CLINICAL THERAPEUTICs/VoL. 2 6 , No .

7, 2 0 0 4
Onset of Analgesia and Analgesic Efficacy of
Tramadol / Acet ami nophen and Codei ne/ Acet ami nophen/ I buprof en
in Acut e Postoperative Pain: A Single-Center, Single-Dose,
Randomi zed, Act i ve- Cont r ol l ed, Paral l el -Group Study in
a Dent al Surgery Pain Model
Young-Soo Jung, DDS, MSD, 1 Dong Kee Kim, PhD, 2 Moon-Key Kim, DDS, MSD, 1
Hyung-Jun Kim, DDS, MSD, 1 In-Ho Cha, DDS, PhD, 1 and Eui -Wung Lee, DDS, PhD 1
~Department of Oral and Maxillofacial Surgery, Oral Science Research Center, College of Dentistry, and 2Department
of Biostatistics, College of Medicine, Yonsei University, Seoul, Korea
A B S T R A C T
Background: The c ombi na t i on of t r amadol a n d a c e t a mi n o p h e n has de mons t r a t e d good efficacy i n var i ous cl i n-
ical pai n model s . However , t her e is a n e e d for c ompa r i s ons of t he onset of anal gesi a a n d ot her meas ur es of anal-
gesic efficacy wi t h t hi s c ombi na t i on a n d ot her s t r ong c ombi na t i on anal gesi cs for t he ma n a g e me n t of acut e pai n.
Obj e c t i ve : The goal of t hi s s t udy was t o c o mp a r e t he t i me t o ons et of anal gesi a a n d ot her me a s ur e s of
anal gesi c efficacy wi t h t r a ma d o l / a c e t a mi n o p h e n 75/ 650 mg (Tr/Ac) a n d c o d e i n e / a c e t a mi n o p h e n / i b u p r o f e n
20/ 500/ 400 mg (Co/ Ac/ Ib) i n t he ma n a g e me n t of acut e pa i n aft er oral surgery.
Methods: Thi s was a si ngl e-cent er, si ngl e- dose, r a ndomi z e d, act i ve- cont r ol l ed, par al l el - gr oup s t u d y i n he a l t hy
subj ect s wh o h a d u n d e r g o n e surgi cal ext r act i on of >1 i mp a c t e d t hi r d mol a r r equi r i ng b o n e r emoval . Wh e n
pat i ent s r e por t e d at least mo d e r a t e pa i n after dent al s ur ger y (score >5 on a 10- poi nt scale), t hey wer e r a n d o m-
i zed to 1 of 2 t r e a t me nt gr oups. The t i me t o ons et of anal gesi a was me a s u r e d us i ng a 2- s t opwa t c h t echni que.
The t i mes t o t he ons et of per cept i bl e a n d me a ni ngf ul pa i n relief, pa i n i nt ensi t y, pai n relief, pat i ent ' s overal l assess-
me nt , a n d adver se event s wer e r e c or de d for 6 h o u r s aft er dosi ng.
Results: One h u n d r e d t went y- ei ght subj ect s par t i ci pat ed i n t he study, 64 i n each t r eat ment gr oup. The 2 gr oups
wer e si mi l ar i n t er ms of basel i ne pai n severi t y a nd de mogr a phi c charact eri st i cs ( mean age, 23. 7 and 23. 4 years i n
t he Tr/Ac and Co/Ac/Ib gr oups, respect i vel y; me a n b o d y wei ght , 58. 5 a nd 60. 3 kg). The me di a n t i mes to t he onset
of per cept i bl e pai n relief wer e a respect i ve 21. 0 and 24. 4 mi nut es , a nd t he me di a n t i mes to t he onset of meani ng-
ful pai n relief wer e 56. 4 and 57. 3 mi nut es . Mean total pai n relief and t he s u m of pai n i nt ensi t y di fference wer e also
si mi l ar i n t he early per i od after dos i ng ( 0- 4 hour s) . However, be t we e n 4 and 6 hour s , Co/Ac/Ib was associ at ed wi t h
si gni fi cant differences i n b o t h variables c ompa r e d wi t h Tr/Ac (P < 0. 05). Al t hough si mi l ar t hr ough t he 4- hour
assessment , me a n pai n i nt ensi t y di fference was si gni fi cant l y great er wi t h Co/Ac/Ib at 5 and 6 hour s . The pr opor -
t i on of pat i ent s assessi ng t hei r assi gned t r eat ment as good or bet t er was si gni fi cant l y great er wi t h Co/ Ac/ Ib com-
par ed wi t h Tr/Ac (P < 0. 05). The safety profile of Tr/Ac was compar abl e t o t hat of Co/Ac/Ib.
Conclusions: I n t hi s smal l a n d sel ect ed gr oup of subj ect s, t he ons et of anal gesi a a n d anal gesi c efficacy of Tr/Ac
was c ompa r a bl e to t hat of Co/ Ac/ Ib. Tr/Ac p r o v i d e d r api d a n d effective anal gesi a for acut e pos t oper at i ve dent al
pa i n i n t hi s popul a t i on. (Clin Ther. 2 0 0 4 ; 2 6 : 1 0 3 7 - 1 0 4 5 ) Copyr i ght 2004 Excer pt a Medi ca, Inc.
Key wo r d s : ons et of anal gesi a, anal gesi c c ombi na t i on, anal gesi c efficacy, t r a ma dol / a c e t a mi nophe n, pos t -
oper at i ve pai n.
Accepted Jor publication May 24, 2004.
Pri nt ed i n t he USA. Reproduct i on i n whol e or part is not permi t t ed. 0149 2918/04/$19.00
Copyright 2004 Excerpta Nedica, Inc. 1 0 3 7
CLINICAL THERAPEUTICS
I N T R O D U C T I O N
To reduce the occurrence of adverse events (AEs)
associated wi t h the use of opioid analgesics, these
agents have been combi ned wi t h nonopi oi d agents
such as acet ami nophen to lower the amount of opi-
oid needed to produce an equivalent degree of anal-
gesia. 1,2 Such combi nat i on product s also have been
claimed to produce a synergistic analgesic effect. 1,2
Tramadol plus acet ami nophen is one such anal-
gesic combination. 1 Tramadol hydrochl ori de, whi ch
has weak opioid activity, produces analgesia t hrough
an opioid effect that bi nds mu-opi oi d receptors and
modifies transmission of pain signals t hrough inhibi-
tion of serotonin and norepi nephri ne reupt ake wi t h-
in pain pathways of the central nervous system. 1,3#
Clinical experience indicates that tramadol is associ-
ated wi t h fewer adverse effects t han typical opioids,
not abl y respiratory depression, constipation, and
potential for addiction. 1,3# Furt hermore, tramadol
has been report ed to be effective for various types of
postoperative pain, including dental pai nJ -r Acet-
ami nophen, on the ot her hand, produces analgesia
by elevating the pain t hreshol d t hrough inhibition
of N-met hyl -u-asparat e- or substance P- medi at ed
nitric oxide synthesis and/ or inhibition of prosta-
glandin E 2 release in the central nervous system. 1,8,9
Acet ami nophen, whi ch has excellent antipyretic-
effectiveness and safety profiles, has been available for
- 40 years. 1,8,9
In animal models, the combi nat i on of tramadol
and acet ami nophen in approximately a 1:8 milligram
ratio has been report ed to result in synergistic analge-
sia. 1 Clinical studies have report ed that the combi -
nat i on of t ramadol / acet ami nophen 37.5/325 mg* was
effective and well tolerated in patients wi t h dental
pain, n,12 osteoarthritis flare pain, 13 chronic back and
j oint pain, 1< 15 and fibromyalgia. 16 This combi nat i on
has demonst rat ed comparable efficacy and tolerabil-
ity to the combination of hydrocodone/acetaminophen n
and codei ne/ acet ami nophen. 1~
Use of the combi nat i on of codeine phosphat e/
acet ami nophen/ i buprofen 10/250/200 mg, t whi ch is
not available in the Uni t ed States, has been report ed
to provide good pain relief wi t h no severe AEs in
*Trademark: Ultracet TM (ortho-McNeil Pharmaceutical, Inc., Raritan, New
Jersey).
*Trademark: Myprodol (Adcock Ingrain Ltd., Bryanston, South Africa).
patients wi t h chronic osteoarthritis (n = 28)l r and in
the dental pain model (n = 25). is Codeine is an opi-
oid analgesic and relieves mild to moderat e pain by
bi ndi ng to stereospecific opioid receptors in the cen-
tral nervous system, altering processes affecting per-
ception of and emotional response to pain. > Codeine
is convert ed to the more active drug morphi ne; how-
ever, this conversion is not equal in all patients
or ethnic groups. Ibuprofen is a nonsteroidal anti-
inflammatory drug (NSAID) wi t h analgesic and anti-
pyretic effects. 1,19 It inhibits the activity of the enzyme
cyclooxygenase, resulting in decreased formation of
the prostaglandin and thromboxane precursors of arachi-
donic acid.19
In acute pain, a rapid onset of pain relief is desir-
able. 2,21 Comparisons of the onset of analgesia and
analgesic efficacy of t ramadol / acet ami nophen and
ot her strong analgesic combinations in acute pain are
necessary. To our knowledge, the time of onset of the
analgesic effect of codei ne/ acet ami nophen/ i buprofen
has not been reported. Therefore, the purpose of this
st udy was to compare the time to onset of analgesia
and other measures of analgesic efficacy with tramadol/
acet ami nophen 75/650 mg (Tr/Ac) and codei ne/
acet ami nophen/ i buprofen 20/500/400 mg (Co/Ac/Ib)
in the t reat ment of acute pain after oral surgery. The
surgical extraction of i mpact ed mandi bul ar third
molars, a common oral surgical procedure, i nduces
acute moderat e to severe pain and has been used as a
model for the effectiveness of analgesic agents by
numer ous investigators.2,12,13,18
P A T I E N T S A N D H E T H O D S
I ncl usi on and Excl usi on Cr i t e r i a
Healthy men and women aged >16 years with mod-
erate or severe pain (score >5 on a 10-point scale, with
0 signifying no pain) resulting from oral surgery
involving bilateral extraction of >2 third molars, one
of whi ch was at least a partial bony mandi bul ar
impaction requiring bone removal, were eligible for
participation. Bone removal was considered necessary
to ensure adequate postoperative pain intensity. The
procedure involved 1 day of hospitalization. Women
of childbearing potential had to have a negative uri ne
pregnancy test result on the day of receiving st udy
medication. All patients had to be sufficiently alert to
underst and and communi cat e with the st udy observ-
er and be able to carry out the st udy procedures.
1038
Y.-S. Jung e t al.
Patients were excl uded if t hey had received or used
anot her experi ment al drug or medical device wi t hi n
30 days before screening; had received any analgesic
medi cat i on ot her than short-acting preoperative or
intraoperative anesthetic agents wi t hi n 12 hours
before receiving st udy medication; had taken any
long-acting NSAID wi t hi n 3 days before receipt of
st udy medication; received any ot her analgesic medi -
cation after compl et i on of oral surgery; had a history
of seizure; had a history of drug and/ or alcohol abuse
wi t hi n the past 6 mont hs; had taken monoami ne oxi-
dase inhibitors, tricyclic antidepressants, neurol ep-
tics, or ot her drugs that reduce the seizure threshold
wi t hi n 4 weeks of st udy participation; had renal or
hepatic dysfunction; were sensitive or allergic to tra-
madol, acet ami nophen, codeine, ibuprofen, or ot her
NSAIDs or aspirin; had peptic ul cer disease; had
taken any selective serotonin reupt ake inhibitors, diet
pills, or met hyl pheni dat e wi t hi n 4 weeks of st udy
participation; or were at risk based on the precau-
tions, warnings, and contraindications in the package
inserts for Tr/Ac 22 and Co/ Acf[b. 19
Before patients ent ered the study, the investigators
obtained a medical history and performed a screening
physical examination. After being i nformed of the
nat ure of the study, all patients or the legal represen-
tatives of chi l dren aged <18 years signed a wri t t en
i nformed consent form that had been approved by
the institutional review board.
S t u d y D e s i g n
This was a single-center, single-dose, randomi zed,
act i ve-cont rol l ed, paral l el -group study. Pat i ent s
undergoi ng >1 surgical extraction of an i mpact ed
third molar requiring bone removal were enrolled
over 6 mont hs at the Depart ment of Oral and
Maxillofacial Surgery, Dental College Hospital, Yonsei
University, Seoul, Korea. The surgery was performed
under local anesthesia wi t h 2% lidocaine. The sur-
geon rat ed the surgical t rauma as mild, moderate, or
severe.
When patients report ed moderat e or severe pain
after oral surgery, they were assigned to 1 of 2 treat-
ment groups based on a randomi zat i on code. Single
oral doses of the assigned st udy drugs were packaged
in identical containers containing either Tr/Ac or
Co/Ac/Ib and admi ni st ered to each patient. The 2
product s were not physically identical.
The st udy coordi nat or i nst ruct ed patients in the
use of the stopwatches and assessment scales. Duri ng
the 6 hours after administration of st udy medication,
the st udy coordi nat or recorded patients' assessments
on case-report forms in the day-hospitalization ward.
If the response to st udy drug was inadequate or there
was no analgesic response, suppl ement al analgesia
was available in the form of mefenami c acid 500 mg.
Ou t c o me Me a s u r e s
The time to onset of analgesia was measured using
a 2-stopwatch technique. Two stopwatches were acti-
vated when the st udy drug was administered. At the
onset of perceptible pain relief, the patient st opped
the first watch. At the onset of meaningful pain relief,
the patient st opped the second watch. The st udy
coordi nat or recorded the elapsed times shown on the
watches on patient's charts and case-report forms.
Additional measures of analgesic efficacy i ncl uded
pain intensity, pain relief, use of suppl ement al anal-
gesic medication, and the patient's overall assessment.
When the patient compl ai ned of moderat e or severe
pain (time zero), the baseline pain intensity score was
recorded on the 10-point pain scale. The patient sub-
sequent l y assessed his or her current pain using the
same scale and pain relief from baseline at 30 mi nut es
and 1, 2, 3, 4, 5, and 6 hours after receiving st udy
medication. A 6-hour assessment peri od was used
because of the dosing instructions for Tr/Ac 22 (2 tablets
q4- 6h) and Co/Ac/Ib > (1 or 2 capsules q4h). Pain
relief was rated on a 5-point scale (0 = none, 1 = a little,
2 = some, 3 = a lot, 4 = complete). At the end of the
observation peri od or at withdrawal from the study,
patients compl et ed an overall assessment of st udy
medi cat i on using a 5-point scale (1 = excellent, 2 =
very good, 3 = good, 4 = fair, 5 = poor).
When patients t ook suppl ement al analgesic medi -
cation, t hey were di scont i nued from the study, and
the st udy coordi nat or recorded the time, dose of res-
cue medication, and all ot her efficacy assessments at
the time of withdrawal.
Furt her efficacy assessments i ncl uded total pain
relief (TOTPAR), derived from the sum of recorded
pain relief scores; pain intensity difference (PID), cal-
culated by subtracting each recorded pain intensity
score from the baseline pain intensity score; and
sum of pain intensity difference (SPID), comput ed by
addi ng the calculated PID scores.
1039
CLINICAL THERAPEUTICS
The safety profiles of the st udy treatments were
assessed based on AEs report ed by patients duri ng
the observation period. An AE was defined as any
unfavorable and uni nt ended sign, sympt om, or dis-
ease temporarily associated with the use of an in-
vestigational product. Such surgical consequences
as surface ostitis, ecchymosis, edema, infection, and
paresthesia were not recorded as AEs, because these
consequences do not appear in the i mmedi at e post-
operative period. Blinded st udy investigators j udged
and recorded the relationship bet ween the st udy ther-
apies and the report ed AEs.
S t a t i s t i c a l A n a l y s i s
The st udy was designed to include 128 qualified
patients r andoml y assigned to 1 of 2 t reat ment
groups. The comparability of the demographi c and
baseline characteristics of the 2 t reat ment groups was
tested using the chi-square test or Fisher exact test
for categorical variables (eg, sex) and the t test for con-
tinuous variables (eg, age).
Efficacy anal yses were per f or med usi ng last-
observation-carried-forward methodology. Time to the
onset of perceptible pain relief and time to the onset
of meaningful pain relief were summari zed using
medi ans (95% CIs) and means (SDs) and assessed
using the Wilcoxon rank sum test and the t test.
Kaplan-Meier curves were generated for the rates of
pain relief and meaningful pain relief in each group
and compared using the log-rank test. Mean TOTPAR
and SPID scores were comput ed for the intervals
from 0 to 2 hours, 2 to 4 hours, and 4 to 6 hours.
Between-group differences were tested using the
Wilcoxon r ank sum test.
For the safety-profile analysis, only those signs and
sympt oms that emerged duri ng the st udy were sum-
mari zed for the 2 groups. Between-group differences
in the incidence of drug-related AEs were assessed
using the Fisher exact test.
R E S U L T S
D e m o g r a p h i c a n d B a s e l i n e C h a r a c t e r i s t i c s
One hundr ed twenty-eight patients were enrolled
in the trial and randomi zed equally to the 2 t reat ment
groups. All patients were Asian Koreans, and were
similar in terms of sex, age, body weight, height, and
surgical characteristics (Table I and Table II). Mean
(SD) baseline pain scores were 5.92 (1.00) in the Tr/Ac
Table I. D e mo g r a p h i c characteristics and baseline p a i n
intensity.
Tr/ Ac Co/ Ac/ I b
Characteristic (n = 64) (n = 64)
Sex, no,
Female 37 39
Male 27 25
Age, y
Mean 23.4 23.7
Range 16~40 17 37
Body weight, kg
Mean 58.5 60.3
Range 30 98 44 100
Height, cm
Mean 166.8 167.3
Range 150 188 155 187
Baseline pain score*
5 28 28
6 19 27
7 I I 6
8 6 3
Mean (SD) 5.92 (I . 00) 5.75 (0.82)
Tr / Ac = t r amadol / acet ami nophen 75/ 650 mg; Co/ Ac/ I b = codei ne/
acet ami nophen/ i buprof en 20/ 500/ 400 mg.
~10-point rati ng scale, wi t h 0 representi ng no pain.
group and 5.75 (0.82) in the Co/Ac/Ib group.
Bilateral extraction of mandi bul ar third molars, not
including a maxillary tooth, was the most common
type of oral surgery in this trial (Table II). The surgi-
cal t rauma rating was mainly moderat e (46.8% Tr/Ac,
50.0% Co/Ac/Ib).
Two patients in the Tr/Ac group took suppl ement al
analgesia wi t hi n the 6-hour observation peri od and
were wi t hdrawn from the st udy at the time of receiv-
ing suppl ement al medication. Anot her 2 patients in
the same group report ed perceptible pain relief
but di d not experience meaningful pain relief. Last-
observation-carried-forward met hodol ogy was used
in these 4 cases.
Ti me s t o On s e t of Pai n Rel i ef
Tabl e III summari zes the medi an and mean times
to the onset of perceptible and meaningful pain relief.
The medi an times to the onset of perceptible pain
relief were 21.0 mi nut es (95% CI, 17. 1-25. 0) in the
1040
Y.-S. Jung e t al.
T a b l e II. Surgical c h a r a c t e r i s t i c s .
Tr / Ac Co/ Ac/ I b
(n = 64) (n = 64)
No. (%) o f t eet h extracted
2 ~ 37 (57.8) 36 (56.3)
3 13 (20.3) 7 (10.9)
4 14 (21.9) 21 (32.8)
No. (%) o f bony extractions
I 3 (5.7) 0
2 59 (92.2) 58 (90.6)
3 2 (3.1) 4 (6,3)
4 0 2 (3,1)
Surgical t r auma rating,
no. (%) o f patients
Mild 17 (26.6) 14 (21.9)
Moder at e 30 (46.8) 32 (50.0)
Severe 17 (26.6) 18 ( 28. I )
Tr/Ac = tramadol /acetami nophen 75650 mg; Co/ Ac/ I b = codei ne/
acetaminophen/ibuprofen 20/500/400 mg.
~Bilateral extracLion of mandibular thi rd molars.
Tr/Ac group and 24.4 mi nut es (95% CI, 21. 0-27. 7)
in the Co/Ac/Ib group. The medi an times to the onset
of meaningful pain relief were a respective 56.4 mi n-
utes (95% CI, 48. 7-64. 1) and 57.3 mi nut es (95% CI,
51. 5-63. 0). The differences bet ween groups were not
statistically significant (Fi gure 1 and Fi gur e 2). The
mean (SD) times to the onset of perceptible pain relief
were 26.9 (16.1) mi nut es in the Tr/Ac group and 25.0
(13.7) mi nut es in the Co/Ac/Ib group. The corre-
spondi ng mean times to the onset of meaningful pain
relief were 66.3 (31.3) and 57.0 (23.6) minutes.
Again, the differences bet ween groups were not statis-
tically significant.
O t h e r E f f i c a c y A n a l y s e s
The time-effect curve for PID duri ng the 6-hour
observation peri od is shown in Fi gur e 3. From 0.5 to
4 hours, the 2 drugs had similar effects. However, at
the 5- and 6-hour assessments, PID was significantly
greater wi t h Co/Ac/Ib compar ed wi t h Tr/Ac (P <
0.05).
For TOTPAR and SPID, the differences bet ween the
2 groups were not significant duri ng the first 2 time
intervals (0-2 and 2- 4 hours). However, duri ng the
last interval (4-6 hours), bot h values were signifi-
T a b l e III. S u m m a r y o f m e d i a n a n d m e a n t i m e s t o t h e o n s e t
o f p e r c e p t i b l e a n d m e a n i n g f u l pain r e l i e f .
Tr / Ac C o / A d l b
(n = 64) (n = 64)
Onset o f perceptible pai n relief, min
Median (95% CI)
Mean (SD)
Onset o f meaningful pai n relief, min
Median (95% CI)
Mean (SD)
21.0 24.4
( I 7. I 25.0) (21.(>27.7)
26.9 (16.1) 25.0 (13.7)
56.4 57.3
(48.>64.1) (51.5 63.0)
66.3 (31.3) 57.0 (23.6)
Tr/Ac = tramadol /acetami nophen 75/650 mg; Co/ Ac/ I b = codeine/
acetaminophen/ibuprofen 20/500/400 mg.
cantly greater with Co/Ac/Ib compared with Tr/Ac
(P < 0.05). Mean (SD) peak PID values were 4.4 (1.18)
and 4.8 (0.9) in the Tr/Ac and Co/Ac/Ib groups,
respectively, a nonsignificant difference. Peak pain
relief values were almost identical in the 2 groups
( T a b l e IV).
In the Tr/Ac group, 90.6% of patients gave an over-
all assessment of their assigned t reat ment as good or
better, whereas 100% of the Co/Ac/Ib group gave
such an assessment (P < 0.05) (Fi gure 4).
S a f e t y P r o f i l e
Two of 64 patients (3.1%) who received Tr/Ac
report ed AEs (dizziness and nausea). One of these
patients report ed bot h AEs simultaneously. In the
investigator's j udgment , a correlation bet ween the
nausea and st udy medi cat i on was unlikely. The
Co/Ac/Ib group report ed no AEs. No severe AEs
occurred in either group duri ng this study.
D I S C U S S I O N
This st udy found no difference in the medi an time to
the onset of perceptible pain relief bet ween groups.
The 21-mi nut e medi an time to the onset of percepti-
ble pain relief wi t h Tr/Ac was shorter t han the 34
mi nut es report ed by Fricke et al, 12 who used the
same dose of Tr/Ac in the dental pain model, and
slightly longer t han the 17 mi nut es report ed by
Medve et al, M who also report ed much longer times
to the onset of perceptible pain relief wi t h i buprofen
1041
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SDI.Ln3dv~I3HJ_ I VDI NI I D
Y.-S. Jung e t al .
T a b l e IV. T o t a l pain r e l i e f ( T O T P A R ) , s u m o f pain i n t e n s i t y
d i f f e r e n c e ( S P I D ) , p e a k pain r e l i e f ( P R ) , a n d p e a k
pain i n t e n s i t y d i f f e r e n c e ( P I D ) . V a l u e s a r e m e a n
( S O ) .
T r / A c C o / A c / I b
T r a m a d o l /
He a s ur e / Ti me Point (n = 64) (n = 6 4 ) acet ami nophen
TOTPAR
0 2 Hour s 6.4 ( I . 84) 6.9 ( I . 48)
2~4 Hour s 5.8 (0.74) 6.1 (0.60)
4 6 H o u r s 5. 0 ( I . 2 8 ) * 5.7 ( 0 . 7 7 ) *
SPID
0 2 H o u r s 7.9 ( 2. 98) 8.8 ( 2. 79)
2 ~ i H o u r s 8.1 ( 2. 27) 8.8 ( I . 9 2 )
4 6 H o u r s 6.8 ( 2 . 6 8 ) * 8.2 (2. I I ) *
Peak PR 3.1 (0.37) 3.1 ( 0. 33)
Peak PI D 4. 4 ( I . 1 8 ) 4. 8 (0.9)
Tr / Ac = t r a ma d o l / a c e t a mi n o p h e n 7 5 / 6 5 0 mg; Co/ Ac / I b
a c e t a r ni nophe n/ i bupr of e n 2 0 / 5 0 0 / 4 0 0 rag.
~P < 0 . 0 5 , Wi l c o x o n r ank s um t est .
= c o d e i n e /
(34 minutes) and tramadol alone (51 minutes) and a
similar time of onset wi t h acet ami nophen alone
(18 minutes). M That st udy and anot her by Moller et
al 2 demonst rat ed that acet ami nophen had a rapid
onset of action. In our study, in whi ch acet ami nophen
was a component in bot h st udy treatments, the times
to the onset of meaningful pain relief were similar
bet ween groups.
Given a rapid onset of analgesia, ot her efficacy vari-
ables help characterize the early effects of a drug in
the peri od after drug administration. 2,21 In the pres-
ent study, TOTPAR, PID, and SPID values were simi-
lar bet ween groups in the early peri od after adminis-
tration ( 0- 4 hours), a finding that was consistent
wi t h the onset of pain relief. Peak pain relief and peak
PID were also similar in the 2 groups. However,
bet ween 4 and 6 hours after drug administration,
TOTPAR and SPID values were significantly greater
for Co/Ac/Ib compar ed wi t h Tr/Ac (P < 0.05).
Similarly, al t hough there were no statistical differ-
ences in PID values until the 4-hour assessment,
Co/Ac/Ib became significantly superior to Tr/Ac at the
5- and 6-hour assessments (P < 0.05).
The ant i -i nfl ammat ory action of the ibuprofen
component of Co/Ac/Ib was t hought to be the reason
for the latter results. Many factors in the pain that
C o d e i n e /
acetaminophen/
ibuprofen
9.4
P o o r
[ ] Fair
[ ] Good
[ ] Very good
[ ] Excellent
I 25.0 50.0 15.6
6.3 60.9 32.8
I
20 0 20 40 60 80 1 0 0
% o f P a t i e n t s
F i g u r e 4 . P a t i e n t s ' o v e r a l l a s s e s s m e n t o f s t u d y m e d i c a t i o n .
T h e p r o p o r t i o n o f p a t i e n t s assessing t r e a t m e n t
as good o r b e t t e r w a s significantly g r e a t e r in
t h e c o d e i n e / a c e t a m i n o p h e n / i b u p r o f e n g r o u p c o m -
p a r e d w i t h t h e t r a m a d o l / a c e t a m i n o p h e n g r o u p
( 1 0 0 % vs 9 0 . 6 % , r e s p e c t i v e l y ; P < 0 . 0 5 , F i s h e r
e x a c t t e s t ) .
develops after surgical extraction of i mpact ed third
molars relate to the peripheral i nfl ammat ory reaction
initiated by surgical trauma. Therefore, NSAIDs such
as ibuprofen and ketorolac have been report ed to be
effective for postoperative pain. 23-25 A 6-hour assess-
ment was used in the present st udy because of the
r ecommended dosing of the 2 drugs19,22; ot her st ud-
ies of the onset of analgesia have used similar obser-
vation periods (42o and 621 hours). Thus, the signifi-
cant bet ween-group differences in TOTPAR and SPID
from 4 to 6 hours shoul d not be an effect of the short
assessment period.
Use of Tr/Ac has been associated with dizziness,
headache, nausea, vomiting, somnol ence, and consti-
pation, Mq6'2~ wi t h dizziness and nausea being the
most commonl y report ed AEs (up to 20% and 23%
of patients, respectively). Mq6 In the present study,
only 2 patients (3.1%) in the Tr/Ac group report ed
dizziness and nausea, an ext remel y low incidence
compared with previous reports. Mq6'2~ Although a
potential for seizures is known to be associated wi t h
tramadol, no severe AEs occurred duri ng this study.
Tramadol has a favorable safety profile compar ed
1043
CLINICAL THERAPEUTICS
with traditional opioids, and acetaminophen is useful
in cases in which NSAIDs are contraindicated (eg,
peptic or gastric ulcer). 1,26 Therefore, Tr/Ac may offer
good efficacy with a good safety profile relative to the
combination of Co/Ac/Ib, which includes a tradition-
al opioid and an NSAID.
C O N C L U S I O N S
In this study, the times to the onset of perceptible and
meaningful relief of acute dental pain did not differ
significantly between Tr/Ac and Co/Ac/Ib. TOTPAR,
SPID, and PID were similar between treatments in the
early observation period (0-4 hours), although the
difference in TOTPAR and SPID favored Co/Ac/Ib
from 4 to 6 hours after administration, and the mean
PID was significantly greater with Co/Ac/Ib at 5 and
6 hours. Both treatments were well tolerated in the
population studied. Although the inclusion criteria
limit extrapolation of the findings of this study to the
general population or to other pain models in which
bone pain is not present, the results in this popula-
tion suggest that Tr/Ac provides rapid and effective
analgesia in the management of acute postoperative
pain.
A C K N O WL E D G H E N T S
This research was supported by Janssen Korea Ltd.,
Seoul, Korea. The authors thank Yoo Jung Um and
Moo Young Han, Yonsei University, and Hye Yeon
Park and Jae Eun Jung, Janssen Korea, for assisting in
the preparation of this manuscript.
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Addres s c or r e s ponde nc e to: Professor Eui - Wung Lee, DDS, PhD, Depar t ment of Oral and Maxillofacial Surgery,
College of Dentistry, Yonsei University, 134 Shi nchon- Dong, Seodaemoon- Gu, 120-752, Seoul, Korea. E-mail:
ysj oms@yumc. yonsei . ac. kr
1045