72 Journal of Pain and Symptom Management Vol. 28 No.

1 July 2004

Review Article

A Comprehensive Review of Clinical Trials

on the Efficacy and Safety of Drugs
for the Treatment of Low Back Pain
Thomas J. Schnitzer, MD, PhD, Aimee Ferraro, MS, Elke Hunsche, Dip.rer.pol.,
and Sheldon X. Kong, PhD
Office of Clinical Research and Training (T.J.S.), Northwestern University, Chicago, Illinois;
Battelle Centers for Public Health Research and Evaluation (A.F.), Arlington, Virginia; and
Outcomes Research (E.H., S.X.K.), Merck & Co., Inc., Whitehouse Station, New Jersey, USA

Abstract
A systematic review involving 50 randomized controlled trials (4,863 patients) published
since 1980 was undertaken with the objective of assessing efficacy and safety of low back
pain (LBP) medications. The methodological quality of each trial was evaluated based on
a standardized system. Quality scores ranged from 26 to 82 points on a 100-point scale
(from 0 to 100), indicating an overall moderate quality of the trials reviewed. Limited
evidence was found regarding the effectiveness of drug treatments for LBP and current
studies focused on short-term usage of the therapies. Available evidence supported the
effectiveness of non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in acute and
chronic LBP, of muscle relaxants in acute LBP, and of antidepressants in chronic LBP;
safety results were heterogeneous. More rigorously designed trials should be implemented to
establish comparative efficacy and safety of drugs used to treat chronic and acute LBP. J
Pain Symptom Manage 2004;28:72–95. 쑖 2004 U.S. Cancer Pain Relief Committee.
Published by Elsevier Inc. All rights reserved.

Key Words
NSAIDs, antidepressants, muscle relaxants, analgesics, low back pain, efficacy, safety

Introduction activity limitation in people younger than 45

Chronic and acute low back pain are public
health problems affecting between 70% and
85% of adults at some time in their lives.1 The
annual prevalence of chronic LBP ranges from
15–45%, with point prevalences averaging
30%.2 In the United States, chronic and acute
back pain are the most common causes of
Address reprint requests to: Elke Hunsche, Dip.rer.pol.,
Outcomes Research, Merck & Co., Inc., WS 2E-76, P.O.
Box 100, Whitehouse Station, NJ 08889-0100, USA.
Accepted for publication: October 13, 2003.
years and the second most frequent reasons for
visits to physicians.3,4 Estimates from the UK
show LBP as the largest single cause of absence
from work in 1988–1989 and accounting for
12.5% of all sick days and over £11 billion in
direct and indirect costs in 2000.5,6 Likewise,
data from Sweden indicate that between 1961
and 1991, people diagnosed with chronic and
acute back pain accounted for 11–19% of all
annual sickness absence days.7 Direct costs due
to LBP vary from country to country and may
partially reflect the differences in the organiza-
tion of health care and insurance systems.

쑖 2004 U.S. Cancer Pain Relief Committee 0885-3924/04/$–see front matter

Published by Elsevier Inc. All rights reserved. doi:10.1016/j.jpainsymman.2003.10.015
Vol. 28 No. 1 July 2004 Drugs for the Treatment of Low Back Pain
Timely management and treatment of LBP
are essential to reduce the patient’s pain, re-
store physical functioning, and decrease the
burden of the disease on the patient as well as
on society. A broad range of therapies have
been advocated for the treatment of LBP, in-
cluding oral drugs, physical therapies (e.g., bed
rest, manipulation), surgical procedures, in-
jected drugs (local, intramuscular, epidural,
intradiscal), counterstimulation, and behav-
ioral as well as educational approaches.8 Even
within the realm of oral drugs, there is no con-
sensus about the gold standard of therapy.9,10
Clinical trials have investigated the efficacy and
safety of medications ranging from nonsteroidal
anti-inflammatory drugs (NSAIDs), muscle re-
laxants, and antidepressants to alternative thera-
pies like willow bark extract.
Defining low back pain is a complex task.
In general, acute LBP refers to 0–7 days of pain
(pain-free at onset), chronic LBP is defined as
pain lasting for more than three months, and
sub-acute LBP is classified as pain between
seven days and three months of duration.5
The purpose of this study was to undertake
a systematic review of the efficacy and safety of
oral therapies for the treatment of chronic and
acute LBP including an assessment of the qual-
ity of clinical trials published between January
1980 and October 2002. Methodological qual-
ity scores of each study were calculated to pro-
vide a quantitative measure of the confidence
in the data available. A meta-analysis was not
undertaken in this study due to an insuffi-
cient number of randomized controlled trials
(RCTs) for each individual intervention and
the lack of common efficacy and safety
endpoints assessed. The results of this review
re-confirm, more than 15 years later, the con-
clusion made by the Quebec Task Force on
Spinal Disorders in 19878 that there is still “little
clinical proof or epidemiologic validation to
support the current methods of treating disor-
ders of the spine.”
Methods
Search Strategies
RCTs published in English, French, German,
or Spanish were identified through online
search of the databases of Medline, Embase,
Healthstar, Cochrane, DARE, NSHEED, and
73
HTA (located at the website of the University of
York, UK). The following expressions were used
in combination as title and/or key word search
criteria: low back pain and anti-inflammatory agents/
non-nonsteroidal, muscle relaxant, paracetamol/
acetaminophen, colchicine, cortisone, antidepressant,
opioid, analgesic, oral steroid, or drug therapy (as a
general term).
Inclusion Criteria
A set of criteria was developed for trials to
be included in this review. These were:
• Treatment of chronic or acute LBP (in this
literature review, trials of sub-acute pain
were not included due to the less well-
defined natural history of this condition
and the possibility of greater heterogeneity
of response)
• Treatment with non-selective NSAIDs
(dual COX-1 and COX-2 inhibitors; no
publications of COX-2-selective inhibitors
were available), muscle relaxants, acet-
aminophen (paracetamol), opioid analge-
sics, colchicine, cortisone, antidepressants,
or other oral drugs for LBP
• Clinical trial published between January
1980 and October 2002 in peer-reviewed
and non-peer reviewed journals
• Randomized controlled clinical trial de-
sign (review articles were excluded)
• Clinical trial populations with men and/
or women 18–89 years of age
• Utilization of a quantitative clinical end-
point of efficacy and/or safety of the
drug therapies
Assessment of Methodological Quality
of Studies
Two reviewers blinded with respect to author,
author’s affiliation, and journal independently
assessed the methodological quality of the
RCTs according to the criteria developed by
Koes et al. (Table 1).11 This criteria set was
chosen because it is a published and empirically
tested approach for assessing the methodologi-
cal quality of RCTs specifically for LBP. All el-
igible trials were rated using this set of 16
criteria, which is based on generally accepted
principles of clinical research. Each criterion
was assigned a weight indicating its relative im-
portance. The maximum score for each RCT
was 100 points. Criteria b, c, e, j, k, m, and o were
74
Table 1
Evaluation Criteria for the Methodological
Assessment of Randomized Clinical Trials of Drug
Treatments for Low Back Pain
Criterion Weight
Study population
a. Homogeneity
b. Randomization procedure adequate
c. Similarity of relevant
baseline characteristics
d. Drop-outs described for each
study group separately
e. ⬍20% loss to follow-up
⬍10% loss to follow-up
f. ⬎50 subjects in the smallest group
⬎100 subjects in the smallest group
Treatment
g. Treatments included in
protocol described
h. Placebo-controlled
i. Pragmatic study
j. Co-treatment avoided
Effect
k. Patients blinded
l. Outcome measures relevant
m. Blinded outcome assessments
n. Follow-up period adequate
Data presentation and analysis
o. Intention to treat analysis
p. Frequencies of most important out-
comes presented for each treatment group
Total score 100
For details see Appendix A.
used to assess the internal validity of the trials.
Appendix A provides additional detail regard-
ing the scoring criteria in Table 1. When dis-
agreement occurred between the reviewers, a
meeting was held to reach a consensus. Meet-
ings were only called early in the review process
to rectify discrepancies in scoring for criteria c,
g, l, and m. Once a more explicit coding pro-
tocol was delineated, no more meetings were
necessary. This assessment method yielded a
scoring list, in which higher scores indicate
trials of higher methodological quality (Table
2).
This systematic review of randomized clinical
trials meets the majority of the recommenda-
tions for meta-analyses set by the Quality Of
Reporting Of Meta-analyses (QUOROM) state-
ment, which consist of a checklist of 18 items
including the reporting of search strategies,
selection criteria, validity assessment, data ab-
straction, study characteristics, and data synthe-
sis.12 Some of the checklist items do not apply
to this review, as they refer to meta-analytic ap-
proaches only.
Schnitzer et al. Vol. 28 No. 1 July 2004
For purposes of this review, methodological
scores for all 50 studies were divided into three
approximately equal groups to determine low,
medium, and high quality studies. This method
was used, as there is no published system of
categorization that is generally accepted. One-
2 third of studies (17) fell within the low quality
4
5 range of 0–46, slightly more than one-third (18)
within the medium quality range of 47–63, and
3 slightly less than one-third (15) within the high
2 quality range of 64–100. Studies of the same
2 score at the boundary of a range were placed
8 in the higher of the two groups, resulting in an
9
unequal split of the studies. The outcomes of
10 the studies are discussed in relation to their
methodological scores.
5
5
5 Efficacy and Safety Measures
Seven efficacy outcomes were identified and
5
10 assessed. Categories of efficacy included pain
10 intensity, patient global assessment of pain,
5 back pain-specific functional status, time to
5 return to work, back pain-related physiological
5 effects (i.e., range of motion, muscle strength,
etc.), generic functional status, and health care
consumption (i.e., consumption of analgesics
and health care costs). Withdrawals due to ad-
verse events and frequencies of specific adverse
events (e.g., gastrointestinal, CNS-related, and
sleep-related) were reviewed to assess the safety
of drug therapies. Appendix B details specific
efficacy and safety measures analyzed. For pur-
poses of this systematic review, significant im-
provement in at least two of the seven categories
of efficacy from baseline was considered suffi-
cient proof of efficacy of the respective treat-
ment, if the study was an active-comparator
controlled RCTs. For placebo-controlled RCTs,
significant difference in the treatment effects on
at least two efficacy endpoints between placebo
and the active comparator(s) was chosen as the
efficacy criterion. Although specific adverse
events are often reported, discontinuations
due to adverse events were considered as the
safety outcome of importance for this system-
atic review.
Data Extraction
Data were extracted from publications using
a standardized tabular format, including author,
year of publication, trial design, drug regimens,
efficacy outcomes, and adverse events (Table 3).
Three independent reviewers extracted data
 Vol. 28 No. 1 July 2004
Table 2
Methodological Scores of Clinical Trials in Low Back Pain
Scores for Method Criteria
Total Score
ID Author, Year a(2) b(4) c(5) d(3) e(4) f(17) g(10) h(5) i(5) j(5) k(5) l(10) m(10) n(5) o(5) p(5) (100)

Chronic
NSAIDs
3 Hickey, 198213 2 4 1 2 4 0 8 0 5 5 5 10 10 0 0 5 61
4 Videman and Osterman, 198414 1 1 3 2 4 0 8 0 5 0 5 8 8 0 0 5 50
1 Berry et al., 198215 2 1 0 2 4 0 8 5 5 5 5 4 4 0 0 2 47
2 De Moor and Ooghe, 198216 2 1 5 2 2 0 6 0 0 0 0 4 2 0 0 2 26
Antidepressants
9 Goodkin et al., 199017 2 1 5 3 4 0 8 5 5 5 5 8 10 0 0 5 76
Dickens et al., 200018

Drugs for the Treatment of Low Back Pain

8 2 4 5 0 4 0 10 5 5 5 2 8 10 0 5 5 70
6 Atkinson et al., 199919 2 4 5 3 0 0 10 5 5 0 5 6 10 0 5 5 65
7 Atkinson et al., 199820 2 4 5 3 0 0 8 5 5 0 5 6 10 0 5 5 63
11 Schreiber et al., 200121 2 4 4 2 0 0 8 0 5 5 2 4 8 0 0 5 49
5 Alcoff et al., 198222 2 1 3 3 2 0 6 5 0 0 5 8 8 0 0 2 45
10 Pheasant et al., 198123 2 1 3 3 0 0 6 0 0 0 5 6 2 0 0 5 33
Muscle Relaxants
12 Salzmann et al., 199224 2 1 4 2 0 8 10 5 5 5 5 10 8 0 5 5 75
Opioid Analgesics
14 Schnitzer et al., 200025 1 4 3 2 0 17 10 5 0 5 5 6 8 0 0 5 71
13 Muller et al., 199826 2 1 3 1 4 0 10 0 5 5 5 4 2 0 5 3 50
Mixed and Other
16 Chrubasik et al., 199927 2 2 5 2 4 8 8 5 5 5 5 6 4 0 5 5 71
15 Chrubasik et al., 200028 2 2 4 2 4 8 10 5 5 5 5 4 2 0 5 5 68
17 Worz et al., 199629 2 2 3 3 2 0 10 5 5 5 5 6 5 0 5 5 63
Acute
NSAIDs
19 Amlie et al., 198630 2 1 4 2 4 17 8 5 0 3 5 8 8 0 0 5 72
29 Szpalski and Hayes, 199431 2 1 5 2 4 0 8 5 5 5 5 6 10 0 0 5 72
26 Kuhlwein et al., 199032 2 4 4 3 4 8 8 0 5 5 5 8 9 0 0 5 70
28 Pohjolainen et al., 200033 2 4 5 1 4 8 6 0 5 5 5 8 10 0 0 5 68
25 Innes et al., 199734 1 4 4 0 4 8 8 0 5 3 5 6 6 5 0 5 64
20 Bakshi et al., 199435 2 1 5 2 0 8 8 0 5 5 5 6 8 0 5 3 63
(continued)

75
 76
Table 2
(Continued)
Scores for Method Criteria
Total Score
ID Author, Year a(2) b(4) c(5) d(3) e(4) f(17) g(10) h(5) i(5) j(5) k(5) l(10) m(10) n(5) o(5) p(5) (100)

31 Weber et al., 199336 2 1 3 0 4 8 10 5 0 5 5 6 6 0 0 5 59

27 Orava, 198637 2 1 5 1 4 8 8 0 5 0 5 10 0 0 0 5 54
23 Bruggemann et al., 199038 2 1 2 1 2 17 8 0 0 0 5 4 4 0 0 3 49
21 Borenstein et al., 199039 2 1 3 0 4 0 10 0 0 5 0 8 8 0 0 5 46
30 Valdes, 199240 2 1 3 0 0 0 6 0 5 5 5 4 8 0 0 5 44
22 Brown et al., 198641 2 1 1 0 2 0 8 0 5 5 2 8 2 0 0 3 39
24 Evans et al., 198042 1 2 1 0 4 0 10 0 5 5 0 6 2 0 0 0 36
18 Aghababian et al., 198643 2 1 3 1 0 0 8 0 5 0 0 8 0 0 0 3 31
Muscle Relaxants
35 Dapas et al., 198344 2 1 5 2 2 17 8 5 5 5 5 10 10 0 0 5 82
36 Ternelin, 199845 1 4 5 1 2 17 6 5 5 5 5 10 10 0 0 5 81

Schnitzer et al.
33 Berry and Hutchinson, 198846 2 1 3 2 4 8 6 5 5 5 5 6 6 0 0 5 63
32 Berry and Hutchinson, 198847 2 1 4 2 2 8 6 5 5 3 5 6 6 0 0 5 60
34 Bouchier-Hayes, 198448 2 1 2 0 2 0 6 5 5 5 0 6 4 0 0 5 43
Opioid Analgesics
37 Palangio et al., 200249 2 4 4 2 2 8 8 0 5 3 5 8 6 0 5 3 65
Mixed and Other
41 Marcel et al., 199050 1 1 5 2 4 0 8 5 5 5 5 8 8 0 0 5 62
42 Metscher et al., 200051 2 1 1 3 2 8 8 0 0 3 5 4 8 3 0 5 53
44 Monti, 200052 2 4 3 3 4 0 4 0 5 3 5 6 8 0 0 5 52
40 Haimovic and Beresford, 198653 2 4 3 2 0 0 8 5 5 0 5 6 2 5 0 3 50
43 Middleton, 198454 2 1 2 2 4 8 6 0 5 5 2 4 2 0 0 3 46
46 Sweetman et al., 198755 2 1 4 0 2 0 6 0 0 0 5 10 10 0 0 5 45
45 Stein et al., 199656 2 1 3 2 2 0 6 0 5 5 5 4 8 0 0 5 43
39 Dominguez, 200157 1 1 1 0 0 0 6 0 0 0 5 6 9 2 0 5 36
38 Basmajian, 198858 0 1 1 0 4 0 6 5 5 0 5 2 2 0 0 2 33
Chronic and Acute

Vol. 28 No. 1 July 2004

NSAIDs
47 Aoki et al., 198359 0 1 2 0 4 17 8 0 5 0 5 8 8 0 0 0 58
48 Stevanovic, 198660 2 1 3 0 4 0 4 0 0 5 5 6 10 0 0 3 43
49 Waikakul and Soparat, 199561 1 4 3 1 4 0 8 0 0 0 0 8 8 0 0 5 42
Mixed and Other
50 Schnebel and Simmons, 198762 2 1 3 2 4 0 2 0 0 0 0 4 6 5 0 5 34
 Vol. 28 No. 1 July 2004
Table 3
Summary of Drug Treatment Studies for Chronic and Acute Low Back Pain
ID Author, Year Studya LOEb Regimen Efficacy Results Adverse Events (AE)

Chronic
NSAIDs
1 Berry et al., 198215 R, DB, C, PC, 2 1b Patients randomly assigned Evaluations of reduction of global pain using 18 patients while on naproxen sodium,
weeks n ⫽ 37 to 6 different orders of Visual Analog Scale (VAS) and Simple 16 on diflunisal, and 18 on placebo
treatment: Descriptive Scale were significantly better for reported AEs; 11 patients
■ naproxen sodium 550 naproxen sodium versus placebo (P ⬍ 0.01); discontinued drug treatments; only 4
mg 2/day and naproxen sodium versus diflunisal—VAS patients discontinued without taking
■ diflunisal 500 mg 2/day measure only—(P ⬍ 0.05); significant all three treatments
■ placebo preference for active treatments as

Drugs for the Treatment of Low Back Pain

compared to placebo (P ⬍ 0.05)
2 De Moor and R, M, 8 weeks 1b ■ indomethacin 50 mg 3/ Statistically significant differences were seen in 7 indomethacin patients vs. 1
Ooghe, 198216 n1 ⫽ 30 n2 ⫽ 30 day favor of oxamethacin after 4 weeks for oxamethacin patient withdrew due to
■ oxamethacin 100 mg decrease in pain intensity (P ⬍ 0.05) and AEs (P ⬍ 0.10); 33.3% of
3/day patients’ positive assessment of therapy indomethacin patients vs. 13.3% of
(P ⫽ 0.2); disappearance of symptoms by the oxamethacin patients reported AEs
end of treatment was seen among 53% of (P ⬍ 0.10), primarily gastrointestinal
indomethacin patients vs. 67% of
oxamethacin patients
3 Hickey, 198213 R, DB, 4 weeks 1b ■ diflunisal 500 mg 2/day 4 paracetamol patients vs. 10 diflunisal patients 1 paracetamol patient withdrew due to
n1 ⫽ 16 n2 ⫽ 14 ■ paracetamol 1000 mg considered the therapy efficacy ‘good’ or AEs; 2 diflunisal patients reported
4/day ‘excellent’ (P ⫽ 0.01); 1 paracetamol patient AEs: mild nausea, mild generalized
withdrew due to inefficacy bruising and nose bleeds
4 Videman and R, DB, P, 6 weeks 1b ■ indomethacin 25 mg Average change of pain (horizontal analog 2 patients in indomethacin group
Osterman, 198414 n1 ⫽ 14 n2 ⫽ 14 tid scale) from initial to 6 weeks: 17.6 to 8.2 for withdrew due to AEs; 13
■ piroxicam 20 mg once indomethacin (P ⬍ 0.001), 18.0 to 9.9 for indomethacin patients vs. 6 piroxicam
a day plus placebo 2/ piroxicam (P ⬍ 0.01), no significant patients reported AEs
day difference between groups; number of
patients with severe limitation diminished in
both groups
Antidepressants
5 Alcoff et al., 198222 R, DB, PC, 8 weeks 1b ■ imipramine Statistically significant clinical parameters 5 imipramine patients withdrew due to
n1 ⫽ 28 n2 ⫽ 22 hydrochloride 75 mg 2/ comparing imipramine vs. placebo: number AEs: dry mouth, constipation,
day of days had to lie down for 2 hours or more lethargy and impaired sexual
■ placebo 2/day (P ⫽ 0.002), number of days with at least function; 22 of 28 patients (78.6%)
some restriction of normal activity on imipramine reported dry mouth
(P ⫽ 0.004), limitation of work (P ⫽ 0.004),
limitation of recreational activities
(P ⫽ 0.001)
(continued)

77

Table 3
(Continued)
ID Author, Year Studya LOEb Regimen
6 Atkinson et al., R, DB, PC, 8 weeks 1b ■ maprotiline 150 mg
199919 n1 ⫽ 33 n2 ⫽ 34 daily
n3 ⫽ 36 ■ paroxetine 30 mg daily
■ diphenhydramine
(placebo) 37.5 mg
7 Atkinson et al., R, DB, PC, 8 weeks 1b ■ nortriptyline 25 mg
199820 n1 ⫽ 38 n2 ⫽ 40 daily for 3 days, 50 mg
daily for 4 days, 75 mg
daily for 3 days, and 100
mg daily for 4 days
■ placebo
8 Dickens et al., R, SB, PC, 56 days 1b ■ paroxetine 20 mg daily Montgomery Asberg Depression Rating Scale,
200018 n1 ⫽ 44 n2 ⫽ 48 ■ placebo
9 Goodkin et al., R, DB, PC, 6 weeks 1b ■ trazodone 50 mg 3/day Pain intensity (Visual Analog Scale), daily life
199017 n1 ⫽ 22 n2 ⫽ 20 for 3 days then increase
trazodone by 50 mg
every third day to
maximum of 200 mg 3/
day
■ placebo
10 Pheasant et al., R, DB, C, 16 weeks 2b ■ amitriptyline 50 mg for 6 Atropine phase: average analgesic usage was
198123 n1 ⫽ 6 n2 ⫽ 10 weeks, bitter lactose wash-
out for 2 weeks, atropine
(placebo) 0.2 mg for 6
weeks, bitter lactose
washout for 2 weeks
■ atropine, washout,
amitriptyline, washout
78
Efficacy Results Adverse Events (AE)
Mean decrease in pain intensity (Descriptor 29 patients withdrew or were dropped
Differential Scale score) was significantly due to AEs, reasons for withdrawal
greater (P ⫽ 0.023) for maprotiline were similar in each group; most
(5.41 ⫾ 4.99) compared to placebo frequently reported AEs were dry
(2.83 ⫾ 3.31); reduction of pain intensity was mouth, insomnia, and sedation
significantly greater (P ⫽ 0.013) for
maprotiline compared to paraoxetine
(2.34 ⫾ 3.52); reduction of pain by 45% vs.
26% vs. 27%
Reduction, in pain intensity measured by Frequency of AEs for patients on
Descriptor Differential Scale for pre-post nortriptyline (28 of 38) was higher
change was significantly greater (P ⫽ 0.055) compared to those on the placebo
for patients on nortriptyline (2.59) as (29 of 40); none of the differences
compared to placebo (0.91); patients on were statistically significant
nortriptyline had a 22% reduction in pain as
compared to 9% on placebo; reduction in
disability measured by Sickness Impact Profile
for pre-post change was significantly greater
Schnitzer et al.
(P ⫽ 0.055) for patients on nortriptyline
(2.85) as compared to placebo (1.05)
None reported
Oswestry Disability Index, and Visual Analog
Scale were used to evaluate the relationship
between pain, depression, and disability;
association of change in depression scores
with change in pain (r ⫽ 0.025, P ⫽ 0.016)
was weaker than change between depression
and disability (r ⫽ 0.49, P ⬍ 0.0005)
3 trazodone patients discontinued
function (Sickness Impact Profile), treatment due to AEs (confusion,
depression (Beck Depression Inventory), peripheral edema, and agitation)
physical activity (Vitalog-PMS-8), and blood
and urine screens were evaluated from
baseline every 2 weeks with no significant
differences between groups—demonstrating
Vol. 28 No. 1 July 2004
no significant advantage for trazodone in
treatment of chronic low back pain
7 patients withdrew due to AEs and
8.7 per week; amitriptyline phase: average other factors; 1 patient reported
usage decreased significantly (46%) to 4.7 sleepiness, dry mouth, bitter taste,
analgesics per week (P ⬍ 0.005) occasional ringing of the ears and
spotted vision during the
amitriptyline phase
(continued)
 Vol. 28 No. 1 July 2004
Table 3
(Continued)
ID Author, Year Studya LOEb Regimen Efficacy Results Adverse Events (AE)

11 Schreiber et al., R, SB, 6 weeks 1b ■ amitriptyline 50–75 mg Moderate or good relief of pain was reported 5 patients dropped out due to AEs: 3
200121 n1 ⫽ 20 n2 ⫽ 20 daily by 82% of the patients on amitriptyline and on amitriptyline and 2 on fluoxetine
■ fluoxetine 20 mg daily 77% of the patients on fluoxetine,
difference between groups was not
significant
Muscle Relaxants
12 Salzmann et al., R, DB, M, PC, 2 1b ■ tetrazepam 50 mg 3 All pain and movement parameters (reduction 4 tetrazepam patients withdrew due to
199224 weeks n1 ⫽ 55 tablets 2/day of daytime pain, reduction of night-time AEs; sleepiness and/or dizziness were
n2 ⫽ 48 ■ placebo 3 tablets 2/day pain, improvement of left/right rotation, most common AEs for both groups
normalization of Schober’s index, etc.)
showed statistically significant improvement
in both groups at Day 14 as compared to

Drugs for the Treatment of Low Back Pain

baseline; the superiority of tetrazepam
reached statistical significance of (P ⫽ 0.011)
after 7 days treatment
Opioid Analgesics
13 Muller et al., 199826 R, DB, C, 15 days 1b ■ paracetamol 500 mg Patients’ assessment of treatment as ‘good’ or 10 paracetamol patients vs. 9 tramadol
n ⫽ 55 and codeine 30 mg 3/ ‘satisfactory’ were similar for paracetamol patients withdrew due to AEs; same
day for 7 days (80%) and tramadol (81%) treated patients; percent of patients receiving
■ tramadol 50 mg 3/day more paracetamol (80%) preferred paracetamol or tramadol reported at
for 7 days treatment as compared to tramadol (69%) least one or more AEs (69%)
14 Schnitzer et al., R, DB, O, P, PC, 4 1b ■ tramadol 200–400 mg Kaplan-Meier estimate of the cumulative 5 of 127 tramadol patients and 6 of 127
200025 weeks n1 ⫽ 127 daily discontinuation rate due to therapeutic placebo patients discontinued
n2 ⫽ 127 ■ placebo capsules daily failure was 20.7% in the tramadol group and treatment during the double-blind
51.3% in the placebo group; mean pain phase due to AEs; commonly
Visual Analog Scores (10-cm scale) among reported AEs with tramadol included
tramadol patients (3.5 cm) was significantly nausea, dizziness, somnolence, and
lower (P ⱕ 0.001) compared to placebo headache
patients (5.1 cm) at the final visit of the
double-blind phase; tramadol patients scored
significantly better on McGill Pain
Questionnaire (P ⫽ 0.0007) and the Roland
Disability Questionnaire (P ⫽ 0.0001)
Mixed and Other
15 Chrubasik et al., R, DB, PC, 4 weeks 1b ■ willow bark extract 120 Proportion of patients who were pain-free as 1 patient suffered a severe allergic
200028 n1 ⫽ 70 n2 ⫽ 70 mg daily measured on a Visual Analog Scale in the reaction to the extract; 2 patients with
n3 ⫽ 70 ■ willow bark extract 240 last week of treatment was 35% in the group short lasting AEs on the high dose
mg daily receiving high dose of extract, 21% on low- group dropped out; 6 patients on
■ placebo dose extract, and 6% on placebo placebo reported mild AEs
(P ⬍ 0.001); significantly more patients on
placebo required tramadol (P ⬍ 0.001)
during each week of the study
(continued)

79
 80
Table 3
(Continued)
ID Author, Year Studya LOEb Regimen Efficacy Results Adverse Events (AE)

16 Chrubasik et al., R, DB, PC, 4 weeks 1b ■ Harpogophytum extract Number of patients who were pain free
199927 n1 ⫽ 66 n2 ⫽ 65 1531 400 mg 3/day
n3 ⫽ 66 ■ Harpogophytum extract
1531 200 mg 3/day
■ lactose placebo 3/day
17 Worz et al., 199629 R, DB, M, P, PC, 1 1b ■ flupirtine maleate 400
week n1 ⫽ 46 mg 4/day (increase of
n2 ⫽ 46 n3 ⫽ 48 dosage over first 5 days)
■ chlormezanone 800 mg
4/day (increase of
dosage over first 5 days)
■ placebo
8 patients withdrew due to AEs: 1 in
without tramadol for at least 5 days in the 1200 mg group (allergic reaction), 6
4th week of treatment: 10 vs. 6 vs. 3 in 600 mg group (virus infections,
(P ⫽ 0.027); median relative change in psychosomatic symptoms, mucorrhea,
overall Arhus Index: 18 vs. 21 vs. 21 (change and skin reaction), 1 in placebo
in each group significant from zero but not group (cardiovascular complaints)
significantly different changes between
groups); 6 patients withdrew due to lack of
efficacy (unbearable pain)
Reduction of pain intensity/stiffness by at least 12 patients withdrew due to AEs: 3
two levels on 5 point scale: 60.9%, 47.8%, flupirtin-maleat, 7 chlormezanone, 2
43.8% (difference to placebo not placebo; incidence of AEs: 14.8%
significant); ‘very good’ or ‘good’ global flupirtine-maleate (3 sleepiness, 1
evaluation by investigator: 47.8%, 45.6%, nausea, 1 dizziness, 4 other), 19.3%
33.4% (flupirtine-maleate significantly better chlormezanone (5 sleepiness, 4 nausea,
than placebo, P ⫽ 0.007) 3 dizziness, 2 headache, 6 other), 7.3%
placebo (2 sleepiness, 5 other)

Schnitzer et al.
Acute
NSAIDs
18 Aghababian et al., R, O, 15 days 2b ■ diflunisal 1000 mg Patients reporting ‘free of pain’ at Day 15 was No patients reported any AEs
198643 n1 ⫽ 16 n2 ⫽ 17 initially then 500 mg 2– greater for diflunisal treated (81%) as
3/day compared to naproxen treated (41%)
■ naproxen 500 mg patients; 81% of patients on diflunisal rated
initially then 250 mg 3– its overall efficacy as ‘very good’ or
4/day ‘excellent’ as compared to 35% of patients
on naproxen
19 Amlie et al., 198630 R, DB, P, PC, 1 1b ■ piroxicam 40 mg 1/day Piroxicam treated patients reported significant 18 (13%) piroxicam patients vs. 24
week n1 ⫽ 140 for 2 days then 20 mg 1/ reduction in Visual Analog Scale scores in (17%) placebo patients reported AEs;
n2 ⫽ 142 day plus paracetamol pain in lying (P ⬍ 0.001), sitting (P ⬍ 0.01), no significant differences in reports
1000 mg 3–4/day as and standing (P ⬍ 0.01) from baseline at Day of AEs between treatment groups
needed 3 as compared to placebo but no significant
■ placebo plus difference at Day 7; significantly greater
paracetamol 1000 mg 3– number of piroxicam treated patients at Day
4 times as needed 7 regained normal back function and
returned to work (P ⬍ 0.05) as compared to

Vol. 28 No. 1 July 2004

20 Bakshi et al., 199435 R, DB, M, 2 weeks
n1 ⫽ 66 n2 ⫽ 66
placebo; piroxicam treated patients consumed
significantly less analgesics (P ⬍ 0.05)
1b ■ diclofenac resinate 75 Investigators’ opinion of efficacy as ‘excellent’ 1 diclofenac patient vs. 3 piroxicam
mg 2/day or ‘good’: 78.8% vs. 83.3%; positive patients withdrew due to
■ piroxicam 20 mg once assessment of therapy by patients: 81.8% vs. gastrointestinal AEs; incidence of AEs:
a day 87.7%; 10 diclofenac vs. 5 piroxicam patients 19.7% vs. 18.2%
withdrew due to early cure; 2 vs. 1 withdrew
due to inefficacy
(continued)
 Vol. 28 No. 1 July 2004
Table 3
(Continued)
ID Author, Year Studya LOEb Regimen Efficacy Results Adverse Events (AE)

21 Borenstein et al., R, O, 2 weeks 1b ■ naproxen 500 mg Patients treated with combination of naproxen 12 naproxen and cyclobenzaprine
199039 n1 ⫽ 20 n2 ⫽ 20 initially then 250 mg 4/ and cyclobenzaprine reported significantly patients vs. 4 naproxen only patients
day less objective muscle spasm and tenderness reported AEs; AEs significantly
■ naproxen 500 mg (P ⬍ 0.05) and greater maximum motion of greater for combination treatment
initially 250 mg 4/day lumbosacral spine (using Schober’s test); no (P ⬍ 0.05) including drowsiness; no
plus cyclobenzaprine 10 significant differences in measures of patient discontinued treatment due to
mg 3/day functional capacity or pain scores between AE
treatment groups
22 Brown et al., 198641 R, SB, O, 15 days 1b ■ diflunisal 1000 mg once Pain relief assessment: diflunisal patients 3 diflunisal patients vs. 5
n1 ⫽ 19 n2 ⫽ 21 initially then 500 mg 2/ experienced mild pain between Days 7 and acetaminophen/codeine patients
day 9 with complete pain relief between Days 12 reported one or more AEs; none of
■ acetaminophen 300 mg and 15; acetaminophen patients experienced the AEs caused any patient to stop

Drugs for the Treatment of Low Back Pain

twice initially then 6/
day plus codeine 30 mg
twice initially then 6/
day
23 Bruggemann et al., R, DB, M, P, 2 1b ■ diclofenac 25 mg plus 56.5% of combination drug patients had no
199038 weeks n1 ⫽ 184 vitamins B1 50 mg, B6 50
n2 ⫽ 192 mg, and B12 0.25 mg 3/
day
■ diclofenac 25 mg
(option to terminate
after 1 week in case of
total pain relief)
24 Evans et al., 198042 R, C, 3 weeks 1b Patients prescribed 3 of Daily pain scores: significantly lower
n ⫽ 60 the following drugs
administered
consecutively for 1 week
each:
■ aspirin 300 mg 3 tablets
4/day
■ dextropropoxyphene
32.5 mg plus
paracetamol 325 mg 2
tablets 4/day
■ indomethacin 50 mg 1
capsule 3/day
■ mefanamic acid 250 mg
2 capsules 3/day
■ paracetamol 500 mg 2
tablets 4/day
■ phenylbutazone 100 mg
1 tablet 3/day
complete pain relief at Day 12 with return of taking the assigned medication
mild pain between 12 and 15 days; drug
acceptability: 4 diflunisal patients vs. 1
acetaminophen/codeine patient rated the
drug as ‘excellent’
No significant difference in AEs; 5.7%
or minor pain after 1 week vs. 49.0% of vs. 3.3% finished the study early due
diclofenac only patients; 56.4% vs. 45.1% to gastrointestinal complaints;
improved from ‘strong/unbearable’ pain to dizziness and headache were also
‘no/minor’ pain after 1 week (statistically reported
significant); 53 vs. 48 patients terminated
study early after 1 week due to total pain
control (difference not statically significant)
Number of patients reporting AEs: 20,
(P ⬍ 0.05) during mefanamic acid treatment 19, 19, 12, 13, 4; number of patients
than during paracetamol and citing AEs as reason for default with
dextropropoxyphene plus paracetomal trial medications: 10, 13, 14, 2, 4, 1
treatments, significantly lower (P ⬍ 0.05)
during aspirin treatment than during
dextropropoxyphene plus paracetamol
treatment; percentage of recommended
doses acceptable to patients: 80.2, 71.7, 76.2,
91.8, 89.8, 96.5, significant between groups
(P ⬍ 0.05); number of defaults in treatment:
13, 17, 14, 8, 9, 6,; patients chose
phenylbutazone and mefanamic acid
significantly more often than aspirin
(P ⬍ 0.05)

81
(continued)
 82
Table 3
(Continued)
ID Author, Year Studya LOEb Regimen Efficacy Results Adverse Events (AE)

25 Innes et al., 1997 34

R, DB, M, 9 days 1b ■ ketorolac 10 mg 4 times Pain intensity measured by Visual Analog 21 ketorolac patients vs. 38
n1 ⫽ 63 n2 ⫽ 60 up to 6/day as needed Scores was not significantly different acetaminophen/codeine patients
■ acetaminophen 600 mg between ketorolac and acetaminophen/ reported at least one or more AEs
with codeine 60 mg 4 codeine treated patients; no significant (P ⫽ 0.0005); 2 ketorolac patients vs.
times up to 6/day as differences in analgesic efficacy, functional 10 acetaminophen/codeine patients
needed capacity, or overall pain relief between reported severe AEs (P ⬍ 0.003); 7
ketorolac and acetaminophen-codeine acetaminophen/codeine treated
treated patients patients withdrew from the study due
to severe AEs (P ⫽ 0.005)
26 Kuhlwein et al., R, DB, M, P, 1 week 1b ■ diclofenac 25 mg plus Pain difference from baseline to Day 3–4: day 1 patient from diclofenac only group
199032 n1 ⫽ 61 n2 ⫽ 61 vitamins B1 50 mg, B6 pain 42.18 vs. 24.03 (P ⫽ 0.001), night pain withdrew due to AE (stomach pain) 1
50 mg, and B12 0.25 mg 28.87 vs. 18.56 (P ⫽ 0.006); mobility pain: patient withrew due to heartburn in
3/day after 3–4 days no pain in 39% vs. 18% combination group
■ diclofenac 25 mg (P ⫽ 0.003), after 7 days no pain in 76% vs.
(option to terminate 46% (P ⬍ 00.5); improvement of mobility

Schnitzer et al.
after 3–4 days in case of parameters: Schober’s sign (P ⫽ 0.012),
total pain relief) Lasegue’s sign (P ⫽ 0.006), finger-bottom-
difference (P ⫽ 0.011), bending to left
(P ⫽ 0.02), bending to right (P ⫽ 0.004); 45
patients stopped treatment early due to total
pain relief: 30 on combination therapy, 15
on diclofenac alone (P ⬍ 0.05); treatment
failure due to lack of efficacy: 6 vs. 13
27 Orava, 198637 R, DB, 1 week 1b ■ diflunisal 500 mg 2/day Pain at rest was reduced to the same extent in 2 diflunisal patients and 6 indomethacin
n1 ⫽ 66 n2 ⫽ 67 ■ indomethacin 50 mg 3/ both groups; patients’ and investigators’ patients withdrew due to AEs
day overall opinion of the treatment efficacy on (P ⬍ 0.05); 18 AEs in 12 diflunisal
Day 7 showed ‘good’ results with no patients; 26 AEs in 21 indomethacin
differences between groups patients
28 Pohjolainen et al., R, DB, 10 days 1b ■ nimesulide 100 mg 2/ Patients’ capacity for daily tasks showed more gastrointestinal AEs were reported
200033 n1 ⫽ 52 n2 ⫽ 52 day improvement in both groups (P ⬍ 0.001), with ibuprofen than nimesulide
■ ibuprofen 600 mg 3/ but a significant difference was found (P ⫽ 0.067); 10 AEs in 7 nimesulide
day between the two groups in favor of patients; 13 AEs in 11 ibuprofen
nimesulide (P ⬍ 0.05) after 10 days patients

Vol. 28 No. 1 July 2004

29 Szpalski and Hayez, R, DB, P, PC, 2 1b ■ tenoxicam 20 mg I.M. Both tenoxicam and placebo treated groups 1 tenoxicam treated patient reported an
199431 weeks n1 ⫽ 37 injection Day 1 then produced significant improvement from AE
n2 ⫽ 36 tenoxicam 20 mg once a baseline in all dynamometric measures
day (P ⬍ 0.05); tenoxicam treated patients had
■ placebo once a day more significant improvement in velocity
(P ⫽ 0.07) and isometric torque in
extension (P ⫽ 0.022)
(continued)
 Vol. 28 No. 1 July 2004
Table 3
(Continued)
ID Author, Year Studya LOEb Regimen Efficacy Results Adverse Events (AE)

30 Valdes, 199240 R, DB, P, 2 weeks 1b ■ nimesulide 200 mg Nimesulide was significantly more effective AEs reported: 16.7% nimesulide (2
n1 ⫽ 30 n2 ⫽ 30 once a day than piroxicam in reducing spontaneous nausea, 2 abdominal pain, 1
■ piroxicam 20 mg once pain (P ⬍ 0.05) and functional impotence dizziness) vs. 36.7% piroxicam (6
a day (P ⬍ 0.01) nausea, 4 abdominal pain, 1
cutaneous rash)
31 Weber et al., R, DB, PC, 4 weeks 1b ■ piroxicam 40 mg once Evaluation of severity of pain measured by 22 piroxicam patients vs. 13 placebo
199336 n1 ⫽ 120 n2 ⫽ 94 a day for 2 days then 20 physician’s exam from baseline to Week 4 patients reported AEs
mg once a day plus was not significantly different in patients
paracetamol 5 mg as treated with piroxicam vs. placebo; pain in
needed back and leg measured by Visual Analog

Drugs for the Treatment of Low Back Pain

■ placebo plus Scale from baseline at Week 4 was not
paracetamol 5 mg as significantly different for patients treated
needed with piroxicam vs. placebo
Muscle Relaxants
32 Berry and Hutchin- R, DB, P, PC, 1 1b ■ tizanidine 4 mg 3/day Evaluation of sciatica, restriction of movement, 24 tizanidine patients vs. 11 placebo pa-
son, 198847 week n1 ⫽ 59 plus aspirin 300 mg pain on movement, pain at rest, and pain at tients reported AEs; significantly more
n2 ⫽ 54 taken as needed night using a Simple Descriptive Scale were tizanidine patients reported central
■ placebo plus aspirin not significantly different between tizanidine nervous system events compared to
300 mg taken as needed and placebo treated patients from baseline placebo patients (P ⬍ 0.003); signifi-
at Days 3 or 7; aspirin consumption was sig- cantly fewer tizanidine patients re-
nificantly lower from baseline to Day 3 ported gastrointestinal events as
(P ⬍ 0.037) and Day 7 (P ⬍ 0.094) for tizani- compared to placebo pa-
dine treated patients tients (P ⬍ 0.018)
33 Berry and Hutchin- R, DB, P, PC, 1 1b ■ tizanidine 4 mg 3/day Significant differences between treatments fa- 5 tizanidine/ibuprofen patients vs. 1 pla-
son, 198846 week n1 ⫽ 51 plus ibuprofen 400 mg voring tizanidine/ibuprofen occurred in cebo/ibuprofen patient withdrew due
n2 ⫽ 54 3/day patients with moderate or severe pain at to AEs; tizanidine/ibuprofen patients
■ placebo plus ibuprofen night (P ⬍ 0.05), at rest (P ⬍ 0.05), on walk- reported significantly fewer gastroin-
400 mg 3/day ing (P ⬍ 0.29) and sciatica (P ⬍ 0.05); over- testinal events vs. placebo/ibuprofen
all helpfulness of treatment for tizanidine/ patients (P ⬍ 0.002); tizanidine/ibu-
ibuprofen was significantly better than pla- profen patients reported significantly
cebo/ibuprofen at Day 3 (P ⬍ 0.05) greater number of central nervous
system events vs. placebo pa-
tients (P ⫽ 0.025)
34 Bouchier-Hayes, R, PC, 5 days 1b ■ chlormezanone 200 mg Visual Analog Score: both groups showed simi- no AEs reported in chlormezanone
198448 n1 ⫽ 25 n2 ⫽ 24 3/day lar reductions in pain over 5 days which group; 2 patients reported AEs in pla-
■ placebo 3/day were statistically significant (P ⬍ 0.05) cebo group: headache, sore eyes, and
number of patients fit for full duty by Day 3: tiredness
7 chlormezanone patients vs. 0 placebo pa-
tients (P ⬍ 0.01)
(continued)

83

Table 3
(Continued)
ID Author, Year Studya LOEb Regimen
35 Dapas et al., 198344 R, DB, PC, 2 weeks 1b ■ baclofen 30–80 mg
n1 ⫽ 100 daily
n2 ⫽ 100 ■ placebo tablets 4/day
36 Ternelin, 199845 R, DB, M, P, PC, 1 1b ■ tizanidine 2 mg plus
week n1 ⫽ 185 diclofenac 50 mg 2/day
n2 ⫽ 176 ■ placebo plus diclofenac
50 mg 2/day
Opioid Analgesics
37 Plangio et al., R, DB, M, P, 8 days 1b ■ hydrocodone 7.5 mg
200249 n1 ⫽ 75 n2 ⫽ 72 plus ibuprofen 200 mg
(HC/IB) up to 5/day
■ oxycodone 5 mg plus
acetaminophen 325 mg
(OX/AC) up to 5/day
Mixed and Other
38 Basmajian, 198858 R, DB, M, P, PC, 7- 1b ■ cyclobenzaprine
10 days n1 ⫽ 43 (Flexeril) 5 mg plus
n2 ⫽ 44 n3 ⫽ 43 diflunisal (Dolobid) 500
n4 ⫽ 45 mg 2/day
■ cyclobenzaprine 5 mg
2/day
■ diflunisal 500 mg 2/day
■ placebo
39 Dominguez, 200157 R, DB, P, 2 weeks 1b ■ meloxicam 7.5 mg plus Proportion of patients with lumbar
n1 ⫽ 15 n2 ⫽ 15 methocarbamol 215 mg
2/day
■ acetylsalicylic acid
(ASA) 325 mg plus
methocarbamol 400 mg
2/day
84
Efficacy Results Adverse Events (AE)
Baclofen scored significantly better (P ⬍ 0.05) 17 baclofen patients withdrew due to
than placebo on all efficacy variables AEs; 67 (68%) baclofen patients vs.
(lumbar pain, local tenderness, paravertebral 29 (30%) placebo patients reported
muscle spasm, interference with daily AEs: 30 of the 67 baclofen patients
activity, limitation of motion, straight-leg- who reported AEs required a
raising test, forward flexion, physician’s reduction in dosage from 80 mg per
opinion, patient’s opinion) when compared day to 60 or 40 mg per day, 28 of
between baseline and Day 14 for patients these 30 patients’ AEs disappeared
with severe symptoms at baseline
Pain scores at rest, movement, and night 22 (12%) tizanidine patients vs. 56
decreased significantly (P ⬍ 0.05) between (32%) placebo patients reported
baseline and Day 8 for both groups, the gastrointestinal AEs (P ⬍ 0.001); 33
decrease was greater in tizanidine group (18%) vs. 18 (10%) reported AEs of
than in placebo group for all variables the central nervous system (P ⬍ 0.05)
(P ⬍ 0.05); overall assessment of efficacy as
‘good’ or ‘very good’: 72% vs. 58%
(P ⬍ 0.05)
Schnitzer et al.
No significant differences between HC/IB and No significant differences in the
OX/AC with regard to mean daily pain proportion of patients experiencing
relief scores, mean daily number of tablets AEs with HC/IB (47, 62.7%) and
of study medication, mean daily number of OX/AC (45, 62.5%)
tablets of supplemental analgesic
medication, global evaluations, or mean
scores on the modified Short-Form Health
Survey (SF-36)
There was little statistically significant None reported
difference between global ratings of cohort
groups except at Day 4, at which time the
combined cyclobenzaprine/diflunisal
showed more improvement (P ⫽ 0.003) and
global ratings showed a significant
difference between groups (P ⫽ 0.006)
Vol. 28 No. 1 July 2004
None reported
inflammation: drop from 80% to 13% with
meloxicam vs. 87% to 40% with ASA
(P ⬍ 0.05); reduction of ‘moderate’ or
‘severe’ pain assessment from baseline to
Day 7: 100% to 60% of meloxicam patients
vs. 93% to 13% of ASA patients (between
groups, P ⬍ 0.05)
(continued)
 Vol. 28 No. 1 July 2004
Table 3
(Continued)
ID Author, Year Studya LOEb Regimen Efficacy Results Adverse Events (AE)

40 Haimovic and R, DB, PC, 1 week 1b ■ dexamethasone 64 mg Early improvement (within 7 days), late None reported
Beresford, 198653 n1 ⫽ 21 n2 ⫽ 12 Day 1, 32 mg Day 2, 16 improvement (within 1 year) and sustained
mg Day 3, 12 mg Day 4, improvement (more than a year) in resting
and 8 mg Days 5 to 7 low-back pain or radicular pain on passive
■ placebo once a day straight-leg raising was not different for
patients on dexamethasone as compared to
those on placebo
41 Marcel et al., R, DB, M, PC, 5 1b ■ thiocolchicoside 4 mg Patient assessment of ‘good’ or ‘excellent’: 4 in the placebo group (dizziness,
199050 days n1 ⫽ 49 2/day 38.7% vs. 14.2% at Day 2 (P ⫽ 0.0002); fatigue, diarrhea, abdominal pain)
n2 ⫽ 49 ■ placebo 2/day 69.4% vs. 32.6% at Day 5 (P ⫽ 0.001); and 4 in the thiocolchicoside group
decrease in the spontaneous pain and (2 diarrhea, paresthesia, sleepiness)
moving disability: no significant difference

Drugs for the Treatment of Low Back Pain

between groups at Day 2; placebo group
patients interrupted treatment for inefficacy
and were prescribed NSAIDs instead, so only
Day 2 results were taken into account
42 Metscher et al., R, DB, M, P, 1 week 1b ■ dextroprofen- Significant reduction of mobility pain after 4 Significantly fewer AEs (causal
200051 n1 ⫽ 97 n2 ⫽ 95 trometamol 25 mg 3/ days in dextroprofen-trometamol patients relationship to treatment) with
day compared to tramadol hydrochloride dextroprofen-trometamol, 10.3% vs.
■ tramadol hydrochloride patients (P ⫽ 0.044); significantly more 22.1% (P ⫽ 0.026); AEs of the central
50 mg 3/day (option to dextroprofen-trometamol patients did not nervous system with tramadol
end study at Day 4 in need rescue medication after Day 1 hydrochloride
case of total pain relief) (P ⫽ 0.011)
43 Middleton, 198454 R, SB, 1 week 1b ■ methocarbamol 400 mg Both treatments improved symptoms as judged 4 Lobak patients vs. 1 Robaxisal Forte
n1 ⫽ 55 n2 ⫽ 52 plus acetylsalicylic acid by both the physicians and patients; patient withdrew due to AEs
325 mg (Robaxisal improvement in activity continued (P ⬍ 0.05): 6 Robaxisal Forte patients
Forte) 4/day throughout the week on both treatments; vs. 14 Lobak patients reported AEs
■ chlormezanone 100 mg there were no specific differences between (P ⬍ 0.05)
plus paracetamol 450 the two treatments regarding symptom
mg (Lobak) 3/day relief; one patient on each of the treatments
withdrew due to lack of efficacy
44 Monti, 200052 R, DB, P, 1 week 1b ■ lysine clonixinate 125 Reductions in pain at touch, pain at active and 2 patients in each group reported
n1 ⫽ 20 n2 ⫽ 20 mg plus cyclobenzaprine passive movement, and muscle contraction somnolence; one patient each in the
5 mg 3/day were similar, but not statistically significant, paracetamol group reported nausea,
■ paracetamol 300 mg between groups; all reductions within groups diarrhea and morning weakness
plus chlorzoxazone 250 between baseline and Day 2 were significant
mg 3/day (P ⬍ 0.05)
45 Stein et al., 199656 R, DB, 5 weeks 1b ■ amitriptyline 150 mg Significant improvement in anxiety (P ⬍ 0.001 None reported
n1 ⫽ 20 n2 ⫽ 19 daily for both drugs) and pain intensity (P ⬍ 0.001
■ acetaminophen 2000 vs. P ⬍ 0.01, respectively) at the end of week
mg daily 5; amitriptyline was more effective than
acetaminophen in reducing pain intensity
from the second week of treatment
(P ⬍ 0.045)

85
(continued)
 86
Table 3
(Continued)
ID Author, Year Studya LOEb Regimen Efficacy Results Adverse Events (AE)

46 Sweetman et al., R, DB, SB, P, 1 1b ■ mefenamic acid 500 mg Differences between the drugs on Day 7 for 10 patients withdrew due to AEs: 3
198755 week n1 ⫽ 40 1 tablet 3/day plus clinician’s assessment: chlormezanone- mefenamic acid, 3 chlormezanone-
n2 ⫽ 42 n3 ⫽ 40 placebo chlormezanone paracetamol was most effective at relieving paracetamol, 4 ethoheptazine-aspirin-
and paracetamol 2 pain on flexion of the spine (P ⬍ 0.5); meprobamate; 13 patients taking
tablets 3/day ethoheptazine-aspirin-meprobamate was least ethoheptazine-aspirin-meprobamate
■ chlormezanone 100 mg effective at relieving pain on extension of reported AEs on Day 7 compared
and paracetamol 450 the spine (P ⬍ 0.5) and at improving the with only 5 on both mefanamic acid
mg 2 capsules 3/day overall condition of the patient (P ⬍ 0.5) and chlormezanone-paracetamol
plus placebo mefanamic (P ⬍ 0.5)
acid 1 tablet 3/day
■ ethoheptazine 75 mg,
meprobamate 150 mg
and aspirin 250 mg, 2
tablets 3/day plus (a)
placebo mefanamic acid

Schnitzer et al.
1 tablet 3/day or (b)
placebo chlormezanone
and paracetamol 2
capsules 3/day
Chronic and Acute
NSAIDs
47 Aoki et al., 198359 R, DB, M, P 1b ■ piroxicam 20 mg once Both drugs were highly effective in relieving 8 indomethacin patients vs. 4 piroxicam
n1 ⫽ 116 a day symptoms, with no statistically significant dif- patients withdrew due to AEs; 11.2%
n2 ⫽ 114 ■ indomethacin 25 mg 3/ ference; difference between treatments was of piroxicam patients vs. 13.2% of in-
day most obvious at the end of Week 1, when a domethacin patients experienced AEs
greater percentage of patients receiving piro-
xicam were rated as ‘very much improved’
(21.6% vs. 11.4%)
48 Stevanovic, 198660 R, DB, P, 2 weeks 1b ■ tenoxicam 20 mg Significant pain reduction and improvement of 3 patients withdrew due to AEs: 1 tenox-
n ⫽ 89 (39 with ■ piroxicam 20 mg subjective symptoms (spontaneous lumbosa- icam, 2 piroxicam; better tolerability
LBP, 50 with sciat- cral pain, mobility pain, local pressure pain, of tenoxicam (2 patients: gastrointesti-
ica) etc.) compared to baseline for both groups; nal disorder, headache) than piro-
significant improvement of most objective pa- xicam (8 patients: 5 gastrointestinal

Vol. 28 No. 1 July 2004

rameters of the mobility of the spine com-
pared to baseline (e.g., finger-bottom-
difference, Schober’s sign, restriction of
mobiliy) for both groups
disorders, 1 diarrhea, 1 headache, 1
skin exanthem, 1 dizziness)
(continued)
Vol. 28 No. 1 July 2004 Drugs for the Treatment of Low Back Pain 87

from a total of 50 articles, including 39 articles

Colchicine treated patients reported sig-

Level of Evidence (LOE): 1a ⫽ SR (with homogeneity) of RCTs; 1b ⫽ Individual RCT (with narrow CI); 2a ⫽ SR (with homogeneity) of cohort studies; 2b ⫽ Individual cohort study (including low qual-
had mild gastrointestinal irritation: 1

(P ⬍ 0.05), particularly vomiting and

nificantly greater number of AEs as
in English, six articles in German, two articles in
2 patients from each group withdrew

ity RCT; e.g., ⬍80% follow-up); 3a ⫽ SR (with homogeneity) of case-control studies; 4 ⫽ Case-series (and poor quality cohort and case-control studies); 5 ⫽ Expert opinion without explicit critical ap-
due to gastrointestinal AEs; 4 vs. 3
French, and three articles in Spanish.

naproxen patient experienced

compared to placebo treated

Adverse Events (AE)

Study: C ⫽ cross-over; O ⫽ open-label; DB ⫽ double-blind; R ⫽ randomized; M ⫽ multi-center; SB ⫽ single-blind; P ⫽ parallel group; SR ⫽ systematic review; PC ⫽ placebo-controlled.
Results
Study Design
headache

diarrhea
The literature search identified 110 articles,
of which 96 met the inclusion criteria for this
review. Of these 96, 46 were excluded because
treated patients from baseline to follow-up at the study was reported in a language other than
English, German, French, or Spanish (n ⫽ 5),
and Million scale were not significantly dif-
McCoy pain drawings, pain analog scales,
Significant change in scores of the Judging

the study was not a randomized controlled trial

Orthopaedic Academic Society between

Evaluation of low back pain measured by

ferent between colchicine and placebo

(P ⬍ 0.0001); no significant differences

(n ⫽ 3), the study assessed treatment of back

Criteria for Therapeutic Results on

profen (P ⬍ 0.0001) and naproxen

injury (n ⫽ 4), the active comparator was not

Lumbago (1984) of the Japanese

baseline and 6th week for loxo-

an oral therapy (e.g., intramuscular injection,

Efficacy Results

epidural therapy, physical therapy) (n ⫽ 13),

or the article was a systematic review or treat-
1, 2, 4, 6, and 12 weeks

ment guideline (n ⫽ 21). Fifty studies met

the inclusion criteria described earlier: 17 fo-
between groups

cused on patients with chronic LBP, 29 on pa-

tients with acute LBP, and 4 included both
conditions.13–62
(Continued)

Different types of medications and doses of

Table 3

individual drugs were used in the reviewed

studies. Of the 17 studies in chronic LBP, four
day for 1 day and every
■ loxoprofen 60 mg 3/

evaluated NSAIDs, seven antidepressants, one

■ naproxen 250 mg 3/

■ colchicine 0.6 mg 8/

muscle relaxants, two opioid analgesics, and

4th day thereafter
Regimen

three drug combinations and other medica-

tions include oral therapies such as willow bark
■ placebo

extract, colchicines, or steroids and studies with

mixed drug combinations [e.g., NSAID and
day

day

muscle relaxant]). In terms of trials in acute

LBP, fourteen assessed NSAIDs, five muscle
LOEb

1b

relaxants, one opioid analgesics, and nine a

R, DB, PC, 12 weeks 2b

combination of drugs. In the four trials includ-

ing both chronic and acute conditions, three
n1 ⫽ 37 n2 ⫽ 36

n1 ⫽ 15 n2 ⫽ 12

involved NSAIDs and one other drugs. The

Studya

R, P, 6 weeks

doses of medications varied between trials, even

though all studies were based on therapeutic
doses recommended for treating chronic or
acute LBP (Table 3). Antidepressants were
evaluated predominantly in treatment of
50 Schnebel and Sim-
Soparat, 199561

chronic LBP, and NSAIDs and muscle relaxants

Author, Year

mons, 198762

in acute LBP.
49 Waikakul and

A randomized, placebo-controlled design was

Mixed and Other

applied in 11 of 17 chronic LBP trials, 11 of 29

acute LBP trials, and 0 of 4 trials in both chronic
and acute LBP (Table 4). The remainder of
praisal.

trials were randomized, active comparator-

ID

controlled trials.
a
b
88
Table 4
Placebo- and Active Comparator-Controlled Trial Design
Placebo-Controlled RCT
Drug class Chronic Acute
NSAID 1 3
Antidepressant 5 0
Muscle relaxant 1 5
Opioid analgesic 1 0
Combinations and other 3 3
Total 11 11
Quality of Clinical Trials
Overall, the 50 randomized controlled trials
were of moderate quality, with a mean ⫾ SD
quality score of 55 ⫾ 14 (median 54; range 26–
82). All 50 studies reviewed had to be ran-
domized and placebo or active comparator
controlled, but methodological quality was lim-
ited due to other factors, for example, inade-
quate description of randomization procedure,
small sample size, incomplete description of
blinding technique, insufficient follow-up period,
or lack of intention-to-treat analysis.
The methodological scores ranged from 26
to 76 points for chronic LBP (58 ⫾ 17), from
31 to 82 for acute LBP (55 ⫾ 14), and from 34
to 58 for trials evaluating both chronic and
acute LBP (44 ⫾ 20) on a 100-point scale.
Eighty-two percent (82%) of chronic LBP trials
had a high or medium quality score (47 points
or higher), whereas 62% of acute LBP trials and
25% of trials assessing both chronic and acute
LBP received quality scores of 47 points or higher.
Trials involving muscle relaxants (for both
chronic and acute LBP) had the highest
methodological quality score (a mean score of
67) and studies assessing NSAIDs in chronic
and acute LBP had the poorest methodological
quality score (a mean score of 52) (Table 2).
This could be due to the fact that most trials
on muscle relaxants were placebo-controlled
whereas most NSAID trials had an active compa-
rator. The methodological quality scores for
opioid analgesics, antidepressants, and combi-
nations and other drugs (for chronic, acute,
and both types of LBP) fell in between (mean
score of 62, 57, and 55, respectively).
Efficacy and Safety of Drug Treatments
for Chronic Low Back Pain
NSAIDs (4 trials). Evidence supports the effi-
cacy of NSAIDs compared to placebo in the
Schnitzer et al. Vol. 28 No. 1 July 2004
Active Comparator-Controlled RCT
Chronic & Acute Chronic Acute Chronic & Acute
0 3 11 3
0 2 0 0
0 0 0 0
0 1 1 0
0 0 6 1
0 6 18 4
treatment of chronic LBP. One placebo-con-
trolled trial of moderate quality found a signifi-
cant efficacy difference in favor of NSAIDs. All
three active comparator studies demonstrated
a significant improvement from baseline for
the NSAIDs analyzed. In terms of safety, the
percentage of patients who withdrew from
NSAIDs due to adverse events ranged from 3%
among oxamethacin patients to 23% among
indomethacin patients (in the same 8-week
trial).
Antidepressants (7 trials). Evidence exists re-
garding the efficacy of antidepressants in the
treatment of chronic LBP. In five RCTs, anti-
depressants were more effective than placebo
in reducing pain and depression. Results did
not seem to be affected by methodological qual-
ity, as studies of low, medium, and high quality
showed significant improvements in pain mea-
sures. Withdrawals due to adverse events ranged
from 10% in fluoxetine patients (6-week study)
to 44% in a study of amitriptyline/atropine that
lasted 16 weeks.
Muscle Relaxants (1 trial). One randomized,
placebo-controlled, high quality study reported
a significant difference between tetrazepam
and placebo. Seven percent (7%) of tetrazepam
patients withdrew due to adverse events in the
2-week study.
Opioid Analgesics (2 trials). Both the placebo-
controlled and the active comparator study
showed evidence for the efficacy of opioid anal-
gesics (i.e., tramadol, tramadol-acetaminophen
(paracetamol) combination, respectively) in
the treatment of chronic LBP. The majority of
tramadol-acetaminophen (paracetamol) treated
patients assessed treatment as ‘good’ or ‘satis-
factory’ in the active comparator trial and in
Vol. 28 No. 1 July 2004 Drugs for the Treatment of Low Back Pain
the other study, tramadol patients scored signif-
icantly better than placebo patients on several
outcomes. Methodological quality was medium
for the active comparator study and high for
the placebo-controlled trial. Safety results
varied between studies; only 4% of tramadol
patients discontinued treatment due to adverse
events in a study of 4 weeks duration whereas
35% of tramadol--acetaminophen (paraceta-
mol) patients withdrew due to adverse events
in a study lasting 15 days.
Drug Combinations and Other Drugs (3 trials).
Three placebo-controlled studies investigating
other drugs were of medium or high method-
ological quality. Willow bark extract was signifi-
cantly better than placebo in the treatment of
chronic LBP. Flupirtine maleate and chlormez-
anone showed no significant differences from
placebo and Harpogophytum extract (1200 mg
and 600 mg) demonstrated significant changes
from baseline but was not significantly different
from placebo. Six percent of Harpogophytum
extract patients, 7% of flupirtine maleate, and
15% of chlormezanone patients withdrew due
to adverse events.
Efficacy and Safety of Drug Treatments
for Acute Low Back Pain
NSAIDs (14 trials). Regarding the treatment of
acute LBP, efficacy results differed between
studies and individual NSAIDs. Two of the three
randomized placebo-controlled trials (i.e., piro-
xicam and tenoxicam) found a statistically sig-
nificant difference in favor of the NSAIDs
compared to placebo. Of the 11 active-compara-
tor controlled trials, nine demonstrated statisti-
cally significant improvements from baseline
among NSAIDs being investigated (i.e., diclo-
fenac, diflunisal, indomethacin, mefanamic
acid, meloxicam, naproxen, nimesulide, and
piroxicam) and two showed no statistically
significant difference from baseline. Demon-
strated efficacy had no relationship to method-
ological quality, as studies of all levels of quality
yielded significant as well as nonsignificant re-
sults. All types of NSAIDs appeared to be well
tolerated, but only four studies of one to two
weeks in duration reported withdrawal rates
due to adverse events (ranging from 2% in
89
diclofenac patients [two weeks] to 13% in tra-
mado-acetaminophen (paracetamol)/codeine
patients [nine days]).
Muscle Relaxants (5 trials). Four of the five pla-
cebo-controlled trials, covering a wide range
of methodological quality, reported significant
improvements by muscle relaxants compared
to placebo. Safety measures varied: three studies
reported no withdrawals due to adverse
events, whereas 17% of baclofen patients with-
drew due to adverse events in a two-week study.
Opioid Analgesics (1 trial). No evidence in sup-
port of the effectiveness of opioid analgesics
(hydrocodone and oxycodone) in treating
acute LBP was found in one active comparator,
high quality study. No patients withdrew due to
adverse events.
Drug Combinations and Other Drugs (9 trials).
Seven active comparator studies (i.e., steroids,
antipsychotics, and mixed combination drug
regimens) showed significant improvements on
at least two efficacy variables from baseline by
the respective drugs in the treatment of acute
LBP. Three trials were of medium to low quality,
possibly due to the variability of drug types
within each study. Only two studies (each one
week in duration) reported withdrawals due to
adverse events: 1.9% of Robaxisal Forte patients
and 10% of ethoheptazine-aspirin-meproba-
mate patients.
Efficacy and Safety of Drug Treatments
for Chronic and Acute Low Back Pain
NSAIDs (3 trials). Three active comparator
studies of NSAIDs (i.e., indomethacin, loxopro-
fen, naproxen, piroxicam, and tenoxicam)
showed significant improvements in most effi-
cacy measures from baseline for the treatment
of both chronic and acute LBP. Studies were of
medium to low quality, perhaps due to small
sample size and lack of placebo-control design.
Withdrawals due to adverse events were re-
ported in all 3 studies and ranged from 1–7%
of patients (tenoxicam and indomethacin pa-
tients, respectively) in trials that lasted 2–6
weeks in duration.
Drug Combinations and Other Drugs (1 trial).
One low quality study showed no significant
90 Schnitzer et al.
difference between colchicine and placebo.
Colchicine-treated patients reported a signifi-
cantly greater number of adverse events, particu-
larly vomiting and diarrhea during this 12-week
study, but no patient withdrew from the trial.
Discussion
Although a number of systematic reviews of
treatments of LBP have been conducted, none
has evaluated trials for the treatment of both
chronic and acute conditions, nor have they
considered different oral drug therapies. Re-
sults of our comprehensive review of 50 clinical
trials published between January 1980 and
October 2002 indicate that in acute LBP, non-
selective NSAIDs are more effective than pla-
cebo and muscle relaxants may also provide
benefit, though the number of placebo-con-
trolled trials evaluating either class of drugs is
limited and the data in regard to muscle relax-
ants are conflicting. In active comparator-con-
trolled studies of NSAIDs in acute LBP, no
consistent differences were observed among the
different NSAIDs evaluated. Data regarding
other therapeutic approaches to the treatment
of acute LBP were inadequate to allow conclu-
sions to be made.
In chronic LBP, NSAIDs and antidepressants
are the only treatments for which adequate
amounts of data are available for review. Both
demonstrate efficacy in placebo-controlled trials.
Muscle relaxants have only been evaluated in a
single trial and opioids were evaluated in two
trials.
The safety and tolerability of treatments for
both acute and chronic LBP were difficult to
assess adequately due to differing definitions,
incompleteness of data reported in publica-
tions, and varying duration of studies. A wide
range of side effects have been reported, oc-
curring with variable frequency, but given the
differing populations studied and the limita-
tions noted above, no conclusions can be
drawn.
Limitations
There are some limitations in the scope of
this systematic review. Publication selection bias
cannot be ruled out, as no effort was made to
identify unpublished trials. Also, for practical
reasons, only trials published in English,
Vol. 28 No. 1 July 2004
German, French, and Spanish were included,
excluding potentially relevant trials published
in other languages.
Another limitation is the choice of the
weights that were assigned to the methodologi-
cal criteria by the reviewers. In the Koes et al.
study,11 a sensitivity analysis was conducted to
assess the robustness of the methodological
quality using three different sets of weights. It
was found that the scores were more or less the
same regardless of the different weighting sys-
tems used. A comparison of the methodological
scores for the 13 trials reviewed in this study
and by Koes et al.11 found that the two sets of
results were comparable.
A third limitation of our review might be the
fact that the scores for the criteria were forced
into a single methodological summary score.
Although this single score is easy to interpret,
it potentially misrepresents the internal valid-
ity in a well-designed trial. This is especially
problematic with trials evaluating clinically less
relevant outcomes and having relatively high
drop-out rates, as they can have high method-
ological quality scores if they meet most of the
other methodological criteria. Additionally, a
recent study by Balk et al.63 concluded that indi-
vidual quality measures are not reliably asso-
ciated with the strength of treatment effect
across studies, so there is no definitive proof
that methodological quality scores are associ-
ated with effect size in clinical trials of LBP.
Efficacy of treatments was evaluated based
on tests for statistically significant differences in
the endpoints studied in individual trials,but
clinical significance of these differences was not
analyzed in the absence of defined minimum
clinically significant/relevant changes for these
efficacy endpoints. No attempt was made to
pool the results across trials given the heteroge-
neity of the study populations, outcome mea-
sures, follow-up times, and comparator drugs.
The conclusions drawn from the literature
are limited by the fact that not many publica-
tions have been reported in recent years, so that
most of the data are at least ten years old and
not necessarily representative of today’s pa-
tient populations. Sixty percent (60%) of the
studies were published before 1993 and 12%
were more than 20 years old. In addition, most
of the studies were of short-term duration,
thereby precluding generalizability of the study
Vol. 28 No. 1 July 2004 Drugs for the Treatment of Low Back Pain
results to chronic pain treatment patterns ob-
served in clinical practice. Only two studies were
longer than eight weeks in duration and over
half (58%) lasted only two weeks or less.
Medium to low quality of the reports does
prevent firm conclusions about the effective-
ness and safety of the respective drugs. Only
30% of the trials were of high quality, including
seven chronic LBP studies, eight acute LBP
studies, and no studies of both chronic and
acute LBP.
Conclusion
Given the ubiquity of the clinical situation
of LBP and the widespread use of a variety of
therapeutic modalities, the lack of high quality
data regarding the efficacy, safety, and tolerabil-
ity, as well as the cost-effectiveness, of different
approaches to therapy is notable. What is
needed is the use of standardized approaches to
the evaluation of therapies in LBP, as has been
done in other fields of musculoskeletal medi-
cine. The application of rigorous clinical trial
methodology accompanied by standardized
outcome measures across multiple domains
would permit a clearer understanding of the
role of different therapeutic modalities, both
pharmacologic and non-pharmacologic. Al-
though many current therapies remain yet to
be evaluated under these conditions, all future
interventions should be expected to meet
such standards.
Acknowledgments
This work was supported in part by Merck &
Co., Inc., Whitehouse Station, NJ, USA. The
authors are grateful to Ms. Simone Crespi and
Dr. Joanne Abed for their editorial assistance
and Ms. Jacqueline Clark for her assistance in
the production of this manuscript.
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94 Schnitzer et al. Vol. 28 No. 1 July 2004

Appendix A
Explanation of Criteria from Table 1

Each criterion must be applied independently of the other criteria.

A. Description of inclusion and exclusion criteria (1 point). Restriction to a homogenous study popula-
tion (1 point).

B. Randomization procedure described (2 points). Randomization procedure that excludes bias (for
example, sealed envelopes) (2 points). Addition: randomized but not explicitly state (1 point).

C. Similarity for: duration of complaints (e.g., pain for 3 months), value of outcome measures (prefer
objective/clinical measures over subjective), age (e.g., 18-75 years), recurrence status (e.g., symptoms
within past 2 weeks), and radiating complaints (e.g., pain spreads to legs or neck) (1 point each).

D. Information from which group and with reason for withdrawal.

E. Loss to follow up: all randomized patients minus the number of patients at main moment of effect
measurement for the main outcome measure, divided by all randomized patients times 100.

F. Smallest group immediately after randomization.

G. NSAID or other drug therapy explicitly described (5 points). All reference treatments explicitly
described (5 points).

H. Comparison with a placebo therapy.

I. Pragmatic study: patients fully naı̈ve (3 points), or time restriction (no treatment for at least one
year) (2 points); naı̈veness evaluated and fully successful (2 points).

J. Other medical interventions are avoided in the design of the study (except analgesics, advice on
posture or use at home of heat, rest, or a routine exercise scheme).

K. Patients blinded: attempt of blinding, (double-) blinding evaluated and fully successful (2 points).
Addition: single-blinding (2 points).

L. Use (measured and reported) of: pain, global measure of improvement, functional status (activities
of daily living), spinal mobility, return to work (or to normal activities) (2 points each).

M. Effect measurement (partly) by a blinded assessor (10 points).

N. Moment of measurement during or just after treatment (3 points). Moment of measurement 6

months or longer (2 points).

O. When loss to follow up is less than 10%: all randomized patients for most important outcome measures,
and on most important moments of effect measurement minus missing values, irrespective of
non-compliance and co-treatments. When loss of follow up>10%: intention to treat (3 points) as
well as an alternative analysis that accounts for missing values (2 points).

P. For most important outcome measures (Addition: frequency 3 points, P, value 2 points more). In case
of (semi) continuous variables presentation of the mean or median with standard error or percentiles
(3 points).
Vol. 28 No. 1 July 2004 Drugs for the Treatment of Low Back Pain 95