Tramadol and Acetaminophen Combination Tablets in the Treatment of Fibromyalgia Pain: A Double-Blind, Randomized, Placebo-Controlled Study
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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 combina- treated subjects also had significantly less pain at the end of the
tion analgesic tablet (37.5 mg tramadol/325 mg acetamino- study (53 ⫾ 32 vs. 65 ⫾ 29 on a visual analog scale of 0 to 100, P
phen) for the treatment of fibromyalgia pain. ⬍0.001), and better pain relief (1.7 ⫾ 1.4 vs. 0.8 ⫾ 1.3 on a scale
METHODS: This 91-day, multicenter, double-blind, random- of –1 to 4, P ⬍0.001) and Fibromyalgia Impact Questionnaire
ized, placebo-controlled study compared tramadol/acetamino- scores (P ⫽ 0.008). Indexes of physical functioning, role-phys-
phen combination tablets with placebo. The primary outcome ical, body pain, health transition, and physical component sum-
variable was cumulative time to discontinuation (Kaplan-Meier mary all improved significantly in the tramadol/acetamino-
analysis). Secondary measures at the end of the study included phen-treated subjects. Discontinuation due to adverse events
pain, pain relief, total tender points, myalgia, health status, and occurred in 19% (n ⫽ 29) of tramadol/acetaminophen-treated
Fibromyalgia Impact Questionnaire scores.
subjects and 12% (n ⫽ 18) of placebo-treated subjects (P ⫽
RESULTS: Of the 315 subjects who were enrolled in the study,
0.09). The mean dose of tramadol/acetaminophen was 4.0 ⫾ 1.8
313 (294 women [94%], mean [⫾ SD] age, 50 ⫾ 10 years)
tablets per day.
completed at least one postrandomization efficacy assessment
CONCLUSION: A tramadol/acetaminophen combination
(tramadol/acetaminophen: n ⫽ 156; placebo: n ⫽ 157). Dis-
continuation of treatment for any reason was less common in tablet was effective for the treatment of fibromyalgia pain with-
those treated with tramadol/acetaminophen compared with out any serious adverse effects. Am J Med. 2003;114:537–545.
placebo (48% vs. 62%, P ⫽ 0.004). Tramadol/acetaminophen- ©2003 by Excerpta Medica Inc.
F
ibromyalgia is a common syndrome characterized inflammatory drugs (NSAIDs), benzodiazepines, and
by widespread pain and tenderness (1). The stan- calcitonin are not more effective than placebo (8,9).
dardization of diagnostic criteria for fibromyalgia Some success has been reported with other pharmaco-
(2) has stimulated research on this disorder, and better logic agents, such as tricyclic antidepressants and fluox-
understanding of the scientific basis of pain over the last etine (10 –15), as well as nonpharmacologic therapies
decade has led to the reformulation of fibromyalgia as a (16,17). Amitriptyline is used commonly, although only
chronic pain state with disordered sensory processing 25% to 30% of patients improve and the beneficial effects
and a heterogeneous clinical presentation (3– 6). The are not sustained (16). One study reported that opioids
generally accepted approach to treating fibromyalgia is a were prescribed to about 15% of fibromyalgia patients in
multimodal regimen that includes patient education, a tertiary care setting (18). The adverse effects of opioids
cognitive behavioral therapy, gentle exercise, and medi- are often a deterrent to patient acceptance, however, and
cations to help with sleep and pain (7). regulatory issues may deter physician prescribing (19).
No medication is currently approved for the treatment There is an increasing realization that a polypharma-
of fibromyalgia in the United States. Nonsteroidal anti- cologic 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/
From the Oregon Health and Science University (RMB), Portland, Or-
egon; Ortho-McNeil Pharmaceutical (MK, NR), Raritan, New Jersey; 325-mg acetaminophen combination tablet has been ef-
and Johnson and Johnson Pharmaceutical Research and Development fective for pain relief among patients who underwent
(RK), Titusville, New Jersey. dental surgery (21), and as add-on therapy in the treat-
This study was supported by a grant (CAPSS-113) from Ortho-
McNeil Pharmaceutical, Inc, Raritan, New Jersey. All investigators were ment of pain due to osteoarthritis not controlled by
financially reimbursed by Ortho-McNeil Pharmaceutical for conduct- NSAIDs (22).
ing this study.
Correspondence should be addressed to Robert M. Bennett, MD,
Tramadol is a centrally acting analgesic that is useful in
Department of Medicine, Oregon Health and Science University the treatment of many pain disorders, including neuro-
(OP09), 3181 SW Sam Jackson Park Road, Portland, Oregon 97201, or pathic pain and fibromyalgia (23–30). Tramadol has a
bennetro@ohsu.edu.
Manuscript submitted March 25, 2002, and accepted in revised form unique mechanism of action that combines mu-opioid
November 27, 2002. activity with inhibition of serotonin/norepinephrine re-
©2003 by Excerpta Medica Inc. 0002-9343/03/$–see front matter 537
All rights reserved. doi:10.1016/S0002-9343(03)00116-5Tramadol/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 ture, or transcutaneous electrical nerve stimulation
other medications to enhance therapeutic efficacy. For within 3 weeks before enrollment; recent use (within 5
example, subactive amounts of acetaminophen and mor- half-lives) of other sedative hypnotics, short-acting anal-
phine exert analgesic effects when given in combination gesics (including acetaminophen), topical medications/
(32). Acetaminophen acts centrally via mechanisms that anesthetics, or muscle relaxants; tender point anesthetic
appear to involve a synergistic interaction between spinal injections within 2 months; systemic steroids within 3
and supraspinal sites (33,34). The approximately 1:8 mg- months; or any investigational drug/device in the prior 30
to-mg tramadol:acetaminophen ratio was based on dem- days.
onstrated synergy in animal models (35). The study was designed in accordance with the Decla-
Fibromyalgia is a central pain state involving distur- ration of Helsinki, and an independent Institutional Re-
bances of neurochemical pathways that are thought to be view Board approved the study protocol. Investigators at
affected by both tramadol and acetaminophen. The pur- 27 sites participated (Appendix).
pose of this study was to examine the analgesic efficacy
and safety of 37.5-mg tramadol/325-mg acetaminophen
Intervention
Before entry into the double-blind phase of the study, all
tablets in the treatment of fibromyalgia pain.
subjects completed a screening and washout phase of up
to 3 weeks’ duration. Subjects were then randomly as-
METHODS signed to receive tramadol/acetaminophen (37.5-mg/
325-mg tablet, ULTRACET™; Ortho-McNeil Pharma-
Study Design and Sample ceutical, Raritan, New Jersey) or matching placebo (Fig-
This out-patient multicenter, randomized, double-blind,
ure 1). Study medication was titrated over a 10-day
placebo-controlled study was conducted in adult subjects
period from one tablet per day to four tablets per day.
aged 18 to 75 years with at least moderate pain from fi-
Thereafter, subjects took one to two tablets four times
bromyalgia, defined as ⱖ40 mm on a 100-mm pain visual
daily, to a maximum of eight tablets per day (total of 300
analog scale. All subjects fulfilled the 1990 American Col-
mg tramadol/2600 mg acetaminophen). Doses were se-
lege of Rheumatology classification guidelines for the di-
lected on the basis of previous studies of tramadol and
agnosis of fibromyalgia (2). Subjects were also required to
acetaminophen for chronic pain, including fibromyalgia
be in general good health, and women were required to be
pain.
practicing contraception or incapable of pregnancy.
Exclusion criteria included previous failure of tram- Randomization/Blinding
adol therapy (4 patients excluded), use of tramadol in the Subjects were assigned sequentially in 1:1 fashion at each
prior 30 days, and any other pain that was more severe site using a randomized list of medication codes. Tram-
than the fibromyalgia pain. Patients were allowed to take adol/acetaminophen or matching placebo tablets were
a low-dose selective serotonin reuptake inhibitor (SSRI) prepared by the sponsor and dispensed in bottles con-
or St. John’s wort (but not both) for depression, and zol- taining 100 tablets. Each bottle had a two-part tear-off
pidem and flurazepam for sleep, provided they had been label; study medication identification was concealed and
on a stable dose of these drugs for at least 1 month. We could only be revealed in case of emergency. Treatment
excluded patients who had used other antidepressants, assignments were not revealed to study subjects, investi-
cyclobenzaprine, antiepileptic drugs for pain, acupunc- gators, clinical staff, or study monitors until all subjects
538 May 2003 THE AMERICAN JOURNAL OF MEDICINE威 Volume 114Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Figure 2. Flow chart of subject disposition.
had completed therapy and the database had been final- 12-question survey used to evaluate sleep habits during
ized. the previous 4 weeks, administered on day 1 and at the
final visit. Scores are transformed to a 0 to 100 scale and
Outcome Measures
used to derive two overall sleep indexes: Sleep Index 6
Visits were scheduled for days 1, 14, 28, 56, and 91 (Figure
(from six of the questions) and Sleep Index 9 (from nine
1). The primary efficacy variable was defined in the pro-
of the questions). Lower values represent better sleep.
tocol as cumulative time to discontinuation due to lack of
A complete medical history, physical examination, and
efficacy. However, because discontinuation due to lack of
urinalysis were performed at the screening visit (day –21)
efficacy may be underestimated owing to competing
and the final visit. Vital signs (sitting pulse, blood pres-
risks, discontinuation for any reason was also analyzed
sure, and weight) were measured at baseline and at each
and this more conservative analysis is highlighted here to
visit. Chemistry and hematology laboratory tests were
reflect clinical practice.
performed at screening and at visits on days 28, 56, and
Secondary variables measured at each visit included
91.
pain on a visual analog scale (100-mm line, from no pain
Adverse events were recorded at each visit, whether
to extreme pain [100]) and a pain relief rating scale (com-
spontaneously reported or in response to general, nondi-
plete ⫽ 4, a lot ⫽ 3, moderate ⫽ 2, slight ⫽ 1, none ⫽ 0,
rected questioning. Adverse events were summarized by
worse ⫽ –1). At the first and last visits, investigators de-
World Health Organization Adverse Reaction Terminol-
termined the number of tender points (of 18) and myal-
ogy body system and preferred term. If a subject discon-
gic score (no pain ⫽ 0, patient complains of pain only ⫽
tinued treatment, all efficacy and safety variables that
1, patient reacts to pain emotionally ⫽ 2, patient with-
were planned for the final visit were recorded at the time
draws or flinches ⫽ 3); an average myalgic score was cal-
of discontinuation.
culated. Subjects also completed the 10-item Fibromyal-
gia Impact Questionnaire (36), the Short Form 36 (SF- Statistical Analyses
36) health survey (37), and a 12-item sleep questionnaire Efficacy analyses were performed on the intent-to-treat
at the first and last visit (38). The Sleep Questionnaire is a sample, comprised of all enrolled subjects who took at
May 2003 THE AMERICAN JOURNAL OF MEDICINE威 Volume 114 539Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Table 1. Demographic Characteristics of the Sample of Sub- 75%). The calculated sample size of 112 subjects per
jects with Fibromyalgia* group was increased approximately 30% to compensate
Tramadol/ for patients who dropped out because of adverse events,
Acetaminophen Placebo for a total of 150 subjects in each group. All analyses were
Characteristic (n ⫽ 156) (n ⫽ 157) performed with SAS Version 6.12 software (Cary, North
Number (%) or Mean ⫾ SD
Carolina).
Age (years) 49 ⫾ 11 51 ⫾ 10
Female sex 145 (93) 149 (95) RESULTS
Race
White 151 (97) 147 (94) A total of 315 subjects were assigned randomly to tram-
Black 4 (3) 10 (6) adol/acetaminophen (n ⫽ 158) or placebo (n ⫽ 157), of
Asian 1 (1) 0 whom 313 were evaluable for efficacy and 312 were evalu-
* Only patients included in the intention-to-treat analyses for efficacy able for safety (Figure 2). Subjects ranged in age from 19
are included in this and subsequent tables. 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
least one dose of study medication and for whom a post- were no significant baseline differences between the two
randomization efficacy measurement was available. Time groups (Tables 1 to 3).
to discontinuation was examined by survival analysis
Primary Efficacy Outcome
techniques, and statistical significance was assessed with
The cumulative rate of discontinuation of therapy for any
the generalized Wilcoxon test. Cox proportional hazards
reason was significantly lower in the tramadol/acetamin-
analyses were performed for two outcomes: discontinua-
ophen group (48% by day 91) than in the placebo group
tion due to any reason and discontinuation due to lack of
(62% by day 91; P ⫽ 0.004; Figure 3A). The cumulative
efficacy; these analyses adjusted for baseline pain and
rate of discontinuation due to lack of efficacy was also
clinical center. Data from small centers (⬍10 subjects)
significantly lower in the tramadol/acetaminophen group
were pooled for this purpose. Secondary efficacy variables
(29% by day 91) than in the placebo group (51% by day
were summarized and assessed with analysis of covari-
91; P ⬍0.001; Figure 3B).
ance adjusting for baseline pain. Changes from baseline
in vital signs and clinical laboratory values were also as- Secondary Outcome Measures
sessed. Proportions of subjects with adverse events were Compared with placebo, the mean final pain score was
compared using the Fisher exact test. Statistical signifi- about 12 mm (18%) lower in the tramadol/acetamino-
cance was set at P ⬍0.05 (two-sided). The sample size was phen group (Table 2; P ⬍0.001). Similarly, mean final
determined to have 90% power to detect a 20% difference pain relief was significantly better in the tramadol/acet-
in discontinuation rates due to lack of efficacy (55% vs. aminophen group than in the placebo group (Table 2;
Table 2. Pain and Symptoms at Baseline and the Final Visit
Baseline Final Visit
Tramadol/ Tramadol/
Acetaminophen Placebo Acetaminophen Placebo
Characteristic (n ⫽ 156) (n ⫽ 157) (n ⫽ 156) (n ⫽ 157) P Value*
Pain score (mm)† 72 ⫾ 14 72 ⫾ 15 53 ⫾ 32 65 ⫾ 29 ⬍0.001
Pain relief score‡ — — 1.7 ⫾ 1.4 0.8 ⫾ 1.3 ⬍0.001
Number of tender points 16 ⫾ 2.2 16 ⫾ 2.3 13 ⫾ 4.9 14 ⫾ 4.3 0.04
Average myalgic score§ 1.7 ⫾ 0.6 1.7 ⫾ 0.6 1.3 ⫾ 0.8 1.5 ⫾ 0.8 0.06
Sleep questionnaire㛳
Sleep Index 6 62 ⫾ 16 61 ⫾ 17 54 ⫾ 18 54 ⫾ 18 0.78
Sleep Index 9 62 ⫾ 16 61 ⫾ 16 55 ⫾ 17 55 ⫾ 18 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 114Tramadol/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 Final Visit
Tramadol/ Tramadol/
Acetaminophen Placebo Acetaminophen Placebo
Characteristic (n ⫽ 156) (n ⫽ 157) (n ⫽ 156) (n ⫽ 157) P Value*
Mean ⫾ SD
†
Fibromyalgia Impact Questionnaire
Total score 54 ⫾ 11 55 ⫾ 11 44 ⫾ 17 50 ⫾ 15 0.008
Physical impairment 4.4 ⫾ 2.4 4.8 ⫾ 2.2 3.7 ⫾ 2.6 4.5 ⫾ 2.5 0.02
Feel good 2.1 ⫾ 2.3 2.1 ⫾ 2.0 4.1 ⫾ 3.1 2.9 ⫾ 2.8 0.001
Work missed 0.9 ⫾ 2.1 0.8 ⫾ 1.9 0.8 ⫾ 2.0 1.1 ⫾ 2.3 0.19
Do job 6.1 ⫾ 2.2 6.4 ⫾ 2.4 5.1 ⫾ 2.8 5.9 ⫾ 2.7 0.04
Pain 7.2 ⫾ 1.7 7.2 ⫾ 1.6 5.7 ⫾ 2.7 6.4 ⫾ 2.5 0.02
Fatigue 8.0 ⫾ 1.7 8.1 ⫾ 1.6 7.0 ⫾ 2.4 7.3 ⫾ 2.4 0.41
Rest 8.1 ⫾ 1.6 8.2 ⫾ 1.6 6.7 ⫾ 2.5 7.2 ⫾ 2.4 0.02
Stiffness 7.7 ⫾ 1.8 7.9 ⫾ 1.6 6.2 ⫾ 2.7 7.0 ⫾ 2.3 0.008
Anxiety 5.5 ⫾ 2.9 5.8 ⫾ 2.9 4.7 ⫾ 3.0 5.5 ⫾ 3.0 0.03
Depression 5.0 ⫾ 2.9 5.0 ⫾ 2.9 4.4 ⫾ 3.1 4.8 ⫾ 3.0 0.25
SF-36 health survey‡
Physical functioning 40 ⫾ 23 37 ⫾ 21 48 ⫾ 26 40 ⫾ 23 0.005
Role-physical 11 ⫾ 23 12 ⫾ 25 29 ⫾ 25 17. ⫾ 29 0.001
Bodily pain 29 ⫾ 13 27 ⫾ 13 40 ⫾ 22 32 ⫾ 19 0.002
General health 48 ⫾ 20 45 ⫾ 22 53 ⫾ 22 47 ⫾ 22 0.08
Vitality 20 ⫾ 17 20 ⫾ 16 30 ⫾ 21 27 ⫾ 20 0.18
Social functioning 52 ⫾ 24 47 ⫾ 27 60 ⫾ 28 53 ⫾ 29 0.26
Role-emotional 38 ⫾ 41 46 ⫾ 42 47 ⫾ 44 46 ⫾ 43 0.41
Mental health 59 ⫾ 20 60 ⫾ 19 64 ⫾ 21 62 ⫾ 19 0.14
Reported health transition 63 ⫾ 24 64 ⫾ 24 50 ⫾ 31 58 ⫾ 28 0.03
Physical component summary 29 ⫾ 7.2 28 ⫾ 7.5 34 ⫾ 9.4 29 ⫾ 8.4 0.001
Mental component summary 41 ⫾ 11 42 ⫾ 11 44 ⫾ 12 43 ⫾ 12 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 There were no treatment-related differences in the an-
group also had a significantly greater decrease in the swers to questions about sleep (Table 2).
number of tender points during the trial, and lower aver- A stable dose of an SSRI for depression was used by 56
age myalgic scores at the end of the trial (Table 2). patients (30 in the tramadol/acetaminophen group and
Forty-two percent (65/156) of the tramadol/acetamin- 26 in the placebo group) for at least 1 month before the
ophen group had at least a 30% reduction in pain score, study. After excluding these patients, discontinuation of
compared with 24% (37/157) of the placebo group (18% the study treatment for any reason (P ⫽ 0.03) or for lack
difference; 95% confidence interval [CI]: 8% to 28%; P of efficacy (P ⫽ 0.002) was still less common in the tram-
⬍0.01). Similarly, 35% (n ⫽ 54) of the tramadol/acet- adol/acetaminophen group.
aminophen-treated subjects had at least a 50% reduction
in pain, compared with 18% (n ⫽ 29) of the placebo- Safety
treated subjects (16% difference; 95% CI: 7% to 26%; P A total of 156 subjects in each group were evaluated for
⬍0.01). safety. Subjects in the tramadol/acetaminophen group
Significant differences favoring the tramadol/acet- took an average of 151 mg/d of tramadol and 1238 mg/d
aminophen group were also found for the total Fibromy- of acetaminophen (mean daily dose of 4.0 ⫾ 1.8 tablets).
algia Impact Questionnaire score, as well as for six of the Adverse events, regardless of relation to study medica-
11 individual subscales, at the end of the study (Table 3). tion, led to study discontinuation in 19% (n ⫽ 29) of
There were also significant differences in several mea- tramadol/acetaminophen subjects and 12% (n ⫽ 18) of
sures of health status at the end of the study (Table 3). placebo subjects (P ⫽ 0.09; Figure 2). In all, 118 subjects
May 2003 THE AMERICAN JOURNAL OF MEDICINE威 Volume 114 541Tramadol/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 commonly occurring treatment-related adverse events in least one adverse event, compared with 87 subjects (56%) the placebo group were nausea (n ⫽ 7 [4%]) and somno- in the placebo group (P ⬍0.001; Table 4). lence (n ⫽ 5 [3%]). No serious adverse event was consid- Treatment-related adverse events (deemed by the in- ered by the investigators to be related to the study medi- vestigators to be related to the study medication) oc- cation. curred in 32 (21%) of tramadol/acetaminophen subjects No clinically relevant trends were identified in changes and 14 (9%) of placebo subjects (P ⫽ 0.005). The most in vital signs or hematology, chemistry, or urinalysis val- commonly occurring (⬎3%) treatment-related adverse ues. All markedly abnormal laboratory values during the events in the tramadol/acetaminophen group were nau- trial were transient, or were thought by the investigator to sea (n ⫽ 14 [9%]), dizziness (n ⫽ 5 [3%]), somnolence be not clinically important or to be attributable to causes (n ⫽ 5 [3%]), and constipation (n ⫽ 5 [3%]). The most other than study medication. 542 May 2003 THE AMERICAN JOURNAL OF MEDICINE威 Volume 114
Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
Table 4. Adverse Events Reported by ⱖ4.5% of Subjects in Ei- marginally effective for fibromyalgia in controlled studies
ther Group (n ⫽ 312) often seem more effective when used as part of a multidi-
Tramadol/ mensional treatment program. For this reason, antide-
Acetaminophen Placebo pressants for the management of depression (but not
Adverse Event (n ⫽ 156) (n ⫽ 156) P Value pain) and two commonly used hypnotics (zolpidem and
Number (%)
flurazepam) were permitted in this study. Furthermore,
subjects were asked not to alter their nonpharmacologic
Nausea 31 (20) 18 (12) 0.06 therapies during the study.
Headache 22 (14) 16 (10) 0.39 Tramadol alone has been shown to be safe and effica-
Pruritus 19 (12) 6 (4) 0.01
cious for the management of fibromyalgia (31). The risk
Dizziness 15 (10) 8 (5) 0.19
Constipation 15 (10) 5 (3) 0.04
of abuse and dependence with tramadol has been found
Somnolence 14 (9) 7 (5) 0.17 to be very low—approximately one reported case per
Sinusitis 10 (6) 11 (7) 1.0 100,000 patient exposures. Reported cases of abuse and
Upper respiratory 10 (6) 12 (8) 0.83 dependence have occurred predominantly (97%) among
tract infection persons with a previous history of substance abuse and
dependence (39).
Acetaminophen has a low therapeutic:toxic ratio, and
DISCUSSION patients should be informed about the inclusion of acet-
aminophen in the combination tablet. Adverse events are
The results of this study demonstrate that a 37.5-mg tra- rare with therapeutic doses of acetaminophen (ⱕ4 g/d),
madol/325-mg acetaminophen combination tablet is a but given the large number of products, both prescription
safe, moderately effective, and well-tolerated medication and over-the-counter, which contain acetaminophen,
for the treatment of fibromyalgia pain and related symp- there is a potential for accidental toxicity when several
toms. Although subjects in the tramadol/acetaminophen acetaminophen products are combined.
group had a statistically significant improvement in the Fibromyalgia is a chronic disorder that often requires
primary outcome measure and many of the secondary lifelong treatment using a multimodal approach to man-
outcome measures as compared with placebo-treated agement (7,40). The current study shows that tramadol/
subjects, improvements from baseline values in the pla- acetaminophen is of moderate benefit over a 13-week pe-
cebo group were also seen (Tables 2 and 3). This is not riod. Further study is needed to determine whether the
unexpected, as pain is responsive to the placebo effect. long-term use of tramadol/acetaminophen will provide
However, pain scores improved by 25% in the tramadol/ enduring benefit in the management of fibromyalgia pain
acetaminophen group compared with 5% in the placebo and symptoms.
group, and more subjects in the tramadol/acetamino-
phen group had substantial (⬎30% or ⬎50%) decreases
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APPENDIX
235–259. The lead investigators and sites for the study are as fol-
21. Medve RA, Wang J, Karim R. Tramadol and acetaminophen tablets lows: Barry Bockow, MD, Arthritis Northwest, Seattle,
for dental pain. Anesth Prog. 2001;48:79 –81. Washington; David G. Borenstein, MD, Arthritis and
22. Silverfield JC, Kamin M, Wu S-C, Rosenthal N. Tramadol/acet- Rheumatism Associates, Washington, D.C; Jacques Cald-
aminophen combination tablets for the treatment of osteoarthritis well, MD, Gainesville Clinical Research Center, Gaines-
flare pain: a multicenter, outpatient, randomized, double-blind, ville, Florida; Ronald D. Emkey, MD, Emkey Arthritis &
placebo-controlled, parallel-group, add-on study. Clin Ther. 2002;
Osteoporosis Clinic, Inc., Wyomissing, Pennsylvania;
24:282–297.
23. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in Mark Ettinger, MD, Clinical Research Center of South
treatment of chronic low back pain. J Rheumatol. 2000;27:772–778. Florida, Stuart, Florida; Geoffrey Gladstein, MD, Stam-
24. Schnitzer TJ, Kamin M, Olson WH. Tramadol allows reduction of ford Therapeutics Consortium, Stamford, Connecticut;
naproxen dose among patients with naproxen-responsive osteoar- Maria Greenwald, MD, AIM, Rancho Mirage, California;
thritis pain: a randomized, double-blind, placebo-controlled study. Alan Kaell, MD, Rheumatology Associates of Long Is-
Arthritis Rheum. 1999;42:1370 –1377.
land, Port Jefferson, New York; Ahmad Kashif, MD,
25. Grond S, Radbruch L, Meuser T, et al. High-dose tramadol in com-
parison to low-dose morphine for cancer pain relief. J Pain Symp-
Nalle Clinic, Charlotte, North Carolina; Warren A. Katz,
tom Manage. 1999;18:174 –179. MD, Presbyterian Medical Center/Arthritis Associates of
26. Stamer UM, Maier C, Grond S, et al. Tramadol in the management Philadelphia, Philadelphia, Pennsylvania; Alan Kivitz,
of post-operative pain: a double-blind, placebo- and drug-con- MD, Altoona Center for Clinical Research, Duncansville,
trolled study. Eur J Anaesthesiol. 1997;14:646 –654. Pennsylvania; Larry Moreland, MD, The University of
27. Lauerma H, Markkula J. Treatment of restless legs syndrome with Alabama at Birmingham Spain Rehabilitation Center,
tramadol: an open study. J Clin Psychiatry. 1999;60:241–244.
Birmingham, Alabama; R. Zorba Paster, MD, Dean Med-
28. Eggers K, Power I. Tramadol hydrochloride—not just another opi-
oid agonist. Br J Clin Pharmacol. 1995;39:338 –339.
ical Center–Oregon, Oregon, Wisconsin; Dianne L.
29. Harati Y, Gooch C, Swenson M, et al. Maintenance of the long-term Petrone, MD, Arthritis Centers of Texas/Research Asso-
effectiveness of tramadol in treatment of the pain of diabetic neu- ciates of North Texas, Dallas, Texas; Ronald Rapoport,
ropathy. J Diabetes Complications. 2000;14:65–70. MD, Phase III Clinical Research, Fall River, Massachu-
544 May 2003 THE AMERICAN JOURNAL OF MEDICINE威 Volume 114Tramadol/Acetaminophen for Fibromyalgia/Bennett et al
setts; Sanford H. Roth, MD, Arizona Research and Edu- ippe Saxe, MD, Arthritis Associates of South Florida, Del-
cation, Phoenix, Arizona; Ralph Rothenberg, MD, Rheu- ray Beach, Florida; Thomas J. Schnitzer, MD, Northwest-
matology Associates, Inc, Youngstown, Ohio; Gary E. ern Center for Clinical Research, Chicago, Illinois;
Ruoff, MD, Westside Family Medical Center, Kalama- William J. Shergy, MD, RANA—Clinical Research,
zoo, Michigan; I. Jon Russell, MD, The University of Huntsville, Alabama; Tammi Shlotzhauer, MD, Roches-
Texas Health Science Center at San Antonio, San Anto- ter Clinical Research, Inc., Rochester, New York; Stuart
nio, Texas; Daniel Sager, MD, Clinical Research Group of Silverman, MD, Osteoporosis Medical Center, Beverly
Oregon, Portland, Oregon; Bruce Samuels, MD, Straf- Hills, California; Muhammad B. Yunus, MD, University
ford Medical Associates, Dover, New Hampshire; Phil- of Illinois College of Medicine at Peoria, Peoria, Illinois.
May 2003 THE AMERICAN JOURNAL OF MEDICINE威 Volume 114 545You can also read
