palangio2002

CLINICAL THERAPEUTICSVVOL. 24, NO. I, 2002
Combination Hydrocodone and Ibuprofen Versus
Combination Oxycodone and Acetaminophen in the
Treatment of Moderate or Severe Acute Low Back Pain
Mark Palangio, MS, Elena Morris, BS, RPh, Ralph I: Doyle, Jr, BA,
Bruce E. DornseiJ; PhD, and Thomas J. Valente, MD
Abbott Laboratories,
Parsippany, New Jersey
ABSTRACT
Background: Introduced in 1997, the combination of hydrocodone and ibuprofen is the
only fixed-dose combination analgesic containing an opioid and ibuprofen that has been
approved by the US Food and Drug Administration.
Objective: This study compared the efficacy and tolerability of combination
hydrocodone 7.5 mg and ibuprofen 200 mg (HC/IB) with those of combination oxycodone 5 mg
and acetaminophen
325 mg (OX/AC) in the treatment of moderate or severe acute low
back pain.
Methods: This was a multicenter, randomized, double-blind,
parallel-group,
repeatdose study lasting up to 8 days. The recommended dosing of the study medications was 1
tablet every 4 to 6 hours, not to exceed 5 tablets per day. If adequate pain relief was not
obtained, patients were permitted to take up to 4 doses per day of supplemental analgesic
medication-the
nonopioid component of the assigned study medication (ibuprofen 200
mg or acetaminophen 325 mg). Measures of efficacy included mean daily pain relief scores
(0 = no relief, 1 = slight relief, 2 = moderate relief, 3 = good relief, and 4 = complete relief), mean daily number of tablets and doses of study medication, mean daily number of
tablets and doses of supplemental
analgesic medication, global evaluation (poor, fair,
good, very good, or excellent), and results on the modified 36-item Short-Form Health
Survey (SF-36). All efficacy measures were analyzed on an intent-to-treat basis. Tolerability was evaluated based on adverse events reported spontaneously or elicited by the investigators using nonsuggestive
questioning, as well as on the number of patients discontinuing treatment because of adverse events.
Accepted for publication October 23, 2001.
Printed in the USA. Reproduction
0149.2918/02/$19,00
in whole or part is not permitted.
87
CLINICAL THERAPEUTICS”
Results:
The study enrolled
147
patients (75 HC/IB, 72 OX/AC). The most
common cause of low back pain was
muscular/ligamentous
injury
(97/147;
66.0%), followed by degenerative
disk
disease (27/147; 18.4%). At baseline, 80
patients (54.4%) reported experiencing
moderate pain, and 67 patients (45.6%)
reported experiencing severe pain. There
were no significant differences between
HC/IB and OX/AC with regard to mean
(LSD) daily pain relief scores (2.40 + 1.06
vs 2.50 +- 1.01, respectively), mean daily
number of tablets of study medication
(1.80 f 1.70 vs 2.20 + 1.60), mean daily
number of doses of study medication (1.80 +
1.65 vs 2.10 + 1.58), mean daily number of tablets of supplemental analgesic
medication (0.60 + 1.13 vs 0.50 + 0.99),
mean daily number of doses of supplemental analgesic medication (0.60 + 1.07
vs 0.50 f 0.90), global evaluations,
or
mean scores on the modified SF-36. In
addition, there were no significant differences in the proportion of patients experiencing adverse events with HC/IB (47;
62.7%) and OX/AC (45; 62.5%). Adverse
events were consistent with those generally associated with the component analgesics and predominantly
involved the
central nervous system and gastrointestinal system.
Conchsions:
The results of this study
suggest that HC/IB and OX/AC are similarly effective and tolerable in relieving
moderate or severe acute low back pain.
Additional controlled longitudinal
trials
are necessary to evaluate the clinical utility of HC/IB in treating acute low back
pain.
Key words: acetaminophen, acute pain,
combination analgesics, hydrocodone, ibuprofen, low back pain, oxycodone. (Clin
Thel: 2002;24:87-99)
88
INTRODUCTION
Acute low back pain is the most commonly reported type of pain condition and
the fifth most common reason for a physician visit in the United States, according
to data from the National Ambulatory
Medical Care Survey.’ It has been estimated that 90% of all US adults will experience either acute or chronic low back
pain at some point in their life2 and that
50% of those in the workforce will have
at least 1 episode of low back pain each
year.” Acute low back pain is responsible
for direct health care expenditures of >$20
billion annually in the United States, and,
when indirect costs are included, the aggregate impact on the economy has been
estimated at $50 billion per year4
Acute low back pain has heterogeneous
causes, both serious and benign. The
Agency for Health Care Policy and Research of the US Department of Health
and Human Services has categorized back
pain as follows: potentially serious spinal
conditions, sciatica (herniated disk), and
nonspecific back symptoms.5 Potentially
serious spinal conditions, which include
tumor, infection,
fracture, and spinal
stenosis (cauda equina syndrome), require
immediate
medical attention.
Sciatica,
which involves nerve-root compromise
with pain radiating to a lower extremity,
is often debilitating but usually subsides
with conservative
therapy. Nonspecific
back symptoms, which involve neither a
serious underlying condition nor nerveroot compromise, are frequently the result
of acute muscular-ligamentous
injuries or
age-related degenerative processes affecting the intervertebral
disks and facet
joints. Nonspecific back symptoms are the
most common type of acute back pain and
usually improve without intervention.6
M. PALANGIO
ET AL.
Acute low back pain has an excellent
prognosis, with 60% to 80% of patients
improving within 2 weeks of the onset of
pain.7 Because the natural history of acute
low back pain is self-limiting in the majority of cases, analgesic therapy is often
provided solely for short-term symptomatic relief. For mild acute low back pain,
a nonopioid analgesic such as acetaminophen or a nonsteroidal anti-inflammatory
drug (NSAID) is indicated; for more severe pain, an opioid may be prescribed
for a limited time period.7-‘0 Fixed-dose
combination opioid-nonopioid
analgesics
have been shown to be useful in treating
acute low back pain, although their superiority to single-entity
analgesics in this
pain model remains unclear.’ l-l3 Providing analgesia by both peripheral and central mechanisms,
combination
opioidnonopioid analgesics have demonstrated
an additive analgesic effect in a number
of other acute pain models.t4
Combination hydrocodone 7.5 mg and
ibuprofen
200 mg* (HC/IB) has been
available for the treatment of acute pain
since 1997 and is the only fixed-dose combination analgesic to contain an opioid
and ibuprofen that is approved by the US
Food and Drug Administration.
Hydrocodone 7.5 mg has been reported to be
approximately
equianalgesic
with oxycodone 5 mg.i5,t6 In 3 placebo-controlled,
single-dose trials in patients with acute
postoperative pain, i7*18HC/IB produced
an analgesic effect that was statistically
significantly
greater than that produced
by either of the component
analgesics
alone (P 2 0.05).
The objective of the present study was
to compare the efficacy and tolerability of
single-tablet doses of HC/IB, a Schedule
III controlled
substance, with those of
combination
oxycodone 5 mg and acet-
aminophen 325 mg (OX/AC),+ a Schedule II controlled substance, administered
for up to 8 days as treatment for acute low
back pain.
PATIENTS
AND METHODS
Inclusion and Exclusion
Criteria
Eligible patients were aged 218 years
and had a diagnosis of acute low back
pain requiring opioid or opioid-nonopioid
combination therapy. Patients with acute
low back pain due to an exacerbation of a
chronic condition (eg, herniated disk, ligamentous injury, osteoporosis, or osteoarthritis), as well as those with first-time injury and/or onset of pain, were eligible,
provided they met the other inclusion criteria and enrolled within 48 hours of injury or onset of pain. At baseline, patients’
self-assessed pain intensity rating had to
be moderate or severe on a scale in which
0 = no pain, 1 = mild pain, 2 = moderate
pain, and 3 = severe pain.
Exclusion criteria consisted of allergic
hypersensitivity
to opioids or antipyretic
analgesics (eg, acetaminophen, NSAIDs);
occurrence of 21 episode of low back pain
requiring treatment with prescription pain
medication
and/or adjuvants within the
month before enrollment; spinal surgery
(including laminectomy, diskectomy, fusion, or other stabilization
procedure)
within 1 year of enrollment;
transcutaneous electrical nerve stimulation during
the study; pain of malignant etiology; significantly impaired cardiac, central nervous system (CNS), gastrointestinal
(GI),
*Trademark:
Vicoprofen@ (Abbott Laboratories,
Abbott Park, Illinois).
tcomponents
and doses matching Percocet@ (Endo
Pharmaceuticals
Inc. Chadds Ford, Pennsylvania).
89
CLINICAL
hematologic, hepatic, renal, or respiratory
function; peptic ulcer disease; a history
of drug or alcohol abuse; pregnancy,
breast-feeding,
or failure of a woman
of childbearing
potential
to use adequate contraception; and use of investigational drug therapy within 30 days before
entering
the study. Patients requiring
physical therapy were not excluded from
the study.
Study Design
This randomized, double-blind, parallelgroup, repeat-dose study was conducted
at 18 sites throughout the United States
and lasted up to 8 days. At each study
site, patients were sequentially assigned
to 1 of 2 active-treatment groups according to a computer-generated
randomization schedule. The protocol was approved
by the institutional review board for each
site. Before enrollment, all patients were
informed of the nature of the study and
gave written consent.
Patients were treated on an outpatient
basis and were required to complete 2 visits within an 8-day period. Visit 1 (day 1)
was baseline, and visit 2 (day 8 or day of
discontinuation)
was the end point. At
baseline, a complete history and physical
examination
were performed,
baseline
pain intensity was recorded, study medications were dispensed, and patient diaries
were provided, with instructions on their
use. Every day, patients were to record in
the diary their end-of-day pain relief rating (using the scale 0 = no relief, 1 =
slight relief, 2 = moderate relief, 3 = good
relief, and 4 = complete relief), the number of tablets and doses of study medication taken, the number of tablets and doses
of supplemental
analgesic
medication
taken, adverse events, and, if applicable,
90
THERAPEUTICS@
the type and frequency of physical therapy prescribed by their physician. The
study coordinators were to make telephone
contact with patients within 48 hours after
visit 1 and 2 days before day 8 to review
concomitant medications, patient diaries,
and adverse-event
information.
At end
point, patients were asked to provide a
global evaluation of their treatment (poor,
fair, good, very good, or excellent), a physical examination was performed, and adverse events were evaluated.
At this final visit, patients also completed a modified version of the 36-item
Short-Form Health Survey (SF-36).i9 The
SF-36 is a well-accepted,
standardized,
multipurpose
survey of general health
consisting of 36 questions falling into 8
categories: physical functioning, physical
role, bodily pain, general health, vitality,
social functioning,
emotional role, and
mental health.i9 In the present study, the
survey was modified to conform with the
study time frame (ie, “past week” instead
of “past 2 days”).
Withdrawal of a patient from the study
was considered if an adequate analgesic
response was not achieved with the assigned study medication and supplemental analgesic medication, if therapy prohibited by the protocol became necessary,
if the patient’s condition became unstable, or if a serious adverse event occurred.
Tolerability was evaluated based on adverse events reported spontaneously
by
patients or elicited by investigators using
nonsuggestive questioning, as well as on
the number of patients discontinuing treatment because of adverse events.
Study Medications
Patients were randomly assigned under
double-blind conditions to receive either
M. PALANGIO ET AL.
HC/IB or OX/AC. All study medications
and supplemental medications were identical in appearance.
The recommended
starting dosage was 1 tablet every 4 to 6
hours. Patients were permitted to administer up to 5 single-tablet doses of study
medication per day for control of their
back pain. They could also take supplemental analgesic medication
(the nonopioid component of the assigned study
medication-ibuprofen
200 mg or acetaminophen 325 mg) if they did not achieve
adequate pain control with study medication. Up to 4 doses per day of supplemental analgesic medication were permitted,
with no more than 1 dose of supplemental analgesic medication to be taken between any 2 doses of study medication.
Whenever possible, supplemental analgesic medication was to be avoided within
I hour of taking study medication.
Medications
having analgesic,
antiinflammatory, or CNS activity (eg, acetaminophen, aspirin, cyclooxygenase-2
inhibitors, NSAIDs, prescription
muscle
relaxants,
sedative-hypnotics,
steroids)
were not permitted during the study period and were discontinued before administration of the study medications using
an adequate, prospectively
determined
washout period. Analgesic adjuvants, such
as tricyclic antidepressants
or selective
serotonin reuptake inhibitors, were permitted as needed.
Statistical Analysis
Differences
between the 2 treatment
groups were analyzed
using a l-way
analysis of variance for continuous variables and the Fisher exact test for categoric variables. The primary measure of
efficacy was the mean daily pain relief
score at end point (day 8 or the day of dis-
continuation).
Based on the findings of a
previous study, 20 the mean (&SD) daily
pain relief score for a l-tablet dose of
HC/IB was expected to be -1.86 f 1.09.
Based on a MEDLINE search using the
terms acetaminophen,
oxycodone,
and
pain relief score, no information appears
to be available on the expected mean daily
pain relief scores for a l-tablet dose of
OX/AC. The null hypothesis was constructed to show that the difference in
mean daily pain relief scores between the
2 treatment groups was > 10% of the mean
pain relief score of the HC/IB group. Using the sample-size formula described by
Lin2’ it was estimated that 150 patients
(75 per treatment group) would have to
complete the study to provide 70% power
for the 2-sided 95% CI of the betweengroup difference in mean daily pain relief
scores to be enclosed within 10% of the
mean of the HC/IB group.
Secondary
measures of efficacy included the mean daily number of tablets
and doses of study medication, the mean
daily number of tablets and doses of supplemental analgesic medication, the distribution of global evaluations, and mean
scores on the modified SF-36 at end point.
As a measure of the efficacy of each study
medication, the difference between mean
daily pain relief scores at baseline and
end point was analyzed within each treatment group.
Intent-to-treat analysis was used for all
efficacy measures.
End-point
data for
daily pain relief scores, daily number of
tablets and doses of study medication, and
daily number of tablets and doses of supplemental analgesic medication were calculated as the mean of the last 2 nonmissing postbaseline
measurements.
If
there was only 1 nonmissing postbaseline
measurement, that value was used as the
91
CLINICAL THERAPEUTICS@
mean. If there were no nonmissing postbaseline measurements, the mean for that
patient was defined as missing. Statistical
significance was set at P I 0.05. Data are
presented as mean + SD, unless stated
otherwise.
(60) of patients had 5 to 8 days of exposure to study medication, whereas 20%
(15) had 1 to 4 days of exposure. In the
OX/AC group, 87.5% (63) of patients had
5 to 8 days of exposure to study medication, whereas 12.5% (9) had 1 to 4 days
of exposure.
RESULTS
Patient Disposition
Demographic and
Baseline Characteristics
A total of 147 patients were enrolled in
the study, 75 in the HCAB group and 72
in the OX/AC group. Sixty-four patients
(85.3%) in the HC/IB group completed
the study, as did 61 patients (84.7%) in the
OX/AC group. There were no statistically
significant differences between the 2 treatment groups with respect to the number of
patients who discontinued treatment or the
number who discontinued
treatment for
specific reasons (ie, adverse event, recovery, lack of efficacy, loss to follow-up, and
protocol violation) (Table I).
The mean (*SD) number of days of exposure to study medication was 6.5 ? 2.2
in the HUIB group and 6.9 f 1.9 in the
OX/AC group. In the HUIB group, 80%
There were no statistically significant
differences
between
the 2 treatment
groups with respect to baseline and demographic
characteristics
(Table II).
Overall, the study population included 76
(51.7%) men and 71 (48.3%) women, and
their mean age was 45.4 years. Although
the difference in numbers of male and female patients in each group appeared
large, it was not statistically significant.
The most common source of low back
pain was muscular/ligamentous
injury
(97; 66.0%) followed by degenerative
disk disease (27; 18.4%), herniated disk
(8; 5.4%), facet arthropathy/osteoarthritis
(6; 4.1%), osteoporosis/compression
fracture (2; 1.4%), spinal stenosis (1; 0.7%),
-
Table I. Patient disposition.*
Completed study, no. (%)
Discontinued study, no. (%)
Reason for discontinuation, no. (%)
Adverse event
Recovery
Lack of efficacy
Loss to follow-up
Protocol violation
HCAB
OX/AC
64 (85.3)
61 (84.7)
11 (14.7)
11 (15.3)
8 (10.7)
8 (11.1)
2 (2.7)
1 (1.4)
HCXB = combination hydrocodone 7.5 mg and ibuprofen 200 mg; Ox/AC = combination
acetaminophen 325 mg.
*There were no statistically significant differences between groups.
92
1 (1.4)
_
l(l.3)
-
l(l.4)
oxycodone
5 mg and
M. PALANGIO ET AL.
Table II. Demographic
and baseline characteristics.*
Age, y, mean 2 SD
Sex, no. (%)
Male
Female
Cause of pain, no. (%)
Muscular/ligamentous
injury
Degenerative disk disease
Herniated disk
Facet arthropathylosteoarthritis
Osteoporosis/compression
fracture
Spinal stenosis
Failed back syndrome
Other
Nature of pain, no. (%)
Soft tissue
Mixed
Bone
Neuropathic
Pain intensity at baseline, no. (%)+
Moderate
Severe
HCAB
OX/AC
45.1 f 14.1
45.6 f 15.1
43 (57.3)
32 (42.7)
33 (45.8)
39 (54.2)
50 (66.7)
15 (20.0)
3 (4.0)
3 (4.0)
2 (2.7)
1 (1.3)
_
47
12
5
3
l(l.3)
(65.3)
(16.7)
(6.9)
(4.2)
_
-
i(l.4)
4 (5.6)
42 (56.0)
18 (24.0)
8 (10.7)
7 (9.3)
41
19
6
6
(56.9)
(26.4)
(8.3)
(8.3)
43 (57.3)
32 (42.7)
37 (5 1.4)
35 (48.6)
HC/IB = combination hydrocodone 7.5 mg and ibuprofen 200 mg; OX/AC = combination oxycodone 5 mg and
acetaminophen 325 mg.
*There were no statistically significant differences between groups.
+Pain intensity was rated using the following scale: 0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 =
severe pain.
failed back syndrome (1; 0.7%), and other
(5; 3.4%). The type of pain was most commonly soft tissue (83; 56.5%), followed
by mixed (37; 25.2%), bone (14; 9.5%),
and neuropathic (13; 8.8%). At baseline,
80 patients (54.4%) reported experiencing
moderate pain and 67 (45.6%) reported
experiencing severe pain.
Analgesic Efficacy
Mean daily pain relief scores improved
significantly in each treatment group from
baseline to end point (P < O.OOl), gener-
ally progressing from slight to moderate
relief to moderate to good relief (Table
III). The end-point analyses demonstrated
no statistically significant differences between the 2 groups on any measure of efficacy, including mean daily pain relief
scores, mean daily number of tablets and
doses of study medication,
mean daily
number of tablets and doses of supplemental analgesic medication, and distribution of global evaluations (Table IV).
There were no statistically significant
differences between the 2 groups on any
question on the modified SF-36 (Table V
93
CLINICAL THERAPEUTICY
Table III. Improvements
in mean (LSD) daily pain relief scores,*
Baseline
End Point’
HC/IB (n = 75)
1.80-c 1.11
2.40 k 1.06
<o.oo 1
OX/AC (n = 72)
2.00 + 1.07
2.50 f 1.01
<O.OOl
HC/IB = combination hydrocodone 7.5 mg and ibuprofen 200 mg: OX/AC = combination oxycodone 5 mg and
acetaminophen 325 mg.
*Pain relief was rated using the following scale: 0 = no relief, 1 = slight relief, 2 = moderate relief, 3 = good
relief, and 4 = complete relief.
+End-point data were the mean of the last 2 nonmissing postbaseline measurements. If there was only 1 nonmissing postbaseline measurement, that value was used as the mean. If there were no nonmissing postbaseline
measurements, the mean was defined as missing.
%tatistical significance was set at P < 0.05 (1 -way analysis of variance).
Table IV. End-point* analysis
otherwise stated.)
of efficacy.+ (Values are expressed
HUB
(n = 75)
as mean + SD unless
OX/AC
(n = 72)
Daily pain relief scores
2.40 2 1.06
2.50 f 1.01
Daily no. of tablets of study medication
1.80 + 1.70
2.20 + 1.60
Daily no. of doses of study medication
1.80+ 1.65
2.102
Daily no. of tablets of supplemental
0.60 + 1.13
0.50 + 0.99
0.60 f 1.07
0.50 f 0.90
Daily no. of doses of supplemental
Global evaluation, no. (%)
Poor
Fair
Good
Very good
Excellent
medication
medication
4
7
28
22
(5.3)
(9.3)
(37.3)
(29.3)
11 (14.7)
6
9
24
23
9
1.58
(8.3)
(12.5)
(33.3)
(31.9)
(12.5)
HC/IB = combination hydrocodone 7.5 mg and ibuprofen 200 mg; OX/AC = combination oxycodone 5 mg and
acetaminophen 325 mg.
*End-point data were the mean of the last 2 nonmissing postbaseline measurements. If there was only 1 nonmissing postbaseline measurement, that value was used as the mean. If there were no nonmissing postbaseline
measurements, the mean was defined as missing.
+There were no statistically significant differences between groups.
$Pain relief was rated using the following scale: 0 = no relief, 1 = slight relief, 2 = moderate relief, 3 = good
relief, and 4 = complete relief.
94
M. PALANGIO ET AL.
Table V. Comparison of scores at end point on the physical functioning and bodily pain
portions of the 36-item Short-Form Health Survey’9 (modified to conform with
the study time frame).*
Mean + SD Score
(No. of Respondents)
HClIB
OX/AC
Activities limited by health+
Vigorous activities
Moderate activities
Lifting or carrying groceries
Climbing several flights of stairs
Climbing 1 flight of stairs
Bending, kneeling, or stooping
Walking more than 1 mile
Walking several blocks
Walking I block
Bathing or dressing oneself
1.78
2.22
2.54
2.27
2.60
2.11
2.19
2.34
2.52
2.75
How much bodily pain during the past week’
3.67 f I .02 (72)
3.55 + 1.07 (71)
How much did pain interfere with
normal work during the past week”
2.70 + 0.88 (73)
2.69 + 1.06 (72)
f 0.82 (73)
+ 0.7 1 (73)
f 0.58 (72)
+ 0.73 (73)
+ 0.64 (72)
f 0.74 (73)
f 0.84 (73)
% 0.77 (73)
+ 0.73 (73)
+ 0.46 (73)
HUB = combination hydrocodone 7.5 mg and ibuprofen 200 mg; OX/AC = combination
acetaminophen 325 mg.
*There were no statistically significant differences between groups.
.‘Scale: 1 = yes, limited a lot; 2 = yes, limited a little; 3 = no, not limited at all.
%cale: 1 = none, 2 = very mild, 3 = mild, 4 = moderate, 5 = severe, 6 = very severe.
“Scale: I = not at all, 2 = a little bit, 3 = moderately, 4 = quite a bit, 5 = extremely.
shows data for the physical functioning
and bodily pain items) or in the proportion of patients receiving physical therapy
(5 [6.7%] HC/lB vs 3 [4.2%] OX/AC). In
the HUIB group, physical therapy consisted of chiropractic adjustment (1; 1.3%),
electrotherapy (1; 1.3%), exercise(1; 1.3%)
heating pad (1; 1.3%), ultrasonic massage
(1; 1.3%), and stretching exercise (1; 1.3%).
In the OX/AC group, physical therapy consisted of back adjustment (1; 1.4%), cycling (1; 1.4%) pool/whirlpool (1; 1.4%)
sit-ups (1; 1.4%), stretches ( 1; 1.4%), treadmill (1; 1.4%), and walking (1; 1.4%).
I .76
2.24
2.50
2.07
2.54
2.13
2.13
2.31
2.56
2.72
+ 0.71 (70)
+ 0.74 (72)
f 0.61 (72)
f 0.74 (72)
-c 0.65 (72)
f 0.71 (72)
f 0.80 (72)
f 0.75 (71)
+ 0.7 1 (72)
f 0.45 (72)
oxycodone
5 mg and
Adverse Events
There was no statistically
significant
difference in the proportion of patients experiencing
adverse events between the
HUB group (47; 62.7%) and the OX/AC
group (45; 62.5%) (Table VI). The adverse
events were consistent with those generally associated with the component analgesic medications and predominantly
involved the CNS and the GI system. The
most common adverse events (occurring
in 25% of patients in either treatment
group) were somnolence, dizziness, nau95
CLINICAL THERAPEUTICS”
Table VI. Adverse events.*
Overall no. (%) of patients reporting adverse events
No. (%) of patients reporting common adverse events?
Somnolence
Dizziness
Nausea
Headache
Constipation
Sweating
Vomiting
Pnlritus
HC/IB
OX/AC
(n = 75)
(n = 72)
47 (62.7)
45 (62.5)
19 (25.3)
15 (20.0)
13 (17.3)
6 (8.0)
5 (6.7)
4 (5.3)
3 (4.0)
3 (4.0)
10 (13.9)
8 (1 1.1)
13 (18.1)
10 (13.9)
6 (8.3)
1 (1.4)
7 (9.7)
5 (6.9)
HUB = combination hydrocodone 7.5 mg and ibuprofen 200 mg; OX/AC = combination oxycodone
acetaminophen 325 mg.
“There were no statistically significant differences between groups.
+Occurring in 25% of either treatment group.
sea, headache, constipation,
sweating,
vomiting, and pruritus. There were no statistically significant between-group differences in the proportion of patients experiencing any of the most common adverse
events. Only 1 patient (in the OX/AC
group) experienced a serious adverse event
(acute renal failure), and this was judged
to be unrelated to the study medication.
DISCUSSION
The results of this study suggest that
HC/lB and OX/AC (at a dosage of I tablet
every 4 to 6 hours, not to exceed 5 tablets
per day) are similarly effective in relieving moderate or severe acute low back
pain. At end point, the 2 treatments were
comparable on all measures of efficacy.
Pain relief scores improved significantly
in both groups (P < O.OOl), progressing
from slight to moderate relief at baseline
to moderate to good relief at end point.
Moreover, there was no statistically sig-
96
5 mg and
nificant difference in the proportion of patients experiencing
adverse events between the 2 groups. The types of adverse
events reported were consistent with those
associated with the component analgesics
and predominantly involved the CNS and
the GI system. Adverse events most commonly associated with HC/lB include constipation, dizziness, dyspepsia, headache,
nausea, and somnolence.22
An important limitation of this study was
the lack of control groups receiving either
placebo or the individual
components
of the 2 study medications.
However,
given the paucity of studies evaluating
fixed-dose combination opioid-nonopioid
analgesics in acute low back pain, this
study provides insight into the comparative efficacy and tolerability of 2 widely
used combinations
in this common pain
condition.
The results of this study are consistent
with those of our previous study,2” in
which a 2-tablet dose of HCLlB was as ef-
M. PALANGIO
ET AL.
fective as a 2-tablet dose of OX/AC in
treating moderate or severe postoperative
obstetric or gynecologic pain. Other studies have demonstrated the effectiveness of
various combination
opioid-nonopioid
analgesics in treating acute low back pain,
although the advantages of these combinations over single-entity
analgesics in
this condition are not clear. Wiesel et al”
compared combination oxycodone and aspirin (1 tablet QID), acetaminophen alone
(1 tablet BID), and codeine 60 mg alone
(QID) over 14 days in 75 patients with
acute low back pain. In that study, combination
oxycodone
and aspirin
and
codeine alone resulted in more pain relief
than did acetaminophen,
particularly
in
the first 3 days of treatment. Brown et alI2
compared combination codeine 30 mg and
acetaminophen 300 mg (1 tablet q4h after
an initial 2-tablet dose) with oral diflunisal 500 mg BID (after a lOOO-mg loading dose) in 40 patients with new-onset
and recurrent acute low back pain over
the course of 15 days. The analgesic efficacy of the 2 therapies was found to be
similar, although diflunisal appeared to be
better tolerated. Most recently, Innes et
al’” compared combination codeine 60 mg
and acetaminophen
600 mg (q4-6h as
needed, up to 6 daily doses) with ketorolac 10 mg (q4-6h as needed, up to 4 daily
doses) in a multicenter,
l-week trial in
123 patients treated in the emergency department for acute musculoskeletal
low
back pain. There were no significant differences in analgesic efficacy, functional
capacity, or overall pain relief between
the 2 treatment groups, although patients
treated with combination
codeine and
acetaminophen reported significantly more
adverse events. Cumulative evidence from
well-controlled clinical trials in a number
of other acute pain models, such as post-
operative pain, indicates that combinations
of opioid and nonopioid analgesics can
achieve an additive analgesic effect.14 Additional studies are needed to clarify the
role of fixed-dose combination analgesics
in the treatment of acute low back pain.
CONCLUSIONS
Based on the results of this study, HC/IB
may be considered an effective alternative to OX/AC in the treatment of acute
low back pain. Given that inflammation
may be an important part of several pain
syndromes,
including
acute low back
pain,’ there is theoretical justification for
the use of HC/IB rather than an opioidacetaminophen
combination.
Additional
controlled longitudinal
trials are necessary to evaluate the clinical utility of
HC/IB in treating acute low back pain.
ACKNOWLEDGMENTS
The authors thank Jianbo Xu of Abbott
Laboratories for his assistance with the
statistical analysis.
The study
investigators
included:
Charles Birbara, MD, Worcester, Mass;
Steven Elliott, MD, Evansville, Ind; John
Ervin, MD, Kansas City, MO; Larry Gilderman, DO, Pembroke Pines, Fla; Raymond Jackson, MD, Southfield,
Mich;
Chester Kessler, MD, Annandale,
Va;
Charles Kistler, DO, Columbus,
Ohio;
Jack Klapper, MD, Denver, Colo; Grant
McKeever,
MD, Houston, Tex; Barry
Miskin, MD, West Palm Beach, Fla; Douglas Owens, MD, Greer, SC; John Pappas,
MD, Lexington, Ky; Sanford Roth, MD,
Phoenix, Ariz; Michael Solomon, MD,
Dunedin, Fla; Mark Turner, MD, Boise,
Idaho; and Ralph Wade, DO, Bountiful,
Utah.
97
CLINICAL THERAPEUTICS@
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Address correspondence
to: Mark Palangio, MS, Abbott Laboratories,
Parkway, Parsippany, NJ 07054. E-mail: [email protected]
300 Interpace
99