain scale: 0 = none, 1 = a little, 2 = some, 3 =
a lot, and 4 = complete.
1081

11. CLINICALTHERAPEUTICS®
Table VI. Number (%) of patients achieving meaningful pain relief.
Ibuprofen Arginate Ibuprofen
200 mg 400 mg 200 mg 400 mg Placebo
Time, min (n = 98) (n = 98) (n = 100) (n = 100) (n = 98)
5 2 (2.0) 0 (0.0) 1 (1.0) 0 (0.0) 0 (0.0)
10 6 (6.1) 6 (6.1) 3 (3.0) 4 (4.0) 7 (7.1)
15 18 (18.4)* 20 (20.4)* 8 (8.0) 10 (10.0) 11 (11.2)
20 28 (28.6)* 38 (38.8)*t* 14 (14.0) 19 (19.0) 17 (17.3)
30 55 (56.1)*t* 59 (60.2)*t~+ 31 (31.0) 38 (38.0) 26 (26.5)
45 68 (69.4)*t 75 (76.5)*~* 46 (46.0) 56 (56.0)+ 32 (32.7)
60 76 (77.6)**~+ 82 (83.7)*t* 61 (61.0)+ 63 (63.0)t 39 (39.8)
90 80 (81.6)t 86 (87.8)*t~ 73 (73.0)* 75 (75.0)+ 42 (42.9)
120 82 (83.7)t 87 (88.8)** 76 (76.0)t 81 (81.0)t 44 (44.9)
180 83 (84.7)t 88 (89.8)*t 78 (78.0)* 82 (82.0)* 45 (45.9)
240 83 (84.7)f 88 (89.8)*t 78 (78,0)t 83 (83.0)t 45 (45.9)
300 83 (84.7)t 88 (89.8)** 78 (78.0)~ 83 (83.0)t 45 (45.9)
360 83 (84.7)* 88 (89.8)*t 78 (78.0)t 83 (83.0)+ 45 (45.9)
*P < 0.05 versus ibuprofen200 rag.
tP < 0.01 versusplacebo.
*P < 0.05 versus ibuprofen400 mg.
with ibuprofen 400 mg from 45 minutes
through 6 hours; with ibuprofen 200 mg,
the corresponding interval was from 1
through 6 hours.
Patients achieved some pain relief in ap-
proximately half the time (15 vs 30 min-
utes) with both doses of ibuprofen arginate
compared with both doses of ibuprofen.
The median time to meaningful relief in
patients treated with ibuprofen arginate 200
and 400 mg was almost half that in pa-
tients treated with ibuprofen 200 mg (29
and 28 minutes, respectively, compared
with 52 minutes). Time to meaningful re-
lief was 15 to 16 minutes faster in patients
treated with either dose of ibuprofen ar-
ginate compared with ibuprofen 400 rag.
Both ibuprofen arginate-treated groups had
significantly faster time to pain half gone
compared with the 2 ibuprofen-treated
groups (P < 0.05): time to pain half gone
was achieved in less than half the time
compared with ibuprofen 200 mg (20 and
45 minutes, respectively) and two thirds of
the time compared with ibuprofen 400 mg
(20 and 30 minutes, respectively) (Table
V). By 20 minutes, statistically significant
differences were seen in the numbers of
patients achieving meaningful relief with
ibuprofen arginate 200 mg compared with
ibuprofen 200 mg and with ibuprofen
arginate 400 mg compared with ibuprofen
400 mg (both, P < 0.05). Differences in
meaningful pain relief between the 2 ac-
tive drugs remained statistically significant
through 1 hour (P < 0.05) (Table VI).
Median remedication times (time to the
second dose) were 4.0 and 4.5 hours with
ibuprofen arginate 200 and 400 mg, re-
spectively, and 4.2 and 5.2 hours with
1082

12. 100 -
90-
80-
30-
70-
c"
.o 60 -
"5 50-
40-
20-
10-
I
-I- Ibuprofen arginate 200 mg
-Jr" Ibuprofen arginate 400 mg
-~-Ibuprofen 200 mg
"O-Ibuprofen 400 mg
-0- Placebo
P. BLACK ET AL.
Time (min)
Figure 2. Percent of patients reporting meaningful pain relief over time.
ibuprofen 200 and 400 mg, respectively
(Table V). All active drugs were scored
significantly higher than placebo on the
patients' global assessment of treatment
(P < 0.05). Ibuprofen arginate 400 mg
and ibuprofen 400 mg were assigned iden-
tical rankings (2.5) and scored signifi-
cantly higher than ibuprofen 200 mg (P <
0.05) (Table IV).
Repeated-Dose Phase
After the initial double-blind, single-
dose phase, 489 patients entered the open-
label, repeated-dose phase of the study
(243 ibuprofen arginate, 246 ibuprofen),
and 488 were analyzed for efficacy. The
demographic characteristics of the 488
patients completing the repeated-dose
phase were essentially identical to those
of the original patient population. The
mean number of doses of study medica-
tion taken (12.2 tablets) and the mean
number of dosing days (4.6 days) were
the same for both treatment groups in the
repeated-dose phase. The number of doses
taken on the first study day ranged from
I to 7 (mean, 3.1 doses) in the ibuprofen
arginate group and from 1 to 6 (mean, 2.9
doses) in the ibuprofen group.
There were no differences between the 2
groups in the number of doses of other anal-
gesics taken and the number of dosing days
for these other analgesics. The initial mean
pain intensity before each dose was higher
for the first few doses in the ibuprofen
arginate group, with pain relief scores gen-
erally slightly higher at the early time
points through the remainder of dosing.
1083

13. CLINICALTHERAPEUTICS®
At dose 2, pain relief was significantly
greater with ibuprofen arginate 200 mg
compared with ibuprofen 200 mg (P <
0.05) (Table VII). At doses 10, 16, and 19,
pain relief was also significantly greater
with ibuprofen arginate 200 mg than with
ibuprofen 200 mg (P < 0.05). However,
the number of patients still dosing at these
later time points was considerably smaller
compared with the number at dose 2.
Patients' global assessments at the end
of treatment were not statistically differ-
ent between the 2 treatments (2.7 ibupro-
fen arginate, 2.6 ibuprofen).
The results of the repeated-dose phase
indicated that as the tissue damage from
dental extraction healed over the course
of the follow-up period, pain levels
declined and the need for analgesic
treatment diminished. In these circum-
stances, any effective analgesic agent
would be expected to provide pain re-
lief. Ibuprofen arginate provided effec-
tive pain relief that was somewhat better
than that provided by ibuprofen, as in-
dicated by patients' noting that ibupro-
fen arginate was marginally better than
ibuprofen.
Table VII. Mean pain relief scores* 1 hour after dosing in the repeated-dose phase.
Ibuprofen Arginate 200 mg Ibuprofen 200 mg
Dose No. of Patients Mean (Range) No. of Patients Mean (Range)
0+ 8 - 6 -
2 235 2.6 (0--4)* 240 2.4 (0-4)
3 193 2.6 (0--4) 199 2.5 (0--4)
4 199 2,6 (0-4) 203 2.5 (0--4)
5 200 2.7 (0-4) 210 2.6 (0-4)
6 195 2.7 (0-4) 188 2.7 (0-4)
7 166 2.6 (04) 186 2.5 (0-4)
8 161 2.7 (0-4) 159 2,7 (0-4)
9 142 2.7 (0-4) 155 2.6 (0-4)
10 125 2.8 (0-4)* 139 2.6 (0-4)
11 108 2.7 (04) 116 2.5 (0-4)
12 107 2.6 (0-4) 111 2.6 (0-4)
13 95 2.7 (0-4) 97 2.6 (04)
~4 85 2.9 (0-4) 91 2.6 (0-4)
15 69 2.8 (0-4) 76 2.7 (04)
16 69 3.0 (04)* 63 2.6 (0-4)
17 65 2.8 (0-4) 63 2.6 (0-4)
18 57 2.9 (0-4) 58 2.7 (1-4)
19 55 3.0 (0-4)* 49 2.6 (0-4)
20 48 2.8 (0-4) 49 2.9 (0-4)
*Scale:0 = none, 1 = a little,
*Noremedication.
~P < 0.05 betweengroups.
2 = some,3 = a lot, 4 = complete.
1084

14. P. BLACK ET AL.
Tolerability
Spontaneously reported adverse events
that occurred in >3% of patients during
the study period are shown in Table VIII
(single-dose phase) and Table IX (single-
and repeated-dose phases). After the single-
dose phase, adverse events were reported
by 43.7% of patients who received ibu-
profen arginate, 36.0% of patients who
received ibuprofen, and 48.5% of patients
who received placebo. After the repeated-
dose phase, the percentages of patients
experiencing adverse events were 44.4%
in the ibuprofen arginate group and 39.8%
in the ibuprofen group. The total inci-
dence of adverse events in the combined
groups (ie, after the repeated-dose phase)
did not differ statistically. No patient ex-
perienced a serious adverse event.
The most common adverse events in all
treatment groups were headache, nausea,
bone disorder, and somnolence. These
events were recorded in approximately
equal numbers of patients in the 2 active-
treatment groups. Specifically, in both the
single- and repeated-dose phases, headache
was reported by 10.7% and 9.3% of patients
receiving ibuprofen arginate 200 mg and
ibuprofen 200 mg, respectively, nausea by
8.6% and 6.9%, bone disorder by 4.1% and
8.5%, and somnolence by 4.5% and 6.5%.
Only 1 patient discontinued the study
due to an adverse event that was possibly
Table VIII. Adverse events occurring in >3% of patients in the single-dose phase.
Ibuprofen Arginate Ibuprofen
200mg 400mg 200mg 400mg Placebo
(n = 100) (n = 99) (n = 100) (n = 100) (n = 99)
Total no. (%) of
patients with
adverse events 51 (51.0) 36 (36.4) 31 (31.0) 41 (41.0) 48 (48.5)
Adverse event, no. (%)
of patients
Nausea 9 (9.0) 11 (11.1) 3 (3.0) 8 (8.0) 7 (7.1)
Headache 12 (12.0) 7 (7.1) 7 (7.0) 9 (9.0) 14 (14.1)
Asthenia 7 (7.0) 5 (5.1) 1 (1.0) 2 (2.0) 2 (2.0)
Somnolence 9 (9.0) 2 (2.0) 4 (4.0) 8 (8.0) 4 (4.0)
Generalized edema 4 (4.0) 6 (6.1) 1 (1.0) 3 (3.0) 4 (4.0)
Dizziness 5 (5.0) 3 (3.0) 3 (3.0) 2 (2.0) 5 (5.1)
Paresthesia 4 (4.0) 4 (4.0) 1 (1.0) 1 (1.0) 1 (1.0)
Vomiting 3 (3.0) 4 (4.0) 1 (1.0) 5 (5.0) 4 (4.0)
Bone disorder 3 (3.0) 3 (3.0) 9 (9.0) 5 (5.0) 11 (11.1)
Infection 2 (2.0) 3 (3.0) 3 (3.0) 4 (4.0) 3 (3.0)
Dyspepsia 2 (2.0) 1 (l.0) 3 (3.0) 0 1 (1.0)
Facial edema 2 (2.0) 0 3 (3.0) 0 2 (2.0)
Pain 0 2 (2.0) I (1.0) 3 (3.0) 2 (2.0)
Trismus 0 1 (1.0) 0 0 2 (2.0)
1085

15. CLINICALTHERAPEUTICS*
Table IX. Adverse events occurring in :-3% of patients in both the single- and repeated-
dose phases, regardless of the initial medication.
Ibuprofen Arginate 200 mg Ibuprofen 200 mg
(n = 243) (n = 246)
Total no. (%) of patients
with adverse events 108 (44.4) 98 (39.8)
Adverse event, no. (%)
of patients
Headache 26 (10.7) 23 (9.3)
Nausea 21 (8.6) 17 (6.9)
Asthenia 14 (5.8)* 3 (1.2)
Edema 13 (5.3) 5 (2.0)
Somnolence 11 (4.5) 16 (6.5)
Bone disorder 10 (4.1) 21 (8.5)
Dizziness 9 (3.7) 9 (3.7)
Paresthesia 9 (3.7) 2 (0.8)
Infection 7 (2.9) 8 (3.3)
Vomiting 7 (2.9) 10 (4.1)
*P < 0.05 versusibuprofen.
drug related. This patient, treated with
ibuprofen arginate 200 mg, experienced
severe dysphagia and pharyngitis after the
60-minute assessment. The patient recov-
ered completely after discontinuation of
the study medication.
DISCUSSION
This study supports the hypothesis that
ibuprofen arginate is as efficacious as ibu-
profen on all measures of analgesia but
has a faster onset of action. During the
single-dose phase, the time to meaningful
pain relief measured by stopwatch and the
time to "some pain relief" and "pain half
gone" assessed at scheduled interview
times were significantly faster with ibu-
profen arginate than with ibuprofen.
The onset of very low levels of pain re-
lief--"any relief" measured by stopwatch
and "a little relief" reported at scheduled
interview times--was similar across the
comparable treatment groups. This result
was consistent with the results of previ-
ous studies, ~2-14in which time to any re-
lief (first perceptible relief) showed a
considerably higher placebo effect than
time to meaningful relief. This finding
confirms the observation that mild levels
of initial pain relief with active drugs
are frequently indistinguishable from
those produced by placebo. A recent study
by Farrar et a121 confirmed that inter-
mediate levels of pain relief are the most
valid indicators of clinically signifi-
cant pain relief. In a study of rapid-acting
oral transmucosal fentanyl, these in-
vestigators found that a criterion of 33%
relief predicted a clinically relevant be-
havior-postponement of remedication--
with the fewest false positives and
1086

16. P. BLACK ET AL.
negatives, whereas many patients re-
ported low levels of relief and remedicated
anyway.
In addition to being statistically signif-
icant, the data from the present study may
be clinically significant, as patients expe-
riencing acute pain wish to receive mean-
ingful pain relief quickly. Furthermore,
essentially equal efficacy was demon-
strated across a broad range of measures
of pain intensity and pain relief, and both
active treatments were shown to be sig-
nificantly better than placebo on all other
efficacy parameters.
The earlier onset of action associated
with ibuprofen arginate did not result in
a shorter duration of pain relief. Times to ad-
ministration of the second dose were similar
with both active treatments in the single-dose
phase of the study, and the total number of
doses taken in the next 5 days was compa-
rable across all active treatments. As the
tissue damage from surgery healed over
the course of the repeated-dose phase,
pain levels declined and the need for
medication diminished. No significant
differences were seen between ibupro-
fen arginate and ibuprofen during this
period.
The safety profile of racemic ibupro-
fen is well established and extensively
documented in the literature.22-26 Con-
sumption of the maximum 6 tablets/d of
ibuprofen arginate would result in total
daily doses of L-arginine of 1110 mg
(16 mg/kg). These doses would be un-
likely to present any risk or to be associ-
ated with serious adverse effects, consid-
ering that the recommended dietary
allowance of arginine is 4.7 to 5.4 g
and that L-arginine is available on the
market for intravenous administration
in doses of 400 to 500 rag. Ibuprofen
arginate has been available in a granu-
lated formulation in many major Euro-
pean countries since 1990. During the pe-
riod from 1997 to 2001, ~17 million pa-
tients have taken the drug, and only 23
adverse drug reactions (10 of which were
gastrointestinal) have been reported to the
manufacturer.
Study Limitations
It is possible that the oral surgery model
used in this study optimized the difference
in onset times between the 2 ibuprofen
formulations. Patients were fasting, a con-
dition that increases the rapidity of onset
of both ibuprofen arginate and ibuprofen.
Also, the relatively uniform degree of
trauma and inflammation in patients un-
dergoing third molar extraction may have
optimized the difference in onset time be-
tween the 2 preparations. For example,
less serious injury may have been more
responsive to the low plasma concentra-
tions that occur in the first hour after ad-
ministration of standard ibuprofen.
Nonetheless, the study data suggest that
ibuprofen arginate may be advantageous
in other painful conditions with dose-
dependent sensitivity to ihuprofen.
CONCLUSIONS
In this population of patients, ibuprofen
arginate was as effective as conventional
ibuprofen but had a faster onset of action.
The 2 formulations had similar tolerabil-
ity profiles. Pharmacokinetic data from
other published studies 1~demonstrate that
ibuprofen arginate has faster absorption,
resulting in higher early plasma concen-
trations. The present results extend these
pharmacokinetic advantages to clinically
meaningful end points in patients with
acute dental pain.
1087

17. CLINICALTHERAPEUTICS®
ACKNOWLEDGMENTS
This study was supported by Zambon Cor-
poration, a subsidiary of Zambon Group
S.p.A., Bresso, Italy. Dr. Pallotta is
Pharma R&D Project Manager and Dr.
Ardia is Pharma R&D Biostatistic Man-
ager at Zambon Group S.p.A.
The contributions of Dr. Max to this ar-
ticle are his personal views and do not
represent the views of the National Insti-
tute of Dental and Craniofacial Research
or the United States government.
The authors thank the following study
personnel: Steven Christensen, MD, Ver-
non Loveless, MD, Hans Malmstrom,
MD, Maano Milles, MD, and George
Mardirossian, MD, who served as princi-
pal investigators or subinvestigators at
each of the study centers; Frances De-
vonshire, RN, Karen Judy, Lisa Sansone
Howell, and Rita Cacciata, clinical study
coordinators; and Tom Norwood, MD,
study statistician.
REFERENCES
I. Collins SL, Moore RA, McQuay HJ, et al.
Single dose oral ibuprofen and diclofenac
for postoperative pain. Cochrane Data-
base Syst Rev. 2000; CD001548.
2. Beaver WT. Impact of non-narcotic oral
analgesics on pain management. Am J
Med. 1988;84:3-15.
3. Phenylpropionic acid derivatives and re-
lated drugs: Ibuprofen. AMA Drug Evalu-
ation. 4th ed. Chicago: American Medical
Association; 1980:79-80.
4. Insel PA. Analgesic-antipyretics and anti-
inflammatory agents: Drugs employed in
the treatment of rheumatoid arthritis and
gout. In: Goodman A, Gilman A, Rall TW,
et al, eds. Goodman and Gilman's The
5.
6.
7.
8.
9.
10.
11.
12.
Pharmacological Basis of Therapeutics.
8th ed. Elmsford, NY: Pergamon Press;
1990:638-681.
Seymour RA, Frame J, Negus TW, et al.
The comparative efficacy of aceclofenac
and ibuprofen in postoperative pain after
third molar surgery. Br J Oral Maxillofac
Surg. 1998;36:375-379.
Cooper SA, Beaver WT. A model to eval-
uate mild analgesia in oral surgery outpa-
tients. J Clin Pharmacol Ther. 1976;20:
241-250.
Cooper SA. The relative efficacy of ibu-
profen in dental pain. Compend Contin
Educ Dent. 1986;7:578,580-581584-588.
Dionne RA, Campbell RA, Cooper SA, et
al. Suppression of postoperative pain by
preoperative administration of ibuprofen
in comparison to placebo, acetaminophen,
and acetaminophen plus codeine. J Clin
Pharmacol. 1983;23:37-43.
Dionne RA, Cooper SA. Evaluation of
preoperative ibuprofen for postoperative
pain after removal of third molars. Oral
Surg Oral Med Oral Pathol. 1978;45:851-
856.
Morris PJ. Report on characterization
studies on PHZ 136 and its components
and solution studies RPT/KRM-93-03.
Data on file, Zambon Group SpA, Milan,
Italy; 1993.
Ceppi Monti N, Gazzaniga A, Gianesello
V, et al. Activity and pharmacokinetics of
a new oral dosage form of soluble ibu-
profen. Arzneimittelforschung.
1992;42:556- 559.
Moote CA. Ibuprofen in the management
of pain. Clin Invest Drugs. 1996;11(Suppl
1):1-7.
1088

18. P. BLACK ET AL.
13. Davies NM. Clinical pharmacokinetics of
ibuprofen, The first 30 years. Clin Phar-
macokinet. 1998;34:101-154.
14. Desjardins PJ, Black P, Milles M, et al. A
comparison of two methods to measure
onset of analgesia. Clin Pharmacol Ther.
1993;53:172. Abstract PII-7.
15. Desjardins PJ, Black P, Milles M, et al.
Measurement of onset of analgesic effect.
J Dent Res. 1994;73:438. Abstract 2688.
16. Desjardins PJ, Black P, Balm TK, et al.
Onset of analgesia: Further validation of a
new stopwatch methodology. Clin Phar-
macol Ther. 1996;59:130. Abstract PI-6.
17. Siegel C, Sunshine A, Richman H, et al.
Meptazinol and morphine in postopera-
tive pain assessed with a new method for
onset and duration. J Clin Pharmacol.
1989;29:1017-1025.
18. Laska EM, Siegel C, Sunshine A. Onset
and duration: Measurement and analysis.
Clin Pharmacol Tiler. 1991;49:1-5.
19. Schachtel BP, Cleves GS, Konerman JP,
et al. A placebo-controlled model to assay
the onset of action of nonprescription-
strength analgesic drugs. Clin Pharmacol
Ther. 1994;55:464-470.
20. US Food and Drug Administration. Guide-
line for the Clinical Evaluation of Anal-
gesic Drugs. Available at: http://www.fda.
gov/cder/guidance/old041fn.pdf. Accessed
May 31,2002.
21.
22.
23.
24.
25.
26.
Farrar JT, Young JP Jr, LaMoreaux L, et
al. Clinical importance of changes in
chronic pain intensity measured on an 1l-
point numerical pain rating scale. Pain.
2001 ;94:149-158.
Laveneziana D, Riva A, Bonazzi M, et al.
Comparative efficacy of oral ibuprofen
arginine and intramuscular ketorolac in
patients with postoperative pain. Clin
Drug lm,est. 1996;ll(Suppl 1):8-14.
Pagnoni B, Vignali M, Colella S, et al.
Comparative efficacy of oral ibuprofen
arginine and intramuscular ketorolac in
patients with postcaesarean section pain.
Clin Drug Invest. 1996;l 1(Suppl 1):15-21.
Borea G, Monopoli R, Colantoni A, et al.
Ibuprofen arginine vs naproxen sodium as
prophylactic oral treatment of pain due
to dental surgery. A randomised, double-
blind, double dummy, placebo-controlled,
multicentre study. Clin Drug Invest. 1996;
Il(Suppl 1):33--40.
Pagnoni B, Ravanelli A, Degradi L, et al.
Clinical efficacy of ibuprofen arginine in
the management of postoperative pain
associated with absorption by suction:
A double-blind, placebo controlled pilot
study. Clin Drug Invest. 1996; 11(Suppl 1):
27-32.
Laveneziana D, Speranza R, Raulli P, et
al. Comparative efficacy of ibuprofen argi-
nine and 13-cyclodextrin piroxicam as
treatment for tension-type headache. Clin
Drug Invest. 1996; 11(Suppl 1):22-26.
Address correspondence to: Paul Desjardins, DMD, Scirex Corporation Inc., 3200 Red
River, Suite 300, Austin, TX 78705.
1089