A meta-analysis of fibromyalgia treatment interventions

A META-ANALYSIS OF FIBROMYALGIA T R E A T M E N T INTERVENTIONS 1,2

Lynn A. Rossy, M.A. and Susan P. Buckelew, Ph.D. University of Missouri-Columbia

Nancy Dorr, Ph.D. Jamestown College

Kristofer J. Hagglund, Ph.D., Julian F. Thayer, Ph.D., Matthew J. McIntosh, M.A., John E. Hewett, Ph.D., and Jane C. Johnson, M.A.

University of Missouri-Columbia

ABSTRACT

Objective: To evaluate and compare the efficacy of pharmacological and nonpharmacological treatments of fibromyalgia syndrome (FMS). Methods: This meta-analysis of 49 fibromyalgia treatment outcome studies assessed the efficacy of pharmacological and nonpharmacological treatment across four types of outcome measures--physical status, self-report of FMS symptoms, psychological status, and daily functioning. Results: After controlling for study design, antidepressants resulted in improvements on physical status and self-report of FMS symptoms. All nonpharmacological treatments were associated with significant improvements in all four categories of outcome measures with the exception that physically-based treatment (primarily exercise) did not significantly improve daily functioning. When compared, nonpharmacological treatment appears to be more efficacious in improving self-report of FMS symptoms than pharmacological treatment alone. A similar trend was suggested for functional measures. Conclusion: The optimal intervention for FMS would include nonpharmacological treatments, specifically exercise and cognitive-behavioral therapy, in addition to appropriate medication management as needed for sleep and pain symptoms.

(Ann Behav Med 1999, 21(2):180-191)

INTRODUCTION Fibromyalgia syndrome (FMS) is one of the most common

disorders seen by rheumatologists and perhaps the most enigmatic. The prevalence of FMS is estimated to be 2% (3.4% for women and .5% for men) (1). The etiology of FMS is still not understood, but symptoms include sleep disturbance, fatigue, pain (especially at tender points), impairment in daily functioning, and often affective distress. Therefore, treatment studies have focused on the efficacy of pharmacologic and nonpharmacologic interventions to relieve the multiple physical and psychological symptoms of FMS.

Over the last 10 years, there has been a marked increase in published research of fibromyalgia. While some reviews of the

a Preparation of this manuscript was supported in part by grants from the National Institute of Health (DHHS 1 T32 HD 07460-02) and the National Institute on Disability and Rehabilitation Research (H133B30039-96).

2 The authors would like to acknowledge the assistance of Christy Mueller in coding studies for this analysis.

Reprint Address: L. A. Rossy, M.A., Department of Psychology, 210 McAlester Hall, University of Missouri, Columbia, MO 65211.

�9 1999 by The Society of Behavioral Medicine.

FMS literature have been conducted, with one exception (2), these reviews have been qualitative in nature. The one published quantitative review (2) examined the results of 24 controlled clinical trials of FMS treatments, evaluating methodological issues including type of outcome measures, the ability of each outcome measure to distinguish between individuals in treatment and placebo groups, and study design. Results indicated that a diversity of outcome constructs and measurement instruments have been used and no two trials have used the same outcome measures. As many as nine different instruments have been used for a single outcome measure. Also, clinically important outcomes such as psychological and functional status were infrequently included in data collection. Moreover, the authors concluded that limitations in study design, such as incomplete blinding of outcome evaluators, inadequate randomization, flaws in participant selection and group allocation, and inappropriate analysis of data render valid interpre- tation of findings untenable. This review thoroughly addressed the methodological aspects of research in FMS, but did not examine treatment efficacy.

The objective of the current meta-analysis was to provide a quantitative review of the efficacy of pharmacological and nonpharmacological FMS treatment across four outcome domains commonly used in clinical practice including physical status, self- report of FMS symptoms, psychological status, and daily functioning. This study answered five main questions: (a) With regard to pharmacological treatment of FMS, do antidepressants, muscle relaxants, nonsteroidal anti-inflammatory drugs (NSAIDs), or other medications result in improvement in the four outcome domains? (b) If so, which of these pharmacological treatments have the greatest effect? (c) With regard to nonpharmacological treatment of FMS, does physically-based treatment, psychologically-based treatment, or a combination of physically-based and psychologically-based treatments produce symptom reduction? (d) Which of these nonpharmacological treatments has the greatest effect? and (e) Does pharmacological or nonpharmacological treatment demonstrate the most improvement?

METHOD Literature Search

Computerized and manual methods were used to identify studies to be included in the meta-analysis. The computer search was conducted using MEDLINE (1966-November 1996), PsycINFO (1967-October 1996), CINAHL The Nursing and Allied Health database (1982-September 1996), and Dissertation Abstracts (1861-September 1996). Reference sections were manually searched in all of the identified treatment outcome study

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Fibromyalgia Treatment VOLUME 21, NUMBER 2, 1999 181

articles and in major review papers (3-13). A manual search was conducted of 1995 and 1996 issues of four journals from which the greatest number of treatment outcome studies had been identified (i.e. Arthritis and Rheumatism, Clinical Rheumatology, Journal of Rheumatology, and Scandinavian Journal of Rheumatology). Ab- stracts from Supplements to the Journal of Musculoskeletal Pain, Scandinavian Journal of Rheumatology, and Arthritis and Rheuma- tism were manually searched over the past 4 years. Solicitation letters were sent to primary authors requesting copies of other outcome studies that they had conducted, published or unpub- lished. Solicitation letters were also sent to the primary authors of studies or abstracts to request additional data when effect sizes could not be calculated from published results. Only studies or abstracts written in English were retained for review.

Inclusion and Exclusion Criteria Studies were included in the meta-analysis if: (a) at least one

treatment group was exclusively comprised of adult participants with fibromyalgia; (b) major outcome variables included physical status, self-report of FMS symptoms, psychological status, and/or daily functioning; and (c) they contained sufficient statistical information to calculate effect sizes on outcome variables.

Thirty-three of the 48 identified pharmacological treatment studies and abstracts and 16 of the 38 identified nonpharmacological treatment studies and abstracts met the inclusion criteria and were included in the meta-analysis. The main reason studies or abstracts were excluded from the meta-analysis was insufficient data available to calculate effect sizes (i.e. no statistics or insufficient statistics were reported) (14-21,11,22-36). Studies included in the final sample are listed in the Appendix.

Coding Sample size, multiple effect size information, methodology,

control and treatment group characteristics, treatment characteristics, and outcome measures with statistics necessary to calculate effect sizes were coded by one of two independent raters. Each fifth study was coded by both independent raters. A 98% mean rate of agreement was attained for studies coded by both raters with a range from 98% to 100% agreement. Discrepancies in coding were resolved by discussing the criteria and refining them if necessary.

Treatment-Related Variables: Pharmacological treatments were categorized as antidepressants, muscle relaxants, NSAIDs, and other. The "other" category included all pharmacological treatments not included in the antidepressants, muscle relaxants, and NSAIDs categories, as well as treatments that combined two or more categories. Nonpharmacological treatments were categorized as physically-based treatment (e.g. aerobic exercise, muscle strengthening, and stretching), psychologically-based treatment (e.g. biofeedback, relaxation, and cognitive-behavioral), and combination treatment (i.e. treatment which included a combination of physically-based and psychologically-based interventions).

Outcome-Related Variables: Four different categories of outcome variables included physical status, self-report of FMS symptoms, psychological status, and daily functioning. Examples of physical status measures included tender point index, myalgic score, grip strength, and physician global rating of pain symptoms. Examples of self-report of FMS symptoms included participants' report of symptoms such as fatigue, pain, and morning stiffness as measured by questionnaires such as the McGill Pain Questionnaire and visual analog scales. Examples of psychological status included self-report of depression and anxiety as measured by ques-

tionnaires such as the Arthritis Impact Measurement Scales (AIMS) of Depression and Anxiety, the Hamilton Depression and Anxiety Scales, and the Symptom Cbecklist-90-Revised. Examples of daily functioning included self-report of physical activity and daily activities as measured by questionnaires such as the Sickness Impact Profile and the Fibromyalgia Impact Questionnaire.

Methodology-Related Variables: Including methodology- related variables in the meta-analysis is critical for controlling potential effect size inflation due to different types of designs, particularly those associated with uncontrolled research. There- fore, the major methodology-related variable in this analysis was the type of control group used in each study. For pharmacological treatment studies, all studies used either a placebo control group or a no control group design. For nonpharmacological treatment studies, three types of control group designs were used--no control group, placebo/attention control group, and walt list control group. The two other methodology-related variables that were included in the analysis were whether participants were requested to washout or abstain from drug treatment (i.e. antidepressant, tranquilizing, and/or hypnotic drugs) during the study and whether the 1990 American College of Rheumatology (ACR) criteria (37) or an earlier type of criteria was used to classify participants with fibromyalgia.

Calculation of Effect Sizes We initially used g as the effect size index. The g is calculated

by subtracting the control group mean from the treatment group mean and dividing by the pooled standard deviation. Therefore, the results from all studies are expressed in a common metric. For example, a g of +.50 indicates that outcomes from individuals in the treatment condition were one-half of a standard deviation better than outcomes for individuals in the control condition. Alterna- tively, a negative g indicates that outcomes for individuals in the control condition were better than outcomes for individuals in the treatment condition. Because g can overestimate the population effect size, especially for studies with small samples, each g was converted into an adjusted Cohen's d which corrects for this bias (38,39). All effect sizes were calculated by the recta-analytic program DSTAT (40).

Means and standard deviations were used to calculate d-indexes when they were provided in the primary report. If it was specifically reported in the article that there were no pretest differences between the treatment and control groups, posttreatment means and standard deviations for each condition were used to calculate effect sizes. Otherwise, in order to control for pretest differences between treatment conditions, change scores (posttreatment means minus pretreatment means) and pooled standard deviations were used in computing effect sizes. For studies not employing a control group or only reporting within treatment group results, effect sizes were computed by comparing posttreat- merit to pretreatment means and standard deviations.

When means and standard deviations were not reported in the primary report, but the F-statistic was associated with a test of differences between the treatment and control conditions, the d-index was calculated using the F-statistic and degrees of freedom. When only the significance level (p-value) of the difference between treatment and control conditions was reported, d-indexes were computed by transforming p into z (41), then z into Pearson's r, and r into d (42). When a comparison between the treatment and control conditions was only described as nonsignificant and the F or p-value was not reported, an effect size of zero was used as a conservative estimate (43).

182 ANNALS OF BEHAVIORAL MEDICINE Rossy et al.

Statistical Analysis In order to examine each research question, effect sizes were

combined to create average d-indexes within each class of treatment by outcome measure. Because effect sizes from studies with larger samples are more likely to accurately represent the true population effect size, weighted average effect sizes were computed that gave more weight to the more reliable effect sizes obtained from larger samples (39). To weight each d-index according to sample size, separate formulas were used for between- groups designs (39) and within-groups designs (44).

In addition to computing average effect sizes, the 95% confidence interval (CI) for each category of interest (e.g. treatment group or outcome measure) was also computed. If the 95% confidence interval included zero, it was concluded that across all studies there was no relationship between the independent and dependent measures. If the 95 % confidence interval did not include zero, it was concluded that the effect size was greater than would be expected due to sampling error alone.

In addition to examining whether effect sizes differed significantly from zero, we examined also whether effect sizes were significantly different from each other. To do this, we conducted homogeneity analyses (Qb) (45) which examine whether sample error alone accounts for the variation in effect sizes, or whether moderator variables, such as type of treatment or type of outcome, also contribute to variation.

We were frequently able to calculate multiple effect sizes from each primary report. For example, a particular study may have included several self-reports of FMS symptoms (e.g. fatigue, morning stiffness, and pain) and several physical status measures (e.g. tender point index and myalgic score). In these instances, we calculated separate effect sizes for each measure that was available. However, allowing all effect sizes to enter into statistical analyses would seriously violate the independence of data points assumption required to conduct the analyses. Following the recommendations of Cooper (46), we used the independent sample as the unit of analysis and averaged across all outcome measures within each category of interest (i.e. physical status, self-report of FMS symptoms, psychological status, and dally functioning). Thus, average effect sizes within any given outcome measure category have only one effect size from any independent sample.

RESULTS Summary Effect Sizes

Table 1 presents a summary of the effect sizes for each independent sample that used a pharmacological treatment. Table 2 presents a summary of the effect sizes for each independent sample that used a nonpharmacological treatment. In each table, the type of design for each study indicates whether outcomes were reported by comparing a treatment group to a control group (between- groups design and crossover design) or whether pretreatment and posttreatment outcomes were compared within each treatment group (within-groups design). If an article reported that a between- groups study or a crossover study had been designed but statistics reflected a comparison between pretreatment and posttreatment within-group outcomes (47-49), a within-groups design is listed for the corresponding independent sample(s). Within the four outcome categories (physical status, self-report of FMS symptoms, psychological status, and daily functioning), effect sizes for each type of treatment were averaged across dependent measures.

Pharmacological Treatments For measures of physical status and FMS symptoms (see

Table 3), treatment with antidepressants and muscle relaxants was significantly associated with improved outcomes. However, treatment with muscle relaxants was superior to treatment with antidepressants, X2(1) = 12.96, p = .0003, for physical status measures) Although treatment with muscle relaxants was significantly associated with improved psychological status and treatment with antidepressants and was not associated with a significant effect on this measure, there was no statistically significant difference between the two treatments, X2(1) = .04, p = .82. No pharmacological treatment was associated with significantly improved daily functioning. However, the small number of observa- tions for treatment with muscle relaxants and NSAIDs limit the generalizability of these results. Treatment with NSAIDs was not significantly associated with improved outcomes on any measure.

While the effect sizes of the treatment interventions in the "other" category were the most reliable (due to sample size and size of effect) and resulted in positive outcomes across all outcome measures except dally functioning, the heterogeneous nature of this category warranted further investigation. First, a comparison of treatments using one drug, d = .58, 95% CI = (.44, ,72), k = 15, and treatments using a combination of drugs, d = .52, 95% CI = (.26, .78), k = 4, found that both were significantly associated with improved outcome and there was no significant difference between the two treatments, X2(1) = .29, p = .59.

Second, the only types of treatment that were repeated in more than one study were S-adensyl-L-methionine (SAMe), an anti- inflammatory drug with analgesic and antidepressant effects, (six studies) and 5-hydroxytryptophan (two studies) (see Table 1). A comparison of the combination of all six studies using SAMe treatments, d = .61, 95% CI = (.41, .81), k = 6, to the rest of the treatments in the "other" category, d = .47, 95% CI = (.29, .65), k = 10, found both groups were significantly associated with improved outcome and there was no statistically significant difference between the two groups, X2(1) = 1.35, p = .25. SAMe was associated with improvements in physical status, self-report of FMS symptoms, and psychological status (47,49-52), except for one study that found a decline in psychological status (53). Both studies using 5-hydroxytryptophan were associated with a significant improvement on physical status, self-reported FMS symptoms, and psychological status (54,55).

Out of the remaining treatments in the "other" category, cyclobenzaprine and ibuprofen (56), amitriptyline and naproxen (57), and ibuprofen and alprazolam (58) were associated with significant improvements on physical status and self-report of FMS symptoms. A pilot study of topical capsalcin, applied four times dally, demonstrated its efficacy at reducing tenderness of

3 Three independent samples contributed an effect size to more than one pharmacological treatment category (50,51,71). For example, Goldenberg (50) compared outcomes for a treatment group receiving antidepressants, a treatment group receiving NSAIDs, and a control group. Thus, an effect size comparing the antidepressant and control condition contributes to the average effect sizes for antidepressants, and an effect size comparing the NSAIDs and control condition contributes to the average effect sizes for NSAIDs. Although any one independent sample within the antidepressant and NSAIDs categories contributes only one effect size, homogeneity analyses comparing these categories may be biased due to violations of the independence of data points assumption. To examine the impact of violating this assumption on results, we randomly discarded one effect size from each of the three independent samples and reconducted the homogeneity analyses. Results from all analyses remained the same. Thus, we report results from analysis with all effect sizes included in the text.


TABLE 1

Summary of Effect Sizes (ES) by Outcome Measures for Pharmacological Treatment

Source of Type of Group PS SR PSY DF Independent Sample Design Type of Treatment n ES ES ES ES

Bennett et al. (1988) between Carette, McCain, Bell, and Fam (1986) between Carette et al. (1994) between

Carette, Oakson, Guimont, and Steriade (1995)

Caruso et al. (1987) Caruso, Puttini, Cazzola, and Azzolini

(1990) Clark, Tindall, and Bennett (1985) Di Benedetto, Iona, and Zidarich (1993) Fossaluzza and De Vita (1992)

Goldenberg, Felson, and Dinerman (1986)

Goldenberg, Mayskiy, Mossey, Ruthazer, and Schmid (1996)

Grassetto and Varotto (1994) Ianniello et al. (1994) Jacobsen, Danneskiold-Samsoe, and

Andersen ( 1991) Karoliussen and Kvalheim (1995) Kempenaers et al. (1994) McCarty, Csuka, McCarthy, and Trotter

(1994) Moldofsky, Lue, Mously, Roth-Schechter,

and Reynolds (1996)

Norregaard, Volkmann, and Darmeskiold- Samsoe (1995)

Ostuni et al. (1995) Pattrick, Swarmell, and Doherty (1993) Puttini and Caruso (1992) Quimby, Gratwick, Whituey, and Block

(1989) Reynolds, Moldofsky, Saskin, and Lue

(1991) Russell, Fletcher, Michalek, McBroom,

and Hester (1991)

Russell, Michalek, Flechas, and Abraham (1995)

Santandrea, Montrone, Sarzi-Puttini, Boc- cassini, and Caruso (1993)

Scudds, McCain, Rollman, and Harth (1989)

Tavoni, Vitali, Bombardieri, and Pasero (1987)

Vaeroy, Abrahamsen, Forte, and Kass (1989)

Volkmann et al. (1997) Wolfe, Cathey, and Hawley (1994) Yunus, Masi, and Aldag (1989)

crossover

cyclobenzaprine 40 .09 .26 amitriptyline 27 .12 .24 amitriptyline 78 .23 .20 cyclobenzaprine 70 .25 .30 amitriptyline 22 .32 .74*

between dothiepin 26 .74* .74* between 5-hydroxytryptophan 24 1.06" .96* 1.06"

crossover prednisone 20 0 0 within s-adenosyl-l-methionine 15 1.01" .34 .71" within cyclobenzaprine 15 1.96" 1.68" within cyclobenzaprine and ibuprofen 17 1.71" 1.72" between amitriptyline and naproxen 15 .89* .82* between naproxen 15 0 0 between amitriptyline 15 .47 .55 crossover amitriptyline 19 .28 .44 .09 crossover fluoxetine 19 .08 .50 .26 crossover amitriptyline and fluoxetine 19 .61 .97* .33 within s-adenosyl-l-methionine 47 .79* .25 .76* within s-adenosyl-l-methionine 10 1.41" 1.08" .62 between s-adenosyl-l-methionine 17 .31 .55 .70*

between mexiletine 16 .29 .16 between SER282 9 - .47 - . 30 between topical capsaicin 20 .35 .03

crossover zolpidem(5mg) 16 .04 - .10 crossover zolpidem(10mg) 16 .26 .06 crossover zolpidem(15mg) 16 - .34 .03 between citalopram 21 .63* - . 04

within myanserine 10 .38 .89* between chlormezanone 18 - .33 0 within 5 -hydroxy-l-tryptophan 43 1.51 * .97* between cyclobenzaprine 21 .87* .38

crossover cyclobenzaprine 9 - . 14 .23

.01

1.96"

between ibuprofen and alprazolam 15 .29 .24 .12 between ibuprofen 17 .04 .13 .49 between alprazolam 17 .14 .18 - . 16 within ibuprofen and alprazolam 52 .33* .62* - .49* crossover supermalic R 20 - . 17 .06 .10 within supermalic R 16 1.08" .79* .56* within cyclobenzaprine (10 mg) 35 1.33" .48* 0 within cyclobenzaprine (30 mg) 25 1.48" .64* .60* crossover amitriptyline 36 .47 .65*

within s-adenosyl-l-methionine 17 .83* .85*

between carisoprodol, paracetamol, and caffeine 20 .12

crossover s-adenosyl-l-methionine 29 .30 .32 - .14 between fluoxetine 15 - .27 .05 .67 between ibuprofen 20 .15 .06

.04

.24

.30

.57 1.04*

- .51 - .25 - .25

.14

.55

.32

.17

Notes: PS = Physical Status; SR = Self-Report of FMS Symptoms; PSY = Psychological Status; DF = Daily Functioning; * = denotes significant effect size (95 % confidence interval does not encompass zero).


Burckhardt, Mannerkorpi, Hedenberb, and Bjelle (1994)

TABLE 2 Summary of Effect Sizes (ES) by Outcome Measures for Nonpharmacological Treatment

Source of Type of Group Independent Sample Design Type of Treatment n

Banwell and Fiechtner (1992) Buckelew et al. (1998)

Deluze, Bosia, Zirbs, Chantraine, and Vischer (1992)

Ferraccioli et al. (1987) Ferraccioli et al. (1987) Goldenberg et al. (1994) Haanen et al. (1991) McCain, Bell, Mai, and Halliday (1988) Martin et al. (1996) Mengshoel, Komnaes, and Forre (1992) Mengshoel, Forseth, Haugen, Walle-

Hansen, and Forre (1995) Mikkelsson, Isomeri, and Kautianen

(1994) Nichols and Glenn (1994) Nielson, Walker, and McCain (1992)

within exercise and education 17 between biofeedback and relaxation 27 between walking, strengthening, and stretching 28 between biofeedback and exercise 26 between education 28

education and physical therapy (stretch- 28 ing, pool therapy, and walking, cycling, or swimming)

between electroacupuncture 28 .69*

Ostuni et al, (1995) Wigers, Stiles, and Vogel (1996)

within biofeedback 15 4.33* between biofeedback 6 3.18* between cognitive-behavioral 79 between hypnotherapy 20 -.09 between bicycle ergometer 18 1.11" between walking and stretching 18 1.10* between aerobics 11 .26 within exercise (nonaerobic) and 16

cognitive-behavioral within cycling and strengthening 10

between walking and strengthening 8 within cycling or treadmill, stretching, and cog- 25 1.13"

nitive-behavioral within acupuncture 14 .51 between aerobics 16 .96" between cognitive-behavioral 15 .63

PS SR ES ES

. . . . . , . . . . . . . . , , , ,

.40

.58* .40

.53 .48

.41 .19

.18

.10

.50

1.46" 1.30" .40* .76* .67

0 .37

.15

• . . . . • . , .

PSY DF ES ES

.32 .31

.49 .51

.23 .75

.38 .44

.27 .07

.86* .39

.78*

.36 .23

.34

0 .29 - .44 1.15" 1.02" .63*

1.74" .77* .31 ,43 .56

" No ies : PS = Physical Status; SR = Self-Report of FMS symptoms. PsY = Psychological Status; D'F Daily Functioning; * = denotes significant effect size (95% confidence interval does not encompass zero).

TABLE 3 Effect Sizes by Outcome Measure for Pharmacological Treatment

Antidepressants Muscle Relaxants NSAIDs Other

k ES k ES k ES k ES

Physical Status 11 .37a* 7 .89b* 3 .08a 17 .73b* FMS Symptoms 12 .49a* 8 .47a* 3 .06b 17 .50a* Psychological Status 4 .22a 3 .26a* 1 .49a.b 10 .68b* Daily Functioning 4 .15~ 1 .24~ 1 -.25~ 2 .15~

, | | , , , , , , , �9 ,

Notes : For each outcome measure, treatment groups with the same letter subscript do not differ significantly; k = number of independent samples contributing to effect size estimate; ES = weighted effect size; * = denotes significant effect size (95% confidence interval does not encompass zero).

tender points, but not subjective pain and sleep measurements (59). Super Malic R, a proprietary tablet of malic acid (200 mg) and magnesium (50 rag), produced improvement across outcomes, particularly measurements of pain and tenderness, when looking at results from an open label trial, but failed to show significant improvement in the blinded, placebo controlled trial (60). Alpra- zolam, a benzodiazepine approved for the treatment of anxiety and/or anxiety associated with depressive symptoms, appeared to be of greater benefit when used in conjunction with ibuprofen than when used alone (58). However, modest short-term effects of benzodiazepines are generally outweighed by the dangerous side effects of long-term use (61) and most physicians caution against their long-term use.

Nonpharmacologieal Treatments Each type of nonphannacological treatment (physically-based,

psychologically-based, and combination) was associated with

significant improvements on each of the four outcome measures, with one exceptionmfunctional outcome after physically-based treatment (see Table 4). Pairwise comparisons conducted to test for significant differences in effect sizes between the types of treatment for each outcome measure revealed no significant differences. 4

Comparison of Nonpharmacological and Pharmacological Treatments

Overall, both pharmacological and nonpharmacological treatments were associated with improved outcomes for all categories

4 Three independent samples contributed an effect size to both physically- based and psychologically-based categories (55,59,61). As was done with pharmacological treatment, we randomly deleted one effect size from one category and reconducted the homogeneity analysis. All results remained the same and we report results from the entire data set in the text.

F i b r o m y a l g i a T r e a t m e n t

TABLE 4 Effect Sizes by Outcome Measures for Nonpharmacological 1~reatment

Physically-Based Pychologically-Based Combination

Outcome Measure k ES k ES k ES

Physical Status 7 .71a* 6 .60a* 4 .55a* FMS Symptoms 8 .56a* 6 .63a* 3 .63a* Psychological Status 5 .38~* 5 .60a* 3 .56a* Daily Functioning 3 .29~ 3 .38~* 3 .49a*

Notes: For each outcome measure, treatment groups with the same letter subscript do not differ significantly; k = number of independent samples contributing to effect size estimate; ES = weighted effect size; * = denotes significant effect size (95% confidence interval does not encompass zero).

TABLE 5 Comparison of Pharmacological and Nonpharmacological Treatment

Effect Sizes by Outcome Measure

Pharmacological Nonpharmacological

k ES k ES p

Physical Status 34 .66* 13 .69* .67 FMS Symptoms 35 .49* 14 .65* .03 Psychological Status 16 .52* 9 .61" .53 Daily Functioning 6 .19 6 .40* .10

Notes: k = number of independent samples contributing to effect size estimate; ES = weighted effect size; p = significance level for comparison of nonpharmacologicai and pharmacological treatment; * = denotes significant effect size (95% confidence interval does not encompass zero).

of outcome measures, except for daily functioning measured after pharmacological treatment (see Table 5). However, nonpharmacological treatment was superior to pharmacological treatment on self-report of FMS symptoms, X2(1) = 4.87, p = .03, and the same trend was found for functional measures, • = 2.72, p = .10. There were no significant differences between nonpharmacological and pharmacological treatments for measures of physical status, • = .18, p = .67, and psychological status, X2(1) = .38, p = .53.

Methodological Characteristics

Three methodological moderator variables (study design, existing drug treatment washout, and criteria used to classify fibromyalgia participants) were examined. If effect sizes remained the same across these methodological characteristics, we could have more confidence in the validity of the conclusions drawn from the meta-analysis.

To examine whether the magnitude of effect sizes reported previously was moderated by the type of design employed by the primary researchers, we examined the design of pharmacological and nonpharmacological treatment studies separately. For pharmacological treatments, all studies reported results that either reflected a comparison between active medication and a placebo control group or between pretreatment and posttreatment using active medication (no control group). Because individual differences are controlled for in studies using a no control groups design where each participant serves as their own control, we anticipated that effect sizes from no control group studies would show a stronger effect of treatment on outcome measure than studies that compared a treatment group to a control group. Therefore, study design was used as a moderator to determine whether it was systematically related to the magnitude of the effect sizes. A breakdown of effect sizes that were averaged over each type of pharmacological treatment for each type of outcome measure were

V O L U M E 21, N U M B E R 2, 1999 185

TABLE 6 Comparison of Effect Sizes for Placebo Control and No Control Group

Designs by Outcome Measure and Pharmacological Treatment

Placebo Control No Control Group Design Group Design

k ES k ES p

Antidepressants Physical Status 9 .37* 2 .42 .81 FMS Symptoms 10 .41" 2 1.14" .0003 Psychological Status 4 .22 0 - - Daily Functioning 4 .15 0 - -

Muscle Relaxants Physical Status 4 .15 3 1.48" <.0001 FMS Symptoms 5 .23 3 .70* <.0001 Psychological Status 1 .30 2 .24 .73 Daily Functioning 1 .24 0 - -

NSAIDs Physical Status 3 .08 0 - - FMS Symptoms 3 .06 0 - - Psychological Status 1 .49 0 - - Daily Functioning 1 - .25 0 - -

Other Physical Status 11 .29* 8 .88* <.0001 FMS Symptoms 12 .27* 7 .66* <.0001 Psychological Status 5 .31 7 .52* .006 Dally Functioning 2 .15 0 - -

Notes: k = number of independent samples contributing to effect size estimate; ES = weighted effect size; p = significance level for comparison of placebo control and no control group designs; * = denotes significant effect size (95% confidence interval does not encompass zero).

computed according to whether a study used no control group or a placebo control group (see Table 6).

With regard to pharmacological treatments, antidepressants resulted in modest improvements across study design. In studies using a no control group design, treatment with antidepressants was not associated with a statistically significant improvement in physical status measures, however, the effect did not differ significantly from the statistically significant effect found in the studies using a placebo group design. Therefore, we attribute the nonsignificant finding in no control group designs to be due to the very small number of studies in this category and do not question, based on our results, the efficacy of treatment with antidepressants for physical status measures. Muscle relaxants resulted in improvements in both physical status and self-report of FMS symptoms in studies utilizing a no control group design only. No significant improvements were found on these two measures in studies using a placebo control group, a more stringent design. The large discrep- ancy between type of design for treatment with muscle relaxants on physical status and self-report of FMS symptoms precludes any definite conclusions about the efficacy of this treatment.

For nonpharmacological treatments, studies utilized three types of control group des igns- -no control group, placebo/ attention control group, and wait list control group. Placebo/ attention control interventions included placebo (62,63), education (64), physical therapy (65), flexibility (66), and relaxation (67). The groups in the wait list control category were described as wait list (68,69), treatment as usual (70), sedentary (71), and no change in physical activity (72). All three types of control group designs were associated with significant improvements across outcome measures, no-control group d = .74, 95% CI = (.52, .96), k = 6; placebo/attention control d = .61, 94% CI = (.34, .88), k = 6; and wait list control d -- .36, 95% CI = (.10, .62), k = 5. Although analyses examining study design show that wait list control studies


were associated with smaller effects than studies using no control group and placebo/attention control group designs, wait list control group studies still showed a significant effect. Thus, we have confidence in the efficacy of nonpharmacological treatment across study design.

With regard to the methodological question as to whether individuals were asked to washout or abstain from existing drug treatment strategies before participation in a study, only 4 of the 33 pharmacological studies explicitly stated they did not require a washout period (52,53,59,73), and no further analysis of pharmacological studies was considered useful. Although nonpharmacological treatment studies that did not require a washout (62,64, 67-69,74), d = .56, 95% CI = (.36, .76), k = 6, as well as nonpharmacological studies that did require a washout or absten- tion from drugs (63,66,71,75), d = 1.14, 95% CI = (.78, 1.50), k = 5, were associated with significant overall outcomes, nonpharmacological studies that did require a washout showed a significantly larger effect, • = 19.93, p < .00001.

The magnitude of effect sizes may have been moderated by the type of classification criteria used, since not all of the studies used the 1990 ACR criteria. Therefore, an analysis was completed using this variable. The studies using the 1990 ACR criteria, d = .43, 95% CI = (.48, .82), k = 20, and studies using criteria previous to the 1990 ACR criteria, d = .61, 95% CI = (.51, .71), k = 34, were both associated with significant overall outcomes, and there were no significant differences between the two groups, X2(1) = .57, p = .45. Because of these results, no further investigation of differences based on type of criteria were performed.

DISCUSSION

Our analysis of 49 clinical trials including 2,066 participants demonstrates that many pharmacological and nonpharmacological treatments are beneficial for individuals with FMS. Before examining differences due to study design, all broad classes of pharmacological treatments defined in this study, except NSAIDs alone, were associated with significant improvements in physical status and self-report of FMS symptoms. However, when effect sizes were separated by whether a study used a no control group or a placebo control group, several differences in effect sizes emerged within the same treatment. Across study design, antidepressants and muscle relaxants did not result in meaningful improvements in psychological status and daily functioning in the few studies including these outcome measures. This may not be surprising, because the dosages for antidepressants commonly used in these studies are lower than the therapeutic dosages for depression (48,76-78). No pharmacological treatment alone resulted in improved dally functioning (58,60,76,78). However, one trial using a combination of amitriptyline and fluoxetine (77) resulted in improved functional ability as measured by the Fibromyalgia Impact Questionnaire (FIQ). Future research may look at other combinations of selective serotonin reuptake inhibitors in conjunction with tricyclics. NSAIDs are not effective on any dimension of measured outcome except in conjunction with another treatment (e.g. cyclobenzaprine and amiWiptyline) (56-58).

All classes of nonpharmacological treatments were associated with significant improvements in all four categories of outcome measures with the exception that physically-based treatment was not associated with significant improvement of daily functioning. However, this result may be explained by the self-report nature of this measure reflecting self-efficacy of function (a psychological variable) rather than actual physical functioning. When comparing the two types of treatment, nonpharmacological treatment is more

efficacious in improving self-report of FMS symptoms than pharmacological treatment alone. A similar trend is suggested for functional measures.

Results of the analyses of study design highlight the difference between placebo-controlled pharmacological studies and those that did not utilize a placebo. There are several factors that could produce this difference. First, because no control group designs control for individual differences among participants, the design itself is more sensitive to changes in outcome. However, no control group designs (as included in our data set) are open to a host of threats to internal validity that cannot be ruled out in assessing whether posttreatment change is actually due to treatment versus some other factor (e.g. social desirability, experimenter demand). Alternatively, participants receiving the placebo in a placebo control group study could be showing improvement because of the attention paid to them and/or expectancy effects (76,79), and thus, those studies would detect less of a difference between treatment and placebo. Therefore, it is likely that the amount of improvement in participants receiving active medication in placebo control group studies is primarily due to treatment and not attention (placebo). Conversely, the level of improvement in clinical situa- tions may be better estimated by no control group studies, which better simulate a clinic condition.

Analyses of nonpharmacological treatment did not result in significantly different effects between different types of study design. These consistent findings across study design suggest evidence of value added by treatment beyond that attained with placebo, even though, by nature, nonpharmacological treatment is often thought to work through those mechanisms of social interaction, expectations, and attitude change that constitute the key elements of the placebo effect.

The classification of treatment as nonpharmacological, however, is somewhat misleading, since many of these studies (62,64,67-69,74) allowed participants to remain on their current pharmacologic treatments of FMS. When effect sizes were separated by whether or not current pharmacological treatments were allowed during a nonpharmacological treatment intervention, nonpharmacological treatments after washout from medication produced sighificantly larger effect sizes. However, a significant effect was still found for nonpharmacological treatment used in conjunction with medication. The fact that both strategies were associated with significant effects constitutes one of the most important findings of this study and underlines the value of nonpharmacological treatment both with and without concurrent medication. The real life significance of these findings is illustrated by two recent studies and highlights the need for future research that examines the combination of treatments that are being used both inside and outside a medical setting. The first study (80) found that 91% of the patients with FMS had adopted an alternative treatment within the preceding year. The second study's findings also suggest a high degree of complementary treatment use among patients with FMS and, specifically, that poor clinical status is a major predictor of such use (81). The term "complementary" is used because patients tend to use alternative treatments in conjunction with traditional medical care (82). Using empirical research to validate the use of such treatments and then disseminate this information to FMS patients who are seeking complementary treatment should be a priority for future research and educational endeavors.

To date, the one published study that explicitly set out to examine the combination of pharmacological and nonpharmacological treatment utilized a 6-month group treatment outpatient


program (83) and concluded that a program limited to education, cognitive-behavioral therapy, and supervised stretching/aerobic training would be the optimal treatment strategy. Those conclusions are further validated by a recent study that examined differences between a cognitive treatment group, an attention control group using a discussion format, and a wait list control group on self-report measures of pain and affective distress (84). Both the cognitive treatment and the attention control groups received the same educational program which included a physical exercise component. Significant within-group changes were found for both the cognitive treatment and the attention control groups, but not the wait list control group. The cognitive treatment group and the attention control group interventions may have been too similar to create differences in outcomes between the groups at posttreatment on coping and pain control, the two primary variables that distinguish the cognitive treatment and the attention control groups from the wait list control group. Again, the combination of education, physical exercise, and some type of psychological intervention appears to be effacacious in the treatment of FMS. Further research is needed that examines different combinations of treatment and their differential effects on sub- groups of individuals.

Although the results of this analysis did not find any significant differences between studies using the currently recom- mended 1990 ACR criteria and studies which used older criteria, there are a number of reasons to recommend the 1990 ACR criteria for future treatment outcome studies. Given the diagnostic ambig- uity and historical confusion surrounding FMS, this empirically- defined criteria provides a method for researchers to evaluate their treatment on a more distinct and similar population of fibromyalgia patients.

As FMS is a chronic illness, it is important to gain an understanding of the long-term efficacy of treatment. However, all studies conducted to date have used relatively short-term treatment interventions. In the current review, pharmacological treatment studies ranged from 1 week to 6 months, and nonpharmacological treatment studies ranged from 4 to 20 weeks in length. The longest and one of the most well-designed studies of pharmacological treatment of FMS confirmed the short-term (1-month) efficacy of amitriptyline and cyclobenzaprine. Continued treatment over the next 5 months produced an increase in improvement in both the amitriptyline group and the cyclobenzaprine group, but a similar phenomenon observed in the placebo group resulted in no statistical difference between the three groups at the end of treatment (79). No long-term follow-up studies have been conducted on pharmacological treatments that could imply long-term efficacy from their modest short-term effects. Because only five long-term follow-up studies have been conducted on nonpharmacological treatments, they are not included in our analysis. However, they add further support for their use in the treatment of FMS. A 30-month follow-up of cognitive-behavioral therapy suggests its role in the long-term treatment of FMS (85); a 6-month follow-up of electromyograph (EMG) biofeedback found a long-term benefit was observed in 56% of patients (63); a 24-week follow-up of hypnotherapy (12 weeks after treatment ended) found improvement in subjective measurements of FMS (65); and a 6-month follow-up of exercise and cognitive-behavioral therapy found that pain intensity was still reduced from baseline measurements (86). Another recent study that conducted a 6-month follow-up of behavioral and educational interventions found maintenance of significant improvements in depression, self-reported pain behavior, observed pain behavior, and myalgia scores that were reported

at the end of the initial 10-week treatment period (87). This study also examined the role of intervening variables that may serve as active agents of change in clinical outcome. Their findings suggest that the reduction of helplessness beliefs and maladaptive coping strategies should be explicitly targeted in psychosocial interventions of FMS based on their ability to predict improvement in pain, depression, and self-reported pain behavior.

As in any review of the literature, this study is subject to the same recruitment and retention bias that exists in the primary research from which this analysis was conducted. Patients included in these studies were typically recruited from rheumatologists or a registry from a rheumatology clinic, and persons with FMS who seek treatment frequently exhibit multiple psychiatric disorders and high levels of pain and fatigue (88). The prevalence of psychiatric disorders, particularly mood and panic disorders, and psychological disturbance associated with FMS has been high- lighted in a number of studies (88-92). In fact, patients with FMS indicated that the management of psychosocial aspects of their illness is significantly more important to them than to their rheumatologists (93). As this study reveals, a large number of treatment outcome studies neglect to include measurement of these clinically important variables. Thus, identifying treatments with the ability to improve psychological and functional outcome is an important facet of future FMS research. Selection bias can also be introduced into a study by a large dropout rate, which often occurs in medication studies, as well as the different types of diagnostic criteria for FMS. Although not the subject of this review, a recent recta-analysis of treatments in areas as diverse as education to health-related concerns concluded that methodological artifacts, as listed above, are almost as likely to produce an underestimate as an overestimate of effects (94).

The practical and clinical significance of an effect is dependent on the nature of the outcome and its importance to patients or clients. Across treatment groups, the current review found significant effect sizes ranging from .26 to .89 for pharmacological treatments and .38 to .71 for nonpharmacological treatments. A meta-analysis of drug treatment judged effective for arthritis reported effect sizes between .45 and .77 (95) and a meta-analysis of biofeedback and relaxation training for migraine and tension headaches reported a mean effect size of .63 (96). The magnitude of effect sizes in the current review seems sufficiently large, by comparison to similar medical domains, to support the claim that treatment is generally efficacious in practical as well as statistical terms.

Despite all that we know to date, fibromyalgia continues to be a challenging disorder to treat. This is due, in part, to the incomplete understanding of the biological underpinnings as well as the multiple symptoms that characterize FMS. Therefore, treatment has been approached empirically rather than theoreti- cally, focusing on symptom reduction rather than control of the disorder. Moreover, no clear guidelines exist that translate statistically significant research findings into a statement about corresponding significant clinical improvement. The results of this meta- analysis suggest that nonpharmacological treatments are particularly more helpful in managing self-reported FMS symptoms (i.e. pain, fatigue, and morning stiffness) and daily functioning than pharmacological treatment alone. Therefore, the recommendation for optimal treatment of FMS would include nonpharmacological interventions, specifically exercise and cognitive-behavioral therapy, in addition to appropriate medication management as needed for sleep and pain symptoms.


APPENDIX

Studies Included in the Meta-Analysis Banwell B, Fiechtner J: Grip strength in fibromyalgia [ab-

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cyclobenzaprine and placebo in the management of fibrositis: A double-blind controlled study. Arthritis and Rheumatism. 1988, 31(12):1535-1542.

Buckelew SP, Conway R, Parker J, et al: Biofeedback/ relaxation training and exercise interventions for fibromyalgia: A prospective trial. Arthritis Care and Research. 1998, 11:196-209.

Burckhardt CS, Mannerkorpi K, Hedenberb L, Bjelle A: A randomized, controlled clinical trial of education and physical training for women with fibromyalgia. Journal of Rheumatology. 1994, 21:714-720.

Carette S, Bell MJ, Reynolds WJ, et al: Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthritis and Rheumatism. 1994, 37:32-40.

Carette S, McCain GA, Bell DA, Fam AG: Evaluation of amitriptyline in primary fibrositis. A double-blind, placebo- controlled study. Arthritis and Rheumatism. 1986, 29(5):655-659.

Carette S, Oakson G, Guimont C, Steriade M: Sleep electroen- cephalography and the clinical response to amitriptyline in patients with fibromyalgia. Arthritis and Rheumatism. 1995, 38(9):1211- 1217.

Caruso I, Puttini PS, Cazzola M, Azzolini V: Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. Journal of lnternational Medical Research. 1990, 18:201-209.

Caruso I, Sarzi Puttini PC, Boccassini L, et al: Double blind study of dothiepin versus placebo in the treatment of primary fibromyalgia syndrome. Journal of International Medical Re- search. 1987, 15:154-159.

Clark S, Tindall E, Bennett RM: A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis. Journal of Rheumatology. 1985, 12(5):980-983.

Deluze C, Bosia L, Zirbs A, Chantraine A, Vischer TL: Electroacupuncture in fibromyalgia: Results of a controlled trial. British Medical Journal. 1992, 305:1249-1252.

Di Benedetto P, Iona LG, Zidarich V: Clinical evaluation of s-adenosyl-l-methionine versus transcutaneous electrical nerve stimulation in primary fibromyalgia. Current Therapeutic Re- search. 1993, 53(2):222-229.

Ferraccioli G, Ghirelli L, Scita F, et al: EMG-biofeedback training in fibromyalgia syndrome. Journal of Rheumatology. 1987, 14(4):820-825.

Fossaluzza V, De Vita S: Combined therapy with cyclobenzaprine and ibuprofen in primary fibromyalgia syndrome. Interna- tional Journal of Clinical Pharmacological Research. 1992, 12(2):99-102.

Goldenberg DL, Felson DT, Dinerman H: A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis and Rheumatism. 1986, 29(11):1371-1377.

Goldenberg DL, Kaplan KH, Nadeau MG, et al: A controlled study of a stress-reduction, cognitive-behavioral treatment program in fibromyalgia. Journal of Musculoskeletal Pain. 1994, 2(2):53-65.

Goldenberg DL, Mayskiy M, Mossey C, Ruthazer R, Schmid C: A randomized, double-blind crossover trial of fluoxetine and

amitriptyline in the treatment of fibromyalgia. Arthritis and Rheumatism. 1996, 39(11):1852-1859.

Grassetto M, Varotto Z: Primary fibromyalgia is responsive to s-adenosyl-l-methionine. Current Therapeutic Research. 1994, 55(7):797-806.

Haanen HCM, Hoenderdos HTW, van Romunde LKJ, et al: Controlled trial of hypnotherapy in the treatment of refractory fibromyalgia. Journal of Rheumatology. 1991, 18(1):72-75.

Ianniello A, Ostuni PA, Sfriso P, et al: S-adenosyl-1- methionine in Sjogren's Syndrome and fibromyalgia. Current Therapeutic Research. 1994, 55(6):699-706.

Jacobsen S, Danneskiold-Samsoe B, Andersen RB: Oral s-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scandinavian Journal of Rheumatology. 1991, 20:294-302.

Karoliussen OH, Kvalheim L: Effects of mexiletine on pain and other symptoms in primary fibromyalgia [abstract]. Journal of Musculoskeletal Pain. 1995, 3:26.

Kempenaers Ch, Simenon G, Vander Elst M, et al: Effect of an antidiencephaion immune serum on pain and sleep in primary fibromyalgia. Biological Psychiatry. 1994, 30:66-72.

Martin L, Nutting A, Macintosh BR, et al: An exercise program in the treatment of fibromyalgia. Journal of Rheumatol- ogy. 1996, 23(6):1050-1053.

McCain GA, Bell DA, Mai FM, Halliday PD: A controlled study of the effects of a supervised cardiovascular fitness training program on the manifestations of primary fibromyalgia. Arthritis and Rheumatism. 1988, 31(9): 1135-1141.

McCarty DJ, Csuka M, McCarthy G, Trotter D: Treatment of pain due to fibromyalgia with topical capsaicin: A pilot study. Seminars in Arthritis and Rheumatism. 1994, 23(6):41-47.

Mengshoel AM, Forseth KO, Haugen M, Walle-Hansen R, Force O: Multidisciplinary approach to fibromyalgia: A pilot study. Clinical Rheumatology. 1995, 14(2): 165-170.

Mengshoel AM, Komnaes HB, Forre O: The effects of 20 weeks of physical fitness training in female patients with fibromyalgia. Clinical and Experimental Rheumatology. 1992, 10:345- 349.

Mikkelsson M, Isomeri R, Kautianen H: Effects of amitriptyline and cardiovascular fitness training on subjective disturbance of sleep and depression in patients with fibromyalgia. Physical Medicine Research Foundation Symposium. 1994.

Moldofsky H, Lue FA, Mously C, Roth-Schechter B, Rey- nolds WJ: The effect of zolpidem in patients with fibromyalgia: A dose ranging, double blind, placebo controlled, modified crossover study. Journal of Rheumatology. 1996, 23:529-533.

Nichols DS, Glenn TM: Effects of aerobic exercise on pain perception, affect, and level of disability in individuals with fibromyalgia. Physical Therapy. 1994, 74(4):327-332.

Nielson WR, Walker C, McCain GA: Cognitive-behavioral treatment of fibromyalgia syndrome: Preliminary findings. Journal of Rheumatology. 1992, 19(1):98-103.

Norregaard J, Volkmann H, Danneskiold-Samsoe B: A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain. 1995, 61:445 A,A,9.

Ostuni PA, Cassisi GA, Ianniello A, et al: Acupuncture vs. low-dose myanserine in primary fibromyalgia [abstract]. Journal of Musculoskeletal Pain. 1995, 3:88.

Pattrick M, Swannell A, Doherty M: Chlormezanone in primary fibromyalgia syndrome: A double blind placebo controlled study. British Journal of Rheumatology. 1993, 32:55-58.


Puttini PS, Caruso I: Primary fibromyalgia syndrome and 5-hydroxy-L-tryptophan: A 90-day open study. Journal oflnterna- tionalMedicalResearch. 1992, 20(2):182-189.

Quimby LG, Gratwick GM, Whitney CD, Block SR: A randomized trial of cyclobenzaprine for the treatment of fibromyalgia. Journal o f Rheumatology. 1989, 16(19):140-143.

Reynolds WJ, Moldofsky H, Saskin P, Lue FA: The effects of cyclobenzaprine on sleep physiology and symptoms in patients with fibromyalgia. Journal o f Rheumatology. 1991, 18(3):452- 454.

Russell IJ, Fletcher EM, Michalek JE, McBroom PC, Hester GG: Treatment of primary fibrositis/fibromyalgia syndrome with ibuprofen and alprazolam. Arthritis and Rheumatism. 1991, 34(5): 552-560.

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Santandrea S, Montrone F, Sarzi-Puttiniti P, Boccassini L, Caruso I: A double-blind crossover study of two cyclobenzaprine regimens in primary fibromyalgia syndrome. Journal o f Interna- tional Medical Research. 1993, 21:74-80.

Scudds RA, McCain GA, Rollman GB, Harth M: Improve- ments in pain responsiveness in patients with fibrositis after successful treatment with amitriptyline. Journal of Rheumatology. 1989, 16(19):98-103.

Tavoni A, Vitali C, Bombardieri S, Pasero G: Evaluation of S-adenosylmethionine in primary fibromyalgia. American Journal o f Medicine. 1987, 83(5A): 107-110.

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Volkmann H, Norregaard J, Jacobsen S, et al: Double-blinded, placebo controlled cross-over study of intravenous s-adenosyl-1- methionine in patients with fibromyalgia. Scandinavian Journal o f Rheumatology. 1997, 26:206-211.

Wigers SH, Stiles TC, Vogel PA: Effects of aerobic exercise versus stress management treatment in fibromyalgia. A 4.5-year follow-up study. Scandinavian Journal o f Rheumatology. 1996, 25:77-86.

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Yunus MB, Masi AT, Aldag JC: Short-term effects of ibuprofen in primary fibromyalgia syndrome: A double blind, placebo controlled trial. Journal o f Rheumatology. 1989, 16(4):527-532.

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A meta-analysis of fibromyalgia treatment interventions

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