Tramadol and Acetaminophen Combination
Tablets in the Treatment of Fibromyalgia
Pain: A Double-Blind, Randomized,
Placebo-Controlled Study
Robert M. Bennett, MD, Marc Kamin, MD, Rezaul Karim, PhD, Norman Rosenthal, MD
PURPOSE: To evaluate the efficacy and safety of a combination analgesic tablet (37.5 mg tramadol/325 mg acetaminophen) for the treatment of fibromyalgia pain.
METHODS: This 91-day, multicenter, double-blind, randomized, placebo-controlled study compared tramadol/acetaminophen combination tablets with placebo. The primary outcome
variable was cumulative time to discontinuation (Kaplan-Meier
analysis). Secondary measures at the end of the study included
pain, pain relief, total tender points, myalgia, health status, and
Fibromyalgia Impact Questionnaire scores.
RESULTS: Of the 315 subjects who were enrolled in the study,
313 (294 women [94%], mean [⫾ SD] age, 50 ⫾ 10 years)
completed at least one postrandomization efficacy assessment
(tramadol/acetaminophen: n ⫽ 156; placebo: n ⫽ 157). Discontinuation of treatment for any reason was less common in
those treated with tramadol/acetaminophen compared with
placebo (48% vs. 62%, P ⫽ 0.004). Tramadol/acetaminophen-
treated subjects also had significantly less pain at the end of the
study (53 ⫾ 32 vs. 65 ⫾ 29 on a visual analog scale of 0 to 100, P
⬍0.001), and better pain relief (1.7 ⫾ 1.4 vs. 0.8 ⫾ 1.3 on a scale
of –1 to 4, P ⬍0.001) and Fibromyalgia Impact Questionnaire
scores (P ⫽ 0.008). Indexes of physical functioning, role-physical, body pain, health transition, and physical component summary all improved significantly in the tramadol/acetaminophen-treated subjects. Discontinuation due to adverse events
occurred in 19% (n ⫽ 29) of tramadol/acetaminophen-treated
subjects and 12% (n ⫽ 18) of placebo-treated subjects (P ⫽
0.09). The mean dose of tramadol/acetaminophen was 4.0 ⫾ 1.8
tablets per day.
CONCLUSION: A tramadol/acetaminophen combination
tablet was effective for the treatment of fibromyalgia pain without any serious adverse effects. Am J Med. 2003;114:537–545.
©2003 by Excerpta Medica Inc.
F
inflammatory drugs (NSAIDs), benzodiazepines, and
calcitonin are not more effective than placebo (8,9).
Some success has been reported with other pharmacologic agents, such as tricyclic antidepressants and fluoxetine (10 –15), as well as nonpharmacologic therapies
(16,17). Amitriptyline is used commonly, although only
25% to 30% of patients improve and the beneficial effects
are not sustained (16). One study reported that opioids
were prescribed to about 15% of fibromyalgia patients in
a tertiary care setting (18). The adverse effects of opioids
are often a deterrent to patient acceptance, however, and
regulatory issues may deter physician prescribing (19).
There is an increasing realization that a polypharmacologic approach to pain management in fibromyalgia,
by targeting different levels in the pain pathways, needs to
be explored (20). In clinical trials, a 37.5-mg tramadol/
325-mg acetaminophen combination tablet has been effective for pain relief among patients who underwent
dental surgery (21), and as add-on therapy in the treatment of pain due to osteoarthritis not controlled by
NSAIDs (22).
Tramadol is a centrally acting analgesic that is useful in
the treatment of many pain disorders, including neuropathic pain and fibromyalgia (23–30). Tramadol has a
unique mechanism of action that combines mu-opioid
activity with inhibition of serotonin/norepinephrine re-
ibromyalgia is a common syndrome characterized
by widespread pain and tenderness (1). The standardization of diagnostic criteria for fibromyalgia
(2) has stimulated research on this disorder, and better
understanding of the scientific basis of pain over the last
decade has led to the reformulation of fibromyalgia as a
chronic pain state with disordered sensory processing
and a heterogeneous clinical presentation (3– 6). The
generally accepted approach to treating fibromyalgia is a
multimodal regimen that includes patient education,
cognitive behavioral therapy, gentle exercise, and medications to help with sleep and pain (7).
No medication is currently approved for the treatment
of fibromyalgia in the United States. Nonsteroidal anti-
From the Oregon Health and Science University (RMB), Portland, Oregon; Ortho-McNeil Pharmaceutical (MK, NR), Raritan, New Jersey;
and Johnson and Johnson Pharmaceutical Research and Development
(RK), Titusville, New Jersey.
This study was supported by a grant (CAPSS-113) from OrthoMcNeil Pharmaceutical, Inc, Raritan, New Jersey. All investigators were
financially reimbursed by Ortho-McNeil Pharmaceutical for conducting this study.
Correspondence should be addressed to Robert M. Bennett, MD,
Department of Medicine, Oregon Health and Science University
(OP09), 3181 SW Sam Jackson Park Road, Portland, Oregon 97201, or
[email protected].
Manuscript submitted March 25, 2002, and accepted in revised form
November 27, 2002.
©2003 by Excerpta Medica Inc.
All rights reserved.
0002-9343/03/$–see front matter 537
doi:10.1016/S0002-9343(03)00116-5
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Figure 1. Design of the study. Subjects underwent a 3-week washout phase, followed by enrollment and randomization, with dose
escalation (see Methods). bid ⫽ two times daily; hs ⫽ at night; tid ⫽ three times daily; qd ⫽ four times daily.
uptake (31). Acetaminophen is often combined with
other medications to enhance therapeutic efficacy. For
example, subactive amounts of acetaminophen and morphine exert analgesic effects when given in combination
(32). Acetaminophen acts centrally via mechanisms that
appear to involve a synergistic interaction between spinal
and supraspinal sites (33,34). The approximately 1:8 mgto-mg tramadol:acetaminophen ratio was based on demonstrated synergy in animal models (35).
Fibromyalgia is a central pain state involving disturbances of neurochemical pathways that are thought to be
affected by both tramadol and acetaminophen. The purpose of this study was to examine the analgesic efficacy
and safety of 37.5-mg tramadol/325-mg acetaminophen
tablets in the treatment of fibromyalgia pain.
METHODS
Study Design and Sample
This out-patient multicenter, randomized, double-blind,
placebo-controlled study was conducted in adult subjects
aged 18 to 75 years with at least moderate pain from fibromyalgia, defined as ⱖ40 mm on a 100-mm pain visual
analog scale. All subjects fulfilled the 1990 American College of Rheumatology classification guidelines for the diagnosis of fibromyalgia (2). Subjects were also required to
be in general good health, and women were required to be
practicing contraception or incapable of pregnancy.
Exclusion criteria included previous failure of tramadol therapy (4 patients excluded), use of tramadol in the
prior 30 days, and any other pain that was more severe
than the fibromyalgia pain. Patients were allowed to take
a low-dose selective serotonin reuptake inhibitor (SSRI)
or St. John’s wort (but not both) for depression, and zolpidem and flurazepam for sleep, provided they had been
on a stable dose of these drugs for at least 1 month. We
excluded patients who had used other antidepressants,
cyclobenzaprine, antiepileptic drugs for pain, acupunc538
May 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 114
ture, or transcutaneous electrical nerve stimulation
within 3 weeks before enrollment; recent use (within 5
half-lives) of other sedative hypnotics, short-acting analgesics (including acetaminophen), topical medications/
anesthetics, or muscle relaxants; tender point anesthetic
injections within 2 months; systemic steroids within 3
months; or any investigational drug/device in the prior 30
days.
The study was designed in accordance with the Declaration of Helsinki, and an independent Institutional Review Board approved the study protocol. Investigators at
27 sites participated (Appendix).
Intervention
Before entry into the double-blind phase of the study, all
subjects completed a screening and washout phase of up
to 3 weeks’ duration. Subjects were then randomly assigned to receive tramadol/acetaminophen (37.5-mg/
325-mg tablet, ULTRACET™; Ortho-McNeil Pharmaceutical, Raritan, New Jersey) or matching placebo (Figure 1). Study medication was titrated over a 10-day
period from one tablet per day to four tablets per day.
Thereafter, subjects took one to two tablets four times
daily, to a maximum of eight tablets per day (total of 300
mg tramadol/2600 mg acetaminophen). Doses were selected on the basis of previous studies of tramadol and
acetaminophen for chronic pain, including fibromyalgia
pain.
Randomization/Blinding
Subjects were assigned sequentially in 1:1 fashion at each
site using a randomized list of medication codes. Tramadol/acetaminophen or matching placebo tablets were
prepared by the sponsor and dispensed in bottles containing 100 tablets. Each bottle had a two-part tear-off
label; study medication identification was concealed and
could only be revealed in case of emergency. Treatment
assignments were not revealed to study subjects, investigators, clinical staff, or study monitors until all subjects
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Figure 2. Flow chart of subject disposition.
had completed therapy and the database had been finalized.
Outcome Measures
Visits were scheduled for days 1, 14, 28, 56, and 91 (Figure
1). The primary efficacy variable was defined in the protocol as cumulative time to discontinuation due to lack of
efficacy. However, because discontinuation due to lack of
efficacy may be underestimated owing to competing
risks, discontinuation for any reason was also analyzed
and this more conservative analysis is highlighted here to
reflect clinical practice.
Secondary variables measured at each visit included
pain on a visual analog scale (100-mm line, from no pain
to extreme pain [100]) and a pain relief rating scale (complete ⫽ 4, a lot ⫽ 3, moderate ⫽ 2, slight ⫽ 1, none ⫽ 0,
worse ⫽ –1). At the first and last visits, investigators determined the number of tender points (of 18) and myalgic score (no pain ⫽ 0, patient complains of pain only ⫽
1, patient reacts to pain emotionally ⫽ 2, patient withdraws or flinches ⫽ 3); an average myalgic score was calculated. Subjects also completed the 10-item Fibromyalgia Impact Questionnaire (36), the Short Form 36 (SF36) health survey (37), and a 12-item sleep questionnaire
at the first and last visit (38). The Sleep Questionnaire is a
12-question survey used to evaluate sleep habits during
the previous 4 weeks, administered on day 1 and at the
final visit. Scores are transformed to a 0 to 100 scale and
used to derive two overall sleep indexes: Sleep Index 6
(from six of the questions) and Sleep Index 9 (from nine
of the questions). Lower values represent better sleep.
A complete medical history, physical examination, and
urinalysis were performed at the screening visit (day –21)
and the final visit. Vital signs (sitting pulse, blood pressure, and weight) were measured at baseline and at each
visit. Chemistry and hematology laboratory tests were
performed at screening and at visits on days 28, 56, and
91.
Adverse events were recorded at each visit, whether
spontaneously reported or in response to general, nondirected questioning. Adverse events were summarized by
World Health Organization Adverse Reaction Terminology body system and preferred term. If a subject discontinued treatment, all efficacy and safety variables that
were planned for the final visit were recorded at the time
of discontinuation.
Statistical Analyses
Efficacy analyses were performed on the intent-to-treat
sample, comprised of all enrolled subjects who took at
May 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 114 539
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Table 1. Demographic Characteristics of the Sample of Subjects with Fibromyalgia*
Characteristic
Tramadol/
Acetaminophen
(n ⫽ 156)
75%). The calculated sample size of 112 subjects per
group was increased approximately 30% to compensate
for patients who dropped out because of adverse events,
for a total of 150 subjects in each group. All analyses were
performed with SAS Version 6.12 software (Cary, North
Carolina).
Placebo
(n ⫽ 157)
Number (%) or Mean ⫾ SD
Age (years)
Female sex
Race
White
Black
Asian
49 ⫾ 11
145 (93)
51 ⫾ 10
149 (95)
151 (97)
4 (3)
1 (1)
147 (94)
10 (6)
0
RESULTS
A total of 315 subjects were assigned randomly to tramadol/acetaminophen (n ⫽ 158) or placebo (n ⫽ 157), of
whom 313 were evaluable for efficacy and 312 were evaluable for safety (Figure 2). Subjects ranged in age from 19
to 75 years; most were women and white (Table 1). The
mean (⫾ SD) pain score at baseline (on a 0- to 100-mm
visual analog scale) was 72 ⫾ 15 mm (Table 2). There
were no significant baseline differences between the two
groups (Tables 1 to 3).
* Only patients included in the intention-to-treat analyses for efficacy
are included in this and subsequent tables.
least one dose of study medication and for whom a postrandomization efficacy measurement was available. Time
to discontinuation was examined by survival analysis
techniques, and statistical significance was assessed with
the generalized Wilcoxon test. Cox proportional hazards
analyses were performed for two outcomes: discontinuation due to any reason and discontinuation due to lack of
efficacy; these analyses adjusted for baseline pain and
clinical center. Data from small centers (⬍10 subjects)
were pooled for this purpose. Secondary efficacy variables
were summarized and assessed with analysis of covariance adjusting for baseline pain. Changes from baseline
in vital signs and clinical laboratory values were also assessed. Proportions of subjects with adverse events were
compared using the Fisher exact test. Statistical significance was set at P ⬍0.05 (two-sided). The sample size was
determined to have 90% power to detect a 20% difference
in discontinuation rates due to lack of efficacy (55% vs.
Primary Efficacy Outcome
The cumulative rate of discontinuation of therapy for any
reason was significantly lower in the tramadol/acetaminophen group (48% by day 91) than in the placebo group
(62% by day 91; P ⫽ 0.004; Figure 3A). The cumulative
rate of discontinuation due to lack of efficacy was also
significantly lower in the tramadol/acetaminophen group
(29% by day 91) than in the placebo group (51% by day
91; P ⬍0.001; Figure 3B).
Secondary Outcome Measures
Compared with placebo, the mean final pain score was
about 12 mm (18%) lower in the tramadol/acetaminophen group (Table 2; P ⬍0.001). Similarly, mean final
pain relief was significantly better in the tramadol/acetaminophen group than in the placebo group (Table 2;
Table 2. Pain and Symptoms at Baseline and the Final Visit
Baseline
Characteristic
Pain score (mm)†
Pain relief score‡
Number of tender points
Average myalgic score§
Sleep questionnaire㛳
Sleep Index 6
Sleep Index 9
Final Visit
Tramadol/
Tramadol/
Acetaminophen Placebo Acetaminophen Placebo
(n ⫽ 156)
(n ⫽ 157)
(n ⫽ 156)
(n ⫽ 157) P Value*
72 ⫾ 14
—
16 ⫾ 2.2
1.7 ⫾ 0.6
72 ⫾ 15
—
16 ⫾ 2.3
1.7 ⫾ 0.6
53 ⫾ 32
1.7 ⫾ 1.4
13 ⫾ 4.9
1.3 ⫾ 0.8
65 ⫾ 29
0.8 ⫾ 1.3
14 ⫾ 4.3
1.5 ⫾ 0.8
⬍0.001
⬍0.001
0.04
0.06
62 ⫾ 16
62 ⫾ 16
61 ⫾ 17
61 ⫾ 16
54 ⫾ 18
55 ⫾ 17
54 ⫾ 18
55 ⫾ 18
0.78
0.74
* Comparison between final values based on analysis of covariance adjusting for clinical center and baseline
values.
†
0 mm (no pain) to 100 mm (extreme pain) on a visual analog scale.
‡
Complete relief ⫽ 4, a lot ⫽ 3, moderate ⫽ 2, slight ⫽ 1, none ⫽ 0, worse ⫽ ⫺1.
§
Calculated from myalgic scores at each tender point, where no pain ⫽ 0, patient complains of pain only ⫽ 1,
patient reacts to pain emotionally ⫽ 2, and patient withdraws or flinches ⫽ 3.
㛳
Lower scores represent better sleep, on a 0 to 100 scale.
540
May 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 114
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Table 3. Measures of Symptoms (Using the Fibromyalgia Impact Questionnaire) and Overall Health Status (Using Short Form 36)
at Baseline and Final Visit
Baseline
Tramadol/
Acetaminophen
(n ⫽ 156)
Characteristic
Final Visit
Placebo
(n ⫽ 157)
Tramadol/
Acetaminophen
(n ⫽ 156)
Placebo
(n ⫽ 157)
P Value*
Mean ⫾ SD
†
Fibromyalgia Impact Questionnaire
Total score
Physical impairment
Feel good
Work missed
Do job
Pain
Fatigue
Rest
Stiffness
Anxiety
Depression
SF-36 health survey‡
Physical functioning
Role-physical
Bodily pain
General health
Vitality
Social functioning
Role-emotional
Mental health
Reported health transition
Physical component summary
Mental component summary
54 ⫾ 11
4.4 ⫾ 2.4
2.1 ⫾ 2.3
0.9 ⫾ 2.1
6.1 ⫾ 2.2
7.2 ⫾ 1.7
8.0 ⫾ 1.7
8.1 ⫾ 1.6
7.7 ⫾ 1.8
5.5 ⫾ 2.9
5.0 ⫾ 2.9
55 ⫾ 11
4.8 ⫾ 2.2
2.1 ⫾ 2.0
0.8 ⫾ 1.9
6.4 ⫾ 2.4
7.2 ⫾ 1.6
8.1 ⫾ 1.6
8.2 ⫾ 1.6
7.9 ⫾ 1.6
5.8 ⫾ 2.9
5.0 ⫾ 2.9
44 ⫾ 17
3.7 ⫾ 2.6
4.1 ⫾ 3.1
0.8 ⫾ 2.0
5.1 ⫾ 2.8
5.7 ⫾ 2.7
7.0 ⫾ 2.4
6.7 ⫾ 2.5
6.2 ⫾ 2.7
4.7 ⫾ 3.0
4.4 ⫾ 3.1
50 ⫾ 15
4.5 ⫾ 2.5
2.9 ⫾ 2.8
1.1 ⫾ 2.3
5.9 ⫾ 2.7
6.4 ⫾ 2.5
7.3 ⫾ 2.4
7.2 ⫾ 2.4
7.0 ⫾ 2.3
5.5 ⫾ 3.0
4.8 ⫾ 3.0
0.008
0.02
0.001
0.19
0.04
0.02
0.41
0.02
0.008
0.03
0.25
40 ⫾ 23
11 ⫾ 23
29 ⫾ 13
48 ⫾ 20
20 ⫾ 17
52 ⫾ 24
38 ⫾ 41
59 ⫾ 20
63 ⫾ 24
29 ⫾ 7.2
41 ⫾ 11
37 ⫾ 21
12 ⫾ 25
27 ⫾ 13
45 ⫾ 22
20 ⫾ 16
47 ⫾ 27
46 ⫾ 42
60 ⫾ 19
64 ⫾ 24
28 ⫾ 7.5
42 ⫾ 11
48 ⫾ 26
29 ⫾ 25
40 ⫾ 22
53 ⫾ 22
30 ⫾ 21
60 ⫾ 28
47 ⫾ 44
64 ⫾ 21
50 ⫾ 31
34 ⫾ 9.4
44 ⫾ 12
40 ⫾ 23
17. ⫾ 29
32 ⫾ 19
47 ⫾ 22
27 ⫾ 20
53 ⫾ 29
46 ⫾ 43
62 ⫾ 19
58 ⫾ 28
29 ⫾ 8.4
43 ⫾ 12
0.005
0.001
0.002
0.08
0.18
0.26
0.41
0.14
0.03
0.001
0.55
* Comparison between final values, based on an analysis of covariance adjusting for clinical center and baseline values.
†
Total score measured on a 0 to 100 scale; others on a 0 to 10 scale. Lower values represent lesser effects of fibromyalgia, except for “feel good.”
‡
Higher values (on a 0 to 100 scale) indicate a better quality of life, except for “reported health transition.”
SF-36 ⫽ Short Form 36.
P ⬍0.001). Subjects in the tramadol/acetaminophen
group also had a significantly greater decrease in the
number of tender points during the trial, and lower average myalgic scores at the end of the trial (Table 2).
Forty-two percent (65/156) of the tramadol/acetaminophen group had at least a 30% reduction in pain score,
compared with 24% (37/157) of the placebo group (18%
difference; 95% confidence interval [CI]: 8% to 28%; P
⬍0.01). Similarly, 35% (n ⫽ 54) of the tramadol/acetaminophen-treated subjects had at least a 50% reduction
in pain, compared with 18% (n ⫽ 29) of the placebotreated subjects (16% difference; 95% CI: 7% to 26%; P
⬍0.01).
Significant differences favoring the tramadol/acetaminophen group were also found for the total Fibromyalgia Impact Questionnaire score, as well as for six of the
11 individual subscales, at the end of the study (Table 3).
There were also significant differences in several measures of health status at the end of the study (Table 3).
There were no treatment-related differences in the answers to questions about sleep (Table 2).
A stable dose of an SSRI for depression was used by 56
patients (30 in the tramadol/acetaminophen group and
26 in the placebo group) for at least 1 month before the
study. After excluding these patients, discontinuation of
the study treatment for any reason (P ⫽ 0.03) or for lack
of efficacy (P ⫽ 0.002) was still less common in the tramadol/acetaminophen group.
Safety
A total of 156 subjects in each group were evaluated for
safety. Subjects in the tramadol/acetaminophen group
took an average of 151 mg/d of tramadol and 1238 mg/d
of acetaminophen (mean daily dose of 4.0 ⫾ 1.8 tablets).
Adverse events, regardless of relation to study medication, led to study discontinuation in 19% (n ⫽ 29) of
tramadol/acetaminophen subjects and 12% (n ⫽ 18) of
placebo subjects (P ⫽ 0.09; Figure 2). In all, 118 subjects
May 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 114 541
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Figure 3. Kaplan-Meier estimate of time to discontinuation for any reason (A) or for lack of efficacy (B). The P values were computed
using Cox proportional hazards regression analysis adjusting for clinical center and baseline pain. APAP ⫽ acetaminophen.
(76%) in the tramadol/acetaminophen group reported at
least one adverse event, compared with 87 subjects (56%)
in the placebo group (P ⬍0.001; Table 4).
Treatment-related adverse events (deemed by the investigators to be related to the study medication) occurred in 32 (21%) of tramadol/acetaminophen subjects
and 14 (9%) of placebo subjects (P ⫽ 0.005). The most
commonly occurring (⬎3%) treatment-related adverse
events in the tramadol/acetaminophen group were nausea (n ⫽ 14 [9%]), dizziness (n ⫽ 5 [3%]), somnolence
(n ⫽ 5 [3%]), and constipation (n ⫽ 5 [3%]). The most
542
May 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 114
commonly occurring treatment-related adverse events in
the placebo group were nausea (n ⫽ 7 [4%]) and somnolence (n ⫽ 5 [3%]). No serious adverse event was considered by the investigators to be related to the study medication.
No clinically relevant trends were identified in changes
in vital signs or hematology, chemistry, or urinalysis values. All markedly abnormal laboratory values during the
trial were transient, or were thought by the investigator to
be not clinically important or to be attributable to causes
other than study medication.
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Table 4. Adverse Events Reported by ⱖ4.5% of Subjects in Either Group (n ⫽ 312)
Adverse Event
Tramadol/
Acetaminophen
(n ⫽ 156)
Placebo
(n ⫽ 156)
P Value
Number (%)
Nausea
Headache
Pruritus
Dizziness
Constipation
Somnolence
Sinusitis
Upper respiratory
tract infection
31 (20)
22 (14)
19 (12)
15 (10)
15 (10)
14 (9)
10 (6)
10 (6)
18 (12)
16 (10)
6 (4)
8 (5)
5 (3)
7 (5)
11 (7)
12 (8)
0.06
0.39
0.01
0.19
0.04
0.17
1.0
0.83
DISCUSSION
The results of this study demonstrate that a 37.5-mg tramadol/325-mg acetaminophen combination tablet is a
safe, moderately effective, and well-tolerated medication
for the treatment of fibromyalgia pain and related symptoms. Although subjects in the tramadol/acetaminophen
group had a statistically significant improvement in the
primary outcome measure and many of the secondary
outcome measures as compared with placebo-treated
subjects, improvements from baseline values in the placebo group were also seen (Tables 2 and 3). This is not
unexpected, as pain is responsive to the placebo effect.
However, pain scores improved by 25% in the tramadol/
acetaminophen group compared with 5% in the placebo
group, and more subjects in the tramadol/acetaminophen group had substantial (⬎30% or ⬎50%) decreases
in their pain scores. In addition, the total Fibromyalgia
Impact Questionnaire score improved by 16% in the tramadol/acetaminophen group compared with 8% in the
placebo group. Thus, it seems likely that the overall benefit of tramadol/acetaminophen treatment is clinically
meaningful.
Treatment failure is common in fibromyalgia. A metaanalysis of 33 medication studies reported that antidepressants, muscle relaxants, and assorted other
medications had significant effects on physical status and
fibromyalgia symptoms (16). However, these effects were
greater in open-label studies than in placebo-controlled
studies. The reasons for the relative lack of success of
many pharmacologic treatments for fibromyalgia are not
entirely clear. In an attempt to design scientifically rigorous studies in this area, most previous studies have required discontinuing sleep medications and antidepressants. However, poor sleep and depression are associated
with increased symptoms of fibromyalgia. Thus, extensive washout protocols may be self-defeating, and many
rheumatologists believe that medications that are only
marginally effective for fibromyalgia in controlled studies
often seem more effective when used as part of a multidimensional treatment program. For this reason, antidepressants for the management of depression (but not
pain) and two commonly used hypnotics (zolpidem and
flurazepam) were permitted in this study. Furthermore,
subjects were asked not to alter their nonpharmacologic
therapies during the study.
Tramadol alone has been shown to be safe and efficacious for the management of fibromyalgia (31). The risk
of abuse and dependence with tramadol has been found
to be very low—approximately one reported case per
100,000 patient exposures. Reported cases of abuse and
dependence have occurred predominantly (97%) among
persons with a previous history of substance abuse and
dependence (39).
Acetaminophen has a low therapeutic:toxic ratio, and
patients should be informed about the inclusion of acetaminophen in the combination tablet. Adverse events are
rare with therapeutic doses of acetaminophen (ⱕ4 g/d),
but given the large number of products, both prescription
and over-the-counter, which contain acetaminophen,
there is a potential for accidental toxicity when several
acetaminophen products are combined.
Fibromyalgia is a chronic disorder that often requires
lifelong treatment using a multimodal approach to management (7,40). The current study shows that tramadol/
acetaminophen is of moderate benefit over a 13-week period. Further study is needed to determine whether the
long-term use of tramadol/acetaminophen will provide
enduring benefit in the management of fibromyalgia pain
and symptoms.
REFERENCES
1. Crofford LJ, Clauw DJ. Fibromyalgia: where are we a decade after
the American College of Rheumatology classification criteria were
developed? Arthritis Rheum. 2002;46:1136 –1138.
2. Wolfe F, Smythe HA, Yunus MB, et al. The American College of
Rheumatology 1990 criteria for the classification of fibromyalgia:
report of the Multicenter Criteria Committee. Arthritis Rheum.
1990;33:160 –172.
3. Bennett RM. Emerging concepts in the neurobiology of chronic
pain: evidence of abnormal sensory processing in fibromyalgia.
Mayo Clin Proc. 1999;74:385–398.
4. Staud R. Evidence of involvement of central neural mechanisms in
generating fibromyalgia pain. Curr Rheumatol Rep. 2002;4:299 –
305.
5. Lidbeck J. Central hyperexcitability in chronic musculoskeletal
pain: a conceptual breakthrough with multiple clinical implications. Pain Res Manag. 2002;7:81–92.
6. Aaron LA, Bradley LA, Alarcon GS, et al. Psychiatric diagnoses in
patients with fibromyalgia are related to health care-seeking behavior rather than to illness. Arthritis Rheum. 1996;39:436 –445.
7. Bennett RM. The rational management of fibromyalgia patients.
Rheum Dis Clin North Am. 2002;28:181–199.
8. Yunus MB, Masi AT, Aldag JC. Short term effects of ibuprofen in
primary fibromyalgia syndrome: a double blind, placebo controlled
trial. J Rheumatol. 1989;16:527–532.
May 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 114 543
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
9. Russell IJ, Fletcher EM, Michalek JE, et al. Treatment of primary
fibrositis/fibromyalgia syndrome with ibuprofen and alprazolam: a
double-blind, placebo-controlled study. Arthritis Rheum. 1991;34:
552–560.
10. Bennett RM, Gatter RA, Campbell SM, et al. A comparison of cyclobenzaprine and placebo in the management of fibrositis: a double-blind controlled study. Arthritis Rheum. 1988;31:1535–1542.
11. Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebocontrolled, double-blind, flexible-dose study of fluoxetine in the
treatment of women with fibromyalgia. Am J Med. 2002;112:191–
197.
12. Goldenberg D, Mayskiy M, Mossey C, et al. A randomized, doubleblind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852–1859.
13. Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20:294 –302.
14. Caruso I, Puttini PS, Cazzola M, Assolini V. Double-blind study of
5-hydroxytryptophan versus placebo in the treatment of primary
fibromyalgia syndrome. J Int Med Res. 1990;18:201–209.
15. Bennett RM, Clark SR, Walczyk J. A randomized, double-blind,
placebo-controlled study of growth hormone in the treatment of
fibromyalgia. Am J Med. 1998;104:227–231.
16. Rossy LA, Buckelew SP, Dorr N, et al. A meta-analysis of fibromyalgia treatment interventions. Ann Behav Med. 1999;21:180 –191.
17. Singh BB, Berman BM, Hadhazy VA, Creamer P. A pilot study of
cognitive behavioral therapy in fibromyalgia. Altern Ther Health
Med. 1998;4:67–70.
18. Wolfe F, Anderson J, Harkness D, et al. A prospective, longitudinal,
multicenter study of service utilization and costs in fibromyalgia.
Arthritis Rheum. 1997;40:1560 –1570.
19. Passik SD, Weinreb HJ. Managing chronic nonmalignant pain:
overcoming obstacles to the use of opioids. Adv Ther. 2000;17:70 –
83.
20. Rao SG. The neuropharmacology of centrally-acting analgesic
medications in fibromyalgia. Rheum Dis Clin North Am. 2002;28:
235–259.
21. Medve RA, Wang J, Karim R. Tramadol and acetaminophen tablets
for dental pain. Anesth Prog. 2001;48:79 –81.
22. Silverfield JC, Kamin M, Wu S-C, Rosenthal N. Tramadol/acetaminophen combination tablets for the treatment of osteoarthritis
flare pain: a multicenter, outpatient, randomized, double-blind,
placebo-controlled, parallel-group, add-on study. Clin Ther. 2002;
24:282–297.
23. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in
treatment of chronic low back pain. J Rheumatol. 2000;27:772–778.
24. Schnitzer TJ, Kamin M, Olson WH. Tramadol allows reduction of
naproxen dose among patients with naproxen-responsive osteoarthritis pain: a randomized, double-blind, placebo-controlled study.
Arthritis Rheum. 1999;42:1370 –1377.
25. Grond S, Radbruch L, Meuser T, et al. High-dose tramadol in comparison to low-dose morphine for cancer pain relief. J Pain Symptom Manage. 1999;18:174 –179.
26. Stamer UM, Maier C, Grond S, et al. Tramadol in the management
of post-operative pain: a double-blind, placebo- and drug-controlled study. Eur J Anaesthesiol. 1997;14:646 –654.
27. Lauerma H, Markkula J. Treatment of restless legs syndrome with
tramadol: an open study. J Clin Psychiatry. 1999;60:241–244.
28. Eggers K, Power I. Tramadol hydrochloride—not just another opioid agonist. Br J Clin Pharmacol. 1995;39:338 –339.
29. Harati Y, Gooch C, Swenson M, et al. Maintenance of the long-term
effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications. 2000;14:65–70.
544
May 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 114
30. Russell IJ, Kamin M, Bennett RM, et al. Efficacy of tramadol in
treatment of pain in fibromyalgia. J Clin Rheumatol. 2000;6:250 –
257.
31. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid
components independently contribute to the mechanism of action
of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther.
1992;260:275–285.
32. Sandrini M, Romualdi P, Vitale G, et al. The effect of a paracetamol
and morphine combination on dynorphin A levels in the rat brain.
Biochem Pharmacol. 2001;61:1409 –1416.
33. Raffa RB, Stone DJ Jr, Tallarida RJ. Discovery of “self-synergistic”
spinal/supraspinal antinociception produced by acetaminophen
(paracetamol). J Pharmacol Exp Ther. 2000;295:291–294.
34. Sandrini M, Romualdi P, Capobianco A, et al. The effect of paracetamol on nociception and dynorphin A levels in the rat brain.
Neuropeptides. 2001;35:110 –116.
35. Tallarida RJ, Raffa RB. Testing for synergism over a range of fixed
ratio drug combinations: replacing the isobologram. Life Sci. 1996;
58:PL23–PL28.
36. Burckhardt CS, Clark SR, Bennett RM. The fibromyalgia impact
questionnaire: development and validation. J Rheumatol. 1991;18:
728 –733.
37. Jenkinson C, Coulter A, Wright L. Short Form 36 (SF36) health
survey questionnaire: normative data for adults of working age.
BMJ. 1993;306:1437–1440.
38. Hays RD, Stewart AL. Sleep measures. In: Stewart AL, Ware JE Jr,
eds. Measuring Function and Well-Being: the Medical Outcomes
Study Approach. Durham, North Carolina: Duke University Press;
1992:235–259.
39. Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance
program to monitor Ultram® (tramadol hydrochloride) abuse in
the United States. Drug Alcohol Depend. 1999;57:7–22.
40. Littlejohn GO, Walker J. A realistic approach to managing patients
with fibromyalgia. Curr Rheumatol Rep. 2002;4:286 –292.
APPENDIX
The lead investigators and sites for the study are as follows: Barry Bockow, MD, Arthritis Northwest, Seattle,
Washington; David G. Borenstein, MD, Arthritis and
Rheumatism Associates, Washington, D.C; Jacques Caldwell, MD, Gainesville Clinical Research Center, Gainesville, Florida; Ronald D. Emkey, MD, Emkey Arthritis &
Osteoporosis Clinic, Inc., Wyomissing, Pennsylvania;
Mark Ettinger, MD, Clinical Research Center of South
Florida, Stuart, Florida; Geoffrey Gladstein, MD, Stamford Therapeutics Consortium, Stamford, Connecticut;
Maria Greenwald, MD, AIM, Rancho Mirage, California;
Alan Kaell, MD, Rheumatology Associates of Long Island, Port Jefferson, New York; Ahmad Kashif, MD,
Nalle Clinic, Charlotte, North Carolina; Warren A. Katz,
MD, Presbyterian Medical Center/Arthritis Associates of
Philadelphia, Philadelphia, Pennsylvania; Alan Kivitz,
MD, Altoona Center for Clinical Research, Duncansville,
Pennsylvania; Larry Moreland, MD, The University of
Alabama at Birmingham Spain Rehabilitation Center,
Birmingham, Alabama; R. Zorba Paster, MD, Dean Medical Center–Oregon, Oregon, Wisconsin; Dianne L.
Petrone, MD, Arthritis Centers of Texas/Research Associates of North Texas, Dallas, Texas; Ronald Rapoport,
MD, Phase III Clinical Research, Fall River, Massachu-
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
setts; Sanford H. Roth, MD, Arizona Research and Education, Phoenix, Arizona; Ralph Rothenberg, MD, Rheumatology Associates, Inc, Youngstown, Ohio; Gary E.
Ruoff, MD, Westside Family Medical Center, Kalamazoo, Michigan; I. Jon Russell, MD, The University of
Texas Health Science Center at San Antonio, San Antonio, Texas; Daniel Sager, MD, Clinical Research Group of
Oregon, Portland, Oregon; Bruce Samuels, MD, Strafford Medical Associates, Dover, New Hampshire; Phil-
ippe Saxe, MD, Arthritis Associates of South Florida, Delray Beach, Florida; Thomas J. Schnitzer, MD, Northwestern Center for Clinical Research, Chicago, Illinois;
William J. Shergy, MD, RANA—Clinical Research,
Huntsville, Alabama; Tammi Shlotzhauer, MD, Rochester Clinical Research, Inc., Rochester, New York; Stuart
Silverman, MD, Osteoporosis Medical Center, Beverly
Hills, California; Muhammad B. Yunus, MD, University
of Illinois College of Medicine at Peoria, Peoria, Illinois.
May 2003
THE AMERICAN JOURNAL OF MEDICINE威
Volume 114 545