- Email: [email protected]
Advances in the Treatment of Fibromyalgia: Current Status and FutureDirections
Advances in the Treatment of Fibromyalgia: Current Status and Future Directions GRACIELA S. ALARCON, MD, MPH,
LAURENCE A. BRADLEY, PHD
ABSTRACT: Despite significant efforts devoted to understanding the etiopathogenesis of fibromyalgia, its treatment still presents a challenge to practicing clinicians, who must recognize the disorder and quantify the different symptoms in order to treat it. This article discusses recent research to identify sensitive and reliable measures for determining response to treatment among patients with FM, and the elements of therapeutic programs (pharmacologic and nonpharmacologic) for patients with FM along with the empirical or theoretical basis for their use. Future directions, including the need for systematic, controlled outcome studies of therapies and evaluation of variables which may mediate the effects of treatment, as well as demonstration that the effects produced in outcome studies generalize to settings beyond those in which the studies are initially conducted, are also discussed. KEY INDEXING TERMS: Fibromyalgia treatment; Pharmacologic interventions; Cognitive-behavioral interventions; Pain; Outcome. [Am J Med Sci 1998;315(6):397-404.]
A
lthough significant effort has been devoted to determining the etiopathogenesis of fibromyalgia (FM), its treatment still constitutes a challenge for the practicing clinician.! Given that multiple clinical manifestations (eg, irritable bowel syndrome, headache) tend to be associated with this disorder, patients with FM may present to the family physician, the internist, or a number of different specialists. Thus, the first challenge facing the clinician is to recognize the disorder without performing an excessive number of sophisticated ancillary tests.! From the Division of Clinical Immunology and Rheumatology and the Multipurpose Arthritis and Musculoskeletal Diseases Center, The University ofAlabama at Birmingham, Birmingham, Alabama. Correspondence: Graciela S. Alarcon, MD, MPH, 615 MEB, The University of Alabama at Birmingham, Birmingham, AL 35294. Email: [email protected] THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Once the diagnosis of FM has been made, the clinician should try to quantify the different symptoms which the patient presents. In contrast to treatment studies of patients with rheumatoid arthritis, there currently is no consensus regarding the outcome measurements that should be used in FM research to determine the impact of clinical interventions. 2 Nevertheless, the measurement of FM symptoms has been aided by two recent research efforts described below. Two groups of investigators have attempted to identify sensitive and reliable measures for determining response to treatment among patients with FM.3.4 Both groups have demonstrated the sensitivity and reliability of several measures of pain perception, such as the tender point count, myalgic score, and the McGill Pain Questionnaire. 5 One group also has shown that visual analogue scales (VAS) may be used to evaluate patients' perceptions of their sleep quality and physicians' global assessments of patients' health status. 3 The other group has produced evidence that the Arthritis Impact Measurement Scales and the Symptom Checklist90R may be used to reliably assess patients' perceptions of their own health status as well as levels of anxiety and obsessive-compulsive qualities. 4 Indeed, we believe that it is necessary for the clinician to carefully evaluate the clinical symptoms experienced by FM patients (eg, pain, fatigue), as well as their psychological distress and other dimensions of suffering such as perceptions of helplessness, coping resources, and disruption of functional abilities. 6 - 9 Next, the clinician should try to establish realistic goals for the therapeutic program. Although in ideal circumstances, both patient and clinician should strive toward improved control of all symptoms of FM, uniform improvement on all outcome measures is unlikely to occur with the therapeutic modalities presently available. Thus, the primary emphasis should be placed on improved pain control and enhancing or maintaining the patient's ability to function effectively at home and at work (if employed), followed by reduction of other dimensions of suffering. 3 •1O •n Finally, the clinician should select the elements of 397
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a therapeutic program that are appropriate for each patient and discuss with the patient the basis for their use. 1,12-14 It is likely that patients with long histories of psychiatric illness or high levels of other dimensions of suffering will benefit most from referral to interdisciplinary pain treatment programs. 15 Unfortunately, the most important factor in referral to these programs is often whether or not the patient has adequate insurance coverage to receive therapeutic interventions from multiple healthcare providers such as physicians, psychologists, and physical, occupational, and recreational therapists. We will now discuss the elements of therapeutic programs for patients with FM and the empirical or theoretical basis for their use. These elements include pharmacologic interventions as well as nonpharmacologic treatments such as exercise and cognitive-behavioral interventions. Pharmacologic Interventions
The following will be discussed: antidepressants, anxiolytics, and other psychopharmacologic agents, muscle relaxants, anti-inflammatories, analgesics, anesthetics, and miscellaneous agents. Antidepressants, Anxiolytics, and Other Psychopharmacologic Agents. Studies of the effects of the tricy-
clic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have focused almost exclusively on amitriptyline and fluoxetine. Positive findings generally have been reported, although the doses of TCAs and SSRIs used for pain control are smaller than those used for the treatment of depression (unless clinical evidence of a depressive disorder is present). Three early investigations of amitriptyline showed that it was superior to placebo in producing improvements in patient ratings of pain,16-18 tender point measures/ 7,18 and patient or physician ratings of clinical symptoms. 16 ,17 However, the factors responsible for these improvements have not yet been identified. For example, Carette et aP9,20 performed two studies in which FM patients more frequently displayed clinically significant improvements with amitriptyline than with placebo. Nevertheless, clinical improvement was not associated with alterations in the. alpha nonrapid eye movement sleep anomaly (see Harding article in this issue).19 Moreover, at a 6-month follow-up assessment, a similar number of patients in both amitriptyline and placebo conditions showed clinically significant improvements, negating the early evidence for the superiority of amitriptyline. 20 Thus, the positive effects of amitriptyline are not associated with improvement in sleep physiology and they appear to diminish over time. Despite this limitation, amitriptyline is frequently prescribed for patients with FM. Wolfe et al recently produced a 7-year study at six rheumatology centers which revealed that 40% of
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the FM patients at these centers used amitriptyline during the course of the investigation. 21 Only three investigations have examined the efficacy of fluoxetine in patients with FM. Wolfe et aF2 reported that fluoxetine produced improvements in patients' ratings of fatigue, sleep quality, and depression; however, these changes were not superior to those produced by placebo. Similarly, Cantini et al 23 found that fluoxetine was beneficial to patients with FM only if used in combination with cyclobenzaprine. In contrast, Goldenberg et al 24 showed that both fluoxetine and amitriptyline, compared to placebo, produced significantly greater improvements in patients' reports of their overall disability levels (ie, Fibromyalgia Impact Questionnaire) and VAS ratings of pain, global well-being and sleep disturbances. Moreover, the two pharmacologic interventions produced greater improvements when used in combination with each other than when used alone (ie, 20 mg fluoxetine in the morning and 25 mg amitriptyline at bedtime). It was surprising, however, that neither ofthe interventions altered the patients' tender point scores. A small number of investigations have examined the efficacy of other psychopharmacologic compounds for patients with FM. Studies of SSRIs other than fluoxetine (eg, citalopram) have produced negative results. 1,25 Nevertheless, the 7-year study of health services utilization by Wolfe et al showed that 11 % of the FM patients at six centers were prescribed an SSRI during the course of the investigation. 21 A preliminary study of ondansetron, a 5-hydroxytryptamine type 3 receptor antagonist, has documented improvements in pain distribution and intensity and in overall function among a subset of FM patients whose blood serum serotonin levels remained unchanged during treatment. In contrast, those patients in whom serotonin increased from baseline levels failed to respond to this compound. Similar results were obtained in a small number of patients treated with low doses of a related compound, tropisetron. 26 The only anxiolytic that produces positive effects in FM patients is alprazolam, a benzodiazepine. Russell et al showed that the combination of alprazolam and ibuprofen produced significantly greater improvement than placebo in the tender point index and patients' ratings of disease severity.27 However, a recent study of bromazepam and tenoxican revealed that this combination was only marginally superior to placebo in reducing patients' ratings of pain and other symptoms. 28 Despite the paucity of data to support the use of benzodiazepines other than alprazolam, they frequently are prescribed for patients with FM, primarily for the treatment of anxiety disorders common in these patients. 29 Indeed, Wolfe et al 21 showed that 43% of the patients June 1998 Volume 315 Number 6
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seen in six rheumatology centers used anxiolytics over the 7-year study period. In summary, the tricyclic antidepressants and the combination of fluoxetine and amitriptyline are superior to placebo in producing subjective improvements providing in pain, sleep quality, and fatigue. However, the factors which mediate these improvements are not understood. Moreover, the positive effects of the tricyclic medications tend to diminish over time. It is necessary to study systematically whether these effects may be prolonged by rotating the compounds with one another or with either fluoxetine or the combination of alprazolam and ibuprofen, similar to current practice with disease modifying antirheumatic drugs for patients with rheumatoid arthritis. Muscle Relaxants. The only muscle relaxant which has proven to be beneficial in FM is cyclobenzaprine, used alone or in combination with ibuprofen. 2o,30-32 Similar to amitriptyline, however, the effects of cyclobenzaprine are not superior to those of placebo with prolonged use. 20 Nevertheless, Wolfe et al 21 found that 26% of the FM patients treated at six rheumatology centers used cyclobenzaprine during the 7-year investigation. Other centrally active muscle relaxants such as metaxalone and carisoprodol are indicated for the treatment of acute musculoskeletal pain (primarily trauma) and are not recommended for patients with FM. Anesthetics. It has been shown that the parenteral (intravenous) daily administration of anesthetics (such as lignocaine) leads to improved pain levels and mood scores in FM patients for 30 days after administration. 33 Similar results have been reported with other anesthetics such as lidocaine. 34 However, it is unlikely that this therapeutic modality will be used for a large number of patients unless its beneficial efforts prove to be more prolonged. No data are currently available regarding the frequency with which anesthetics are used with FM patients. Analgesics. Patients with FM frequently are prescribed analgesic medications despite the fact that no data are available regarding their efficacy for pain control in this population. Wolfe et al 21 reported that 50% of the patients seen in six rheumatology centers over 7 years used nonnarcotic analgesics; 20% ofthe patients used narcotic analgesics. Indeed, it is not at all unusual to encounter patients with FM who simultaneously use more than one analgesic medication. Considering the high levels ofpsychopathology present in patients with FM who are treated at tertiary care facilities,29 the prescription of narcotic analgesics for these patients should be avoided because in the long run it is likely to be detrimental. In our experience and that of other clinicians, FM patients who receive narcotic analgesics for the control of their pain do not report improvement in the quality or severity of their pain and, in fact, are THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
likely to escalate the use of these compounds, to request more potent drugs, or to combine them with benzodiazepines and other psychopharmacologic agents. Anti-inflammatories. Wolfe et al 21 found that 91% of all FM patients seen at six rheumatology centers over 7 years reported use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. Nevertheless, ibuprofen, the only NSAID that has been systematically studied, has been shown to be beneficial only if used in combination with alprazolam. 27 ,35 Consistent with the results ofthese investigations, our experience suggests that the usefulness of NSAIDs in the treatment of FM is limited. However, patients who present with a defined regional pain syndrome superimposed on their generalized musculoskeletal pain may benefit from the shortterm use of ibuprofen or other NSAID. Patients with FM and joint hypermobility, who are prone to sustain soft-tissue injuries, may also benefit from the short-term use of NSAIDs; otherwise, they should be used on a trial basis, only for a limited time, and with due knowledge of the spectrum of their side effects, especially in older adults. 36 - 38 Greater restraint in the prescription of NSAIDs for FM patients may lead to a reduction in the high use of antacids and H2 antagonists by these individuals. 21 Only one investigation has examined the effects of prednisone on pain, sleep disturbance, morning stiffness, and fatigue in patients with FM.39 It was found that prednisone did not differ from placebo with regard to change in the variables of interest. In fact, both prednisone and placebo tended to produce deteriorations in patient ratings of pain, fatigue, and morning stiffness during the course of the study. Despite the negative findings, Wolfe et al21 found that 24% of the FM patients seen in six rheumatology centers reported use of prednisone over the 7year study period. Other Compounds. A number of other compounds, which do not quite fit within the other categories, have been tried in FM. Most, however, have not been tested in a systematic and scientific fashion, with the exceptions of Super Malic, diencephalon, S-adenosylmethionine, zolpidem, and growth hormone. Super Malic is a proprietary tablet consisting of malic acid and magnesium. The effects of this compound have been examined with mixed results. Super Malic was found to be safe at low doses when used for a relatively short time, but its effects on VAS pain ratings and tender point measures were not superior to those ofplacebo. 40 However, a subsequent open-label trial with a higher dosage of Super Malic produced significant improvements on both measures. 40 Nevertheless, it is impossible to determine to what extent these improvements were due to the higher dosage or to nonspecific effects of the open-label methodology.
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Treatment Advances
Antidiencephalon immune serum has been tested against placebo and amitriptyline in a relatively small number of women with FM; patients treated with this compound showed definite improvement in sleep relative to the other two groups, but no longterm data on its effects are available. 41 S-adenosylmethionine (SAMe) has been studied in two placebocontrolled trials. 42 ,43 Both investigations found that SAMe was superior to placebo in reducing depression, but there were conflicting results with respect to tender point scores. A recent study of zolpidem revealed that this hypnotic agent produced significant improvements, relative to placebo, in patients' quality and quantity of sleep as well as in their energy levels, without altering levels ofpain.44 Finally, growth hormone (GH) supplementation has been evaluated in FM patients with low IGF-llevels. 45 It was found that, compared to placebo, GH produced significant improvements in IGF-l levels, myalgic scores, and ratings of quality of life over a 9-month treatment period. Nonsystemic Pharmacologic Agents. There is little justification for the use of corticosteroids and anesthetics as injections into tender points, with the possible exception of their use when there is a defined regional problem such as localized tendonitis or bursitis. In this case, injections are helpful; likewise, injections into "trigger" rather than tender points may be justifiable and indeed beneficial, although hard data regarding the effects of these investigations are not available. 46 It should be noted that atrophy ofthe underlying skin may occur, especially with the injection of fluorinated corticosteroid compounds, and thus they should be avoided. The use of topical capsaicin, an inhibitor of substance P, or analog substances, has not been studied systematically in FM. Given the chronic and diffuse nature of the musculoskeletal pain in patients with FM, it may be preferable to limit its empirical use to defined anatomic areas where a regional problem is clearly present. Nonpharmacologic Interventions
Given the complexity and chronicity of the clinical manifestations of FM patients and their relatively poor response to. pharmacologic agents, it is not surprising that several non pharmacologic treatment interventions have been tested in these patients with variable success. The outcomes of these interventions have been assessed using many of the same measures which have been employed in studies of the pharmacologic therapies. The following discussion will review the literature concerning the following types of nonpharmacologic interventions: cognitive-behavioral and behavioral therapies, exercise-based programs, and other nonpharmacologic treatments. Cognitive-Behavioral
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and
Behavioral
Therapies.
Bradley47 first suggested the use of these therapies for patients with FM because of the initial findings of their benefits for patients with rheumatoid arthritis 48 and back pain. 49 Indeed, these therapies may be especially beneficial in reducing the high costs of medical services for FM given that they have been shown to reduce these costs among patients with rheumatoid arthritis and recurrent back pain. 5o,51 At present, the cognitive-behavioral and behavioral therapies usually are provided to patients with FM as part of interdisciplinary treatment programs which also include physical therapy, pharmacologic interventions, and fitness training. Both the cognitive-behavioral and behavioral interventions encompass training in relaxation and other coping strategies as well as positive reinforcements for increasing healthy behavior and reducing pain behavior. However, the cognitive-behavioral therapies place relatively greater emphasis on helping patients reduce perceptions of helplessness, restructure negative patterns of thoughts that may lead to frequent pain behaviors, and to develop preventive strategies for coping with situations which are likely to produce increased perceptions of pain and pain behavior. Several investigators have examined the outcomes produced by cognitive-behavioral and behavioral interventions with FM patients. Most have reported that these interventions produced significant reductions in patients' ratings of pain, other clinical symptoms, and functional disability as well as in pain behavior and tender point measures. 12 ,52-55 However, none of these investigators employed attentionplacebo comparison groups to control for the nonspecific effects of prolonged or frequent contact with concerned healthcare professionals. Thus, it is not possible to attribute the treatment gains to the interventions, although it is promising that two investigatorsreported that patient improvements in observed pain behavior, reports of functional ability, and the tender point count were maintained for periods ranging from 6 months to 30 months after treatment termination. 52,55 Two groups of investigators have performed wellcontrolled studies of behaviorally based treatment for patients with FM. Both groups examined the effects of cognitive-behavioral interventions, including electromyographic (EMG) biofeedback, relaxation training, and training in cognitive coping strategies. 56,57 Vlaeyen et al reported that patients who received the cognitive-behavioral intervention did not show greater improvement on any measure of pain or suffering than patients who received an education-based, attention-placebo intervention. 56 As one might expect, the per patient cost of the cognitive-behavioral intervention ($980) was not justified by the outcomes produced. 58 It should be noted, however, that there was poor compliance among the cognitive-behavioral patients with home practice of the June 1998 Volume 315 Number 6
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pain control and coping skills 56 ; thus, the intervention may have failed because many patients did not attempt to fully learn these skills or to incorporate their use in their home and work environments. Buckelew et al 57 compared the effects of a cognitive-behavioral intervention, exercise training, and a combination of the two treatments with an education-based, attention-placebo condition. All treatments were provided in 6 weekly sessions. At 2-year follow-up, all of the active treatments had produced significant improvements in the tender point index relative to the attention-placebo condition. Only exercise training and the combination of exercise and cognitive-behavioral therapy produced significant improvements in physical activity relative to attention-placebo. There were no other group differences on any measure of pain or suffering. However, the investigators suggested that the effects of the cognitive-behavioral and exercise interventions might have been enhanced if the treatments had not been limited to only 6 training sessions. In summary, well-controlled studies of the effects of behaviorally based interventions have produced modest effects that generally are not superior to those of attention-placebo conditions. We believe, however, that the potential power of these interventions has not been adequately assessed due to difficulties with patient compliance 56 and the use of training periods that were much shorter than those used for patients with rheumatoid arthritis (6 weeks vs. 15 weeks).48,57 These methodologic problems must be resolved before the value of cognitive-behavioral and behavioral interventions for patients with FM may be determined. Exercise-Based Programs. Interest in the therapeutic efficacy of physical exercise in patients with FM began with the report by Bennett et al that 80% to 84% of a group ofFM patients fell below the average level of physical fitness established by the American Heart Association. 59 Indeed, McCain et al 60 demonstrated that a 20-week cardiovascular fitness training program was superior to training in flexibility exercise in producing improvements in pain thresholds, subjective ratings of disease activity, and cardiovascular fitness indices. Unfortunately, subsequent investigators have not produced uniformly positive results about the effects of physical exercise on FM patients. Martin et al 61 reported that an exercise program emphasizing cardiovascular fitness and training in strength and flexibility was superior to relaxation training in improving tender point and myalgic scores as well as aerobic fitness. As noted earlier, Buckelew et al found that exercise training produced significant improvement in physical activity, although its effects on the tender point index did not differ from those produced by cognitive-behavioral therapy. 57 Similar exercise programs, however, generally have proTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
duced improvements only in perceptions of self-efficacy or in global ratings of outcome. 62 ,63 At present, then, it appears that the most effective exercise programs for FM are those that closely resemble the program originally developed by McCain et al. 60 However, the effects of these programs will be diminished if patients do not actively participate and comply with the training. 56 Other Nonpharmacologic Treatments. A small number of studies have examined the effectiveness of hypnotherapy,64 frontal EMG biofeedback training,65 and bright-light and hydrogalvanic therapy.66 The hypnotherapy and biofeedback therapies produced some positive results, but these may have been due to the inclusion of relaxation training components in the treatment packages. Bright-light and hydrogalvanic therapy, however, were not beneficial to FM patients. Conclusions
The evidence reviewed in this article indicates that cardiovascular fitness training and several medications (eg, amitriptyline, fluoxetine, and amitriptyline combined with cyclobenzaprine) produce short-term improvements in patients' reports of pain and other symptoms of FM. Cognitive-behavioral and behavioral therapies may also be helpful to patients with FM, but these interventions have not been adequately evaluated in controlled clinical trials. Indeed, none of the treatments examined in this article has been shown to be superior to appropriate placebo interventions over prolonged periods of time (eg, 6 to 12 months). It is not surprising, then, that patients with FM frequently seek alternatives to traditional medical therapies,67 but it is surprising that some physicians prescribe medications for these patients which have not been appropriately evaluated in patients with FM (eg, narcotic analgesics) or which may be appropriate for only a small number of FM patients (eg, prednisone). The modest effectiveness of our current treatments for FM should be considered in light of the fact that our understanding of the etiopathogenesis of this disorder is still quite limited. 1 Nevertheless, as the articles in this issue of the Journal indicate, great gains have been made in the past 5 years in identifying the role of abnormal peripheral (eg, muscle tissue) and central factors (eg, functional activity of the HPA axis and basal ganglia brain structures) in symptom production among patients with FM. Scientific breakthroughs in FM research are likely to occur soon due to the combined efforts of multiple investigators from different disciplines working on what now appear to be isolated phenomena or events, but which may prove to be intertwined. As our understanding ofthe etiopathogenesis ofFM improves, more rational and effective therapeutic programs will be developed. 401
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However, before new therapies are embraced by clinicians and their patients, systematic, controlled outcome studies of these therapies will be needed. We suggest that future investigators of FM treatments adopt an approach similar to that of Carette et al,20 that is, investigators should perform outcome evaluations in which large numbers of subjects are assigned to treatment or appropriate placebo conditions and clinically meaningful outcomes are evaluated with specific criteria for defining positive treatment response. We believe that outcomes should be assessed using measures of both pain and suffering. Moreover, it is essential to evaluate the outcomes of both pharmacologic and nonpharmacologic treatments at posttreatment and follow-up (eg, 6 and 12 months) to determine whether patient improvement tends to diminish over time. It also is necessary to begin to evaluate variables which may mediate the effects of treatment. For example, it would be useful to know whether the beneficial effects of tricyclic antidepressants are associated with changes in functional activity in brain structures involved in processing the sensory or the emotional dimensions of the pain experience. Similarly, it would be beneficial to learn whether any of our treatments affect patients' pain sensitivity under controlled laboratory conditions. 68,69 These evaluations, however, must be performed in a rigorous manner to rule out the influence of extraneous factors on patient performance or functional brain activity.70 Investigators also should assess clinically meaningful measures of change in addition to traditional measures of statistical significance. 71 One especially promising approach is the use of the Reliable Change Index (RCI)12,73 to determine whether or not each subject in a clinical trial produces a posttreatment score which represents a return to normal or near normal functioning. An RCI score may be calculated for each subject by dividing the difference between the individual's pretreatment and posttreatment scores by the standard error of the difference between the two scores. An RCI score greater than 1.96 is considered to be both statistically and clinically meaningful. Demonstration of clinically meaningful change with the RCI would be enhanced by additional evidence that treatment also produces significant reductions in the use of healthcare resources. Finally, it is necessary for investigators to demonstrate that the effects produced in their outcome studies generalize to settings beyond those in which the studies are initially conducted. 3 This requires evidence that the results of treatment outcome studies performed with patients and resources in university-based centers generalize to community settings. For example, it has been shown that cognitivebehavioral interventions for patients with back pain
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are effective both in university-based treatment centers and in local hospital clinics. 49 To summarize, our ability to effectively treat patients with FM currently is limited by our lack of understanding of the etiopathogenesis of the disorder and by the methodologic shortcomings the outcome studies published to date. However, we believe that with advances in basic and clinical FM research described in this issue of the Journal, it will be possible to document statistically and clinically meaningful improvements in patient outcomes in the early stages of the 21st century. Acknowledgments
Preparation of this article was supported by National Institute of Arthritis, Musculoskeletal and Skin Diseases grants lRO l-AR-43136-04 and PO-AR20164, National Center for Research Resources grant 5-MOI-00032, and grants from the American Fibromyalgia Syndrome Association. The authors thank Ella Henderson for her assistance with the technical aspects of this manuscript. References 1. Bradley LA, Alarcon GS. Fibromyalgia. In: Koopman WJ, eq. Arthritis and Allied Conditions: A Textbook ofRheumatology. Baltimore: Williams & Wilkins; 1997:1619. 2. Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum. 1993;36:72940. 3. Simms RW, Felson DT, Goldenberg DL. Development of preliminary criteria for response to treatment in fibromyalgia syndrome. J Rheumatol. 1991; 18:1558-63. 4. Hewett JE, Buckelew SP, Johnson JC, Shaw SE, Huyser B, Fu YZ. Selection of measures suitable for evaluating change in fibromyalgia clinical trials. J Rheumatol. 1995;22:2307-12. 5. Melzack R. The McGill Pain Questionaire: major properties and scoring methods. Pain. 1975; 1:277 -99. 6. Chapman CR, Gavrin J. Suffering and its relationship to pain (review). J Palliat Care. 1993;9:5-13. 7. Burckhardt CS, Clark SR, Bennett RM. The fibromyalgia impact questionnaire: development and validation. J Rheumatol. 1991; 18:728-33. 8. Geisser ME, Robinson ME, Henson CD. The coping strategies questionnaire and chronic pain adjustment: a conceptual and empirical reanalysis. Clin J Pain. 1994; 10:98-106. 9. Hidding A, van Santen M, De Klerk E, Gielen X, Boers M, Geenen R, et al. Comparison between self-report measures and clinical observations offunctional disability in ankylosing spondylitis, rheumatoid arthritis and fibromyalgia. J Rheumatol. 1994;21:818-23. 10. Jensen MP, Turner JA, Romano JM. Correlates of improvement in multidisciplinary treatment of chronic pain. J Consult Clin Psychol. 1994;62:172-9. 11. Simms RW. Controlled trials oftherapy in fibromyalgia syndrome (review). Baillieres Clin Rheumatol. 1994;8:917-34. 12. Bennett RM, Campbell S, Burckhardt C, Clark S, O'Reilly C, Weins A. Balanced approach provides small but significant gains. A multidisciplinary approach to fibromyalgia management. J Musculoskeletal Med. 1991;8:21-32. 13. Bennett RM. Multidisciplinary group programs to treat fibromyalgia patients. Rheum Dis Clin N Am. 1996;22:35167. June 1998 Volume 315 Number 6
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14. Masi AT. Multifaceted treatment actively involves patient. Management of fibromyalgia syndrome: a person-centered approach. J Musculoskeletal Med. 1994;11:27-37. 15. Bradley LA. Behavioral interventions for managing chronic pain. Bull Rheum Dis. 1994;43:2-5. 16. Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline in primary fibrositis: a double-blind, placebocontrolled study. Arthritis Rheum. 1986;29:655-9. 17. Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986;29:1371-7. 18. Scudds RA, McCain GA, Rollman GB, Harth M. Improvements in pain responsiveness in patients with fibrositis after successful treatment with amitriptyline. J Rheumatol. 1989; 16:98-103. 19. Carette S, Oakson G, Guimont C, Steriade M. Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia. Arthritis Rheum. 1995;38:1211-7. 20. Carette S, Bell MJ, Reynolds WJ, Haraoui B, McCain GA, Bykerk VP, et al. Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia: a randomized, double-blind clinical trial. Arthritis Rheum. 1994;37:32-40. 21. Wolfe F, Anderson J, Harkness D, Bennett HM, Caro XJ, Goldenberg DL, et al. A prospective, longitudinal, multicenter study of service utilization and costs in fibromyalgia (see comments). Arthritis Rheum. 1997;40:1560-70. 22. Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol. 1994;23:255-9. 23. Cantini F, Bellandi F, Niccoli L, Di Munno O. Fluoxetin combined with cyclobenzaprine in the treatment of fibromyalgia (in Italian). Minerva Medica. 1994;85:97-100. 24. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmic C. A randomized double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852-9. 25. Norregaard J, Volkmann D, Danneskiold-Samsoe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain. 1995;61:445-9. 26. Samborski W, Stratz T, Lacki JK, Klama K, Mennet P, Muller W. The 5-HT3 blockers in the treatment of the primary fibromyalgia syndrome: a 10-day open study with Tropisetron at a low dose. Materia Med Polona. 1996;28:17-9. 27. Russell IJ, Fletcher EM, Michalek JE, McBroom PC, Hester 00. Treatment of primary fibrositislfibromyalgia syndrome with ibuprofen and alprazolam: a double-blind, placebo-controlled study. Arthritis Rheum. 1991;34:552-60. 28. Carrera JQ, Castano AV, Gomez JP, Rodriguez AF, Medano WH, Rubeio AG, et al. Comparison of tenoxican and bromazepam in the treatment offibromyalgia: a randomized, double-blind, placebo controlled trial. Pain. 1996; 65:221-5. 29. Aaron LA, Bradley LA, Alarcon GS, Alexander RW, Tri· ana-Alexander M, Martin MY, et al. Psychiatric diagnoses in patients with fibromyalgia are related to health care-seeking behavior rather than to illness. Arthritis Rheum. 1996;39:436-45. 30. Bennett HM, Gatter RA, Campbell SM, Andrews RP, Clark SR, Scarola JA. A comparison of cyclobenzaprine and placebo in the management of fibrositis: a double-blind controlled study. Arthritis Rheum. 1988;31:1535-42. 31. Quimby LG, Gratwick GM, Whitney CD, Black SR. A randomized trial of cyclobenzaprine for the treatment of fibromyalgia. J Rheumatol. 1989; 16:140-3. 32. Reynolds WJ, Moldofsky H, Saskin P, Lue FA. The effects of cyclobenzaprine on sleep physiology and symptoms in patients with fibromyalgia. J Rheumatol. 1991; 18:452-4. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
33. Bennett MI, Tai YM. Intravenous lignocaine in the management of primary fibromyalgia syndrome. Int J Clin Pharm Res. 1995; 15:115-9. 34. Sorensen J, Bengtsson A, Backman E, Henriksson KG, Bengtsson M. Pain analysis in patients with fibromyalgia: effects of intravenous morphine, lidocaine, and ketamine. Scand J Rheumatol. 1995;24:360-5. 35. 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 -32. 36. Fries JF, Williams CA, Bloch DA. The relative toxicity of nonsteroidal antiinflammatory drugs. Arthritis Rheum. 1991;34:1353-60. . 37. Fries JF, Spitz PW, Williams CA, Bloch DA, Singh G, Hubert HB. A toxicity index for comparison of side effects among different drugs. Arthritis Rheum. 1990;33:121-30. 38. Griffin MR, Ray WA, Schaffmer W. Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med. 1988; 109:359-63. 39. Clark S, Tindall E, Bennett HM. A double blind crossover trial of prednisone versus placebo in the treatment offibrositis. J Rheumatol. 1985; 12:980-3. 40. Russell IJ, Michalek JE, Flechas JD, Abraham GE. Treatment offibromyalgia syndrome with Super Malic: a randomized, double blind, placebo controlled, crossover pilot study. J Rheumatol. 1995;22:953-8. 41. Kempenaers C, Simenon G, Vander Elst M, Fransolet L, de Mingard P, et al. Effect of an antidiencephalon immune serum on pain and sleep in primary fibromyalgia. Neuropsychobiology. 1994;30:66-72. 42. Jacobsen S, Danneskiold-Samsoe B, Anderson RB. Oral S-adenosylmethionine in primary fibromyalgia: Double-blind clinical evaluation. Scand J Rheumatol. 1991;20:294-302. 43. Tavoni A, Vitali C, Bombardieri S, Pasero G. Evaluation of S-adenosylmethionine in primary fibromyalgia: A doubleblind crossover study. Am J Med. 1987;83:107-10. 44. Moldofsky H, Lue FA, Mously C, Roth·Schechter B, Reynolds WJ. The effect of zolpidem in patients with fibromyalgia: a dose ranging, double blind, placebo controlled, modified crossover study. J Rheumatol. 1996;23:529-33. 45. Bennett RM, Clark SR, Burckhardt CS, Walczyk J. A double-blind placebo-controlled study of growth hormone therapy in fibromyalgia. J Musculoskeletal Pain. 1995;3:110. 46. Borg-Stein J, Stein J. Trigger points and tender points: one and the same? Does injection treatment help? Rheum Dis Clin N Am. 1996;22:305-22. 47. Bradley LA. Cognitive-behavioral therapy for primary fibromyalgia. J Rheumatol. 1989;16:131-6. 48. Bradley LA, Young LD, Anderson KO, Turner RA, Agudelo CA, McDaniel LK, et al. Effects of psychological therapy on pain behavior of rheumatoid arthritis patients. Treatment outcome and six-month followup. Arthritis Rheum. 1987;30:1105-14. 49. Linton SL, Bradley LA, Jensen I, Spangfort E, Sundell L. The secondary prevention of low back pain: a controlled study with follow-up. Pain. 1980;36:197-207. 50. Young LD, Bradley LA, Turner RA. Decreases in health care resource utilization in patients with rheumatoid arthritis following a cognitive-behavioral intervention. Biofeedback Self Reg. 1995;20:259-68. 51. Linton SL, Bradley LA. An 18 month follow-up ofa secondary prevention program for back pain: help and hindrance factors related to outcome maintenance. Clin J Pain. 1992;8:229-36. 52. Bennett HM, Burckhardt CS, Clark SR, O'Reilly CA, Wiens AN, Campbell SM. Group treatment offibromyalgia: a 6 month outpatient program. J Rheumatol. 1996;23:5218. 53. Goldenberg DL, Kaplan KH, Nadeau MG, Brodeur C, Smith J, Schmid CH. A controlled study of a stress-reduc-
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54. 55. 56.
57.
58.
59.
60.
61. 62.
tion, cognitive-behavioral treatment program in fibromyalgia. J Musculoskeletal Pain. 1994;2:53-66. Nielson WR, Walker C, McCain GA. Cognitive-behavioral treatment of fibromyalgia syndrome: preliminary findings. J Rheumatol. 1992; 19:98-103. White KP, Nielson WR. Cognitive-behavioral treatment of fibromyalgia syndrome: a followup assessment. J Rheumatol. 1995;22:717-21. Vlaeyen JWS, Teeken-Gruben NJG, Goossens MEJB, Rutten-van Molken MPMH, Pelt RAGB, van eek H, et al. Cognitive-educational treatment of fibromyalgia: a randomized clinical trial: I. Clinical effects. J Rheumatol. 1996;23:1237-45. Buckelew SP, Conway R, Parker J, Deuser WE, Jennings J, Witty TE. Biofeedback/relaxation training and exercise interventions for fibromyalgia: a prospective trial. Arthritis Care Res. 1998 (in press). Goossens MEJB, Rutten-van Molken MPMH, Leidl HM, Bos SGPM, Vlaeyen JWS, Teeken-Gruben NJG. Cognitive-educational treatment of fibromyalgia: A randomized clinical trial: II. Economic evaluation. J Rheumatol. 1996; 23:1246-54. Bennett HM, Clark SR, Goldberg L, Nelson D, Bonafede RP, Porter J, et al. Aerobic fitness in patients with fibrositis: A controlled study of respiratory gas exchange and 135xe_ non clearance from exercising muscle. Arthritis Rheum. 1989; 32:454-60. McCain GA, Dell 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 Rheum. 1988;31:1135-41. Martin L, Nutting A, MacIntosh BR, Edworthy SM, Butterwick D, Cook J. An exercise program in the treatment of fibromyalgia. J Rheumatol. 1996;23:1050-3. Burckhardt CS, Mannerkorpi K, Hendenberg L, Bjelle A. A randomized, controlled clinical trial of education and physical training for women with fibromyalgia. J Rheumatol. 1994;21:714-20.
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63. Verstoppen FJT, van Santen-Hoeufft 8MS, Bolwijn PH, van der Linden S, Kuippero H. Effects of a group activity program for fibromyalgia patients on physical fitness and well being. J Musculoskeletal Pain. 1997;5:17-28. 64. Haanen HCM, Hoenderdos HTW, van Romande LKJ, Hop WCJ, Mallee C, Terwiel JP, et al. Controlled trial of hypnotherapy in the treatment of refractory fibromyalgia. J Rheumatol. 1991; 18:72-5. 65. Ferraccioli G, Ghirelli L, Scita F, Nolli M, Mozzani M, Fontana S, et al. EMG-biofeedback training in fibromyalgia syndrome. J Rheumatol. 1987; 14:820-5. 66. Gunther V, Mur E, Kinigadner U, Miller C. Fibromyalgia: the effect of relaxation and hydrogalvanic bath therapy on the subjective pain experience. Clin Rheumatol. 1994; 13:573-8. 67. Pioro-Boisset M, Esdaile JM, Fitzcharles M. Alternative medicine use in fibromyalgia syndrome. Arthritis Care Res. 1996;9:13-7. 68. Bendtsen L, Norregaard J, Jensen R, Olesen J. Evidence of qualitatively altered nociception in patients with fibromyalgia. Arthritis Rheum. 1997;40:98-102. 69. Gil KM, Wilson JJ, Edens JL, Webster DA, Abrams MA, Orringer E, et al. Effects of cognitive coping skills training on coping strategies and experimental pain sensitivity in Mrican-American adults with sickle cell disease. Health Psychol. 1996; 15:3-10. 70. Bradley LA, Alarcon GS, Aaron LA, Martin MY, Alberts KR, Sotolongo A, et al. Abnornal pain perception in patients with fibromyalgia: comment on the article by Bendsten, et al. Arthritis Rheum. 1997;40:2275-6. 71. Fortin PR, Stucki G, Katz IN. Measuring relevant change: an emerging challenge in rheumatologic clinical trials. Arthritis Rheum. 1995;38:1027-30. 72. Jacobson NS, Truax P. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol. 1991;59:12-9. 73. Slater MA, Doctor IN, Pruitt SD, Atkinson JR. The clinical significance of behavioral treatment for chronic low back pain: an evaluation of effectiveness. Pain. 1997; 71:257 -63.
June 1998 Volume 315 Number 6
LAURENCE A. BRADLEY, PHD
ABSTRACT: Despite significant efforts devoted to understanding the etiopathogenesis of fibromyalgia, its treatment still presents a challenge to practicing clinicians, who must recognize the disorder and quantify the different symptoms in order to treat it. This article discusses recent research to identify sensitive and reliable measures for determining response to treatment among patients with FM, and the elements of therapeutic programs (pharmacologic and nonpharmacologic) for patients with FM along with the empirical or theoretical basis for their use. Future directions, including the need for systematic, controlled outcome studies of therapies and evaluation of variables which may mediate the effects of treatment, as well as demonstration that the effects produced in outcome studies generalize to settings beyond those in which the studies are initially conducted, are also discussed. KEY INDEXING TERMS: Fibromyalgia treatment; Pharmacologic interventions; Cognitive-behavioral interventions; Pain; Outcome. [Am J Med Sci 1998;315(6):397-404.]
A
lthough significant effort has been devoted to determining the etiopathogenesis of fibromyalgia (FM), its treatment still constitutes a challenge for the practicing clinician.! Given that multiple clinical manifestations (eg, irritable bowel syndrome, headache) tend to be associated with this disorder, patients with FM may present to the family physician, the internist, or a number of different specialists. Thus, the first challenge facing the clinician is to recognize the disorder without performing an excessive number of sophisticated ancillary tests.! From the Division of Clinical Immunology and Rheumatology and the Multipurpose Arthritis and Musculoskeletal Diseases Center, The University ofAlabama at Birmingham, Birmingham, Alabama. Correspondence: Graciela S. Alarcon, MD, MPH, 615 MEB, The University of Alabama at Birmingham, Birmingham, AL 35294. Email: [email protected] THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Once the diagnosis of FM has been made, the clinician should try to quantify the different symptoms which the patient presents. In contrast to treatment studies of patients with rheumatoid arthritis, there currently is no consensus regarding the outcome measurements that should be used in FM research to determine the impact of clinical interventions. 2 Nevertheless, the measurement of FM symptoms has been aided by two recent research efforts described below. Two groups of investigators have attempted to identify sensitive and reliable measures for determining response to treatment among patients with FM.3.4 Both groups have demonstrated the sensitivity and reliability of several measures of pain perception, such as the tender point count, myalgic score, and the McGill Pain Questionnaire. 5 One group also has shown that visual analogue scales (VAS) may be used to evaluate patients' perceptions of their sleep quality and physicians' global assessments of patients' health status. 3 The other group has produced evidence that the Arthritis Impact Measurement Scales and the Symptom Checklist90R may be used to reliably assess patients' perceptions of their own health status as well as levels of anxiety and obsessive-compulsive qualities. 4 Indeed, we believe that it is necessary for the clinician to carefully evaluate the clinical symptoms experienced by FM patients (eg, pain, fatigue), as well as their psychological distress and other dimensions of suffering such as perceptions of helplessness, coping resources, and disruption of functional abilities. 6 - 9 Next, the clinician should try to establish realistic goals for the therapeutic program. Although in ideal circumstances, both patient and clinician should strive toward improved control of all symptoms of FM, uniform improvement on all outcome measures is unlikely to occur with the therapeutic modalities presently available. Thus, the primary emphasis should be placed on improved pain control and enhancing or maintaining the patient's ability to function effectively at home and at work (if employed), followed by reduction of other dimensions of suffering. 3 •1O •n Finally, the clinician should select the elements of 397
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a therapeutic program that are appropriate for each patient and discuss with the patient the basis for their use. 1,12-14 It is likely that patients with long histories of psychiatric illness or high levels of other dimensions of suffering will benefit most from referral to interdisciplinary pain treatment programs. 15 Unfortunately, the most important factor in referral to these programs is often whether or not the patient has adequate insurance coverage to receive therapeutic interventions from multiple healthcare providers such as physicians, psychologists, and physical, occupational, and recreational therapists. We will now discuss the elements of therapeutic programs for patients with FM and the empirical or theoretical basis for their use. These elements include pharmacologic interventions as well as nonpharmacologic treatments such as exercise and cognitive-behavioral interventions. Pharmacologic Interventions
The following will be discussed: antidepressants, anxiolytics, and other psychopharmacologic agents, muscle relaxants, anti-inflammatories, analgesics, anesthetics, and miscellaneous agents. Antidepressants, Anxiolytics, and Other Psychopharmacologic Agents. Studies of the effects of the tricy-
clic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have focused almost exclusively on amitriptyline and fluoxetine. Positive findings generally have been reported, although the doses of TCAs and SSRIs used for pain control are smaller than those used for the treatment of depression (unless clinical evidence of a depressive disorder is present). Three early investigations of amitriptyline showed that it was superior to placebo in producing improvements in patient ratings of pain,16-18 tender point measures/ 7,18 and patient or physician ratings of clinical symptoms. 16 ,17 However, the factors responsible for these improvements have not yet been identified. For example, Carette et aP9,20 performed two studies in which FM patients more frequently displayed clinically significant improvements with amitriptyline than with placebo. Nevertheless, clinical improvement was not associated with alterations in the. alpha nonrapid eye movement sleep anomaly (see Harding article in this issue).19 Moreover, at a 6-month follow-up assessment, a similar number of patients in both amitriptyline and placebo conditions showed clinically significant improvements, negating the early evidence for the superiority of amitriptyline. 20 Thus, the positive effects of amitriptyline are not associated with improvement in sleep physiology and they appear to diminish over time. Despite this limitation, amitriptyline is frequently prescribed for patients with FM. Wolfe et al recently produced a 7-year study at six rheumatology centers which revealed that 40% of
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the FM patients at these centers used amitriptyline during the course of the investigation. 21 Only three investigations have examined the efficacy of fluoxetine in patients with FM. Wolfe et aF2 reported that fluoxetine produced improvements in patients' ratings of fatigue, sleep quality, and depression; however, these changes were not superior to those produced by placebo. Similarly, Cantini et al 23 found that fluoxetine was beneficial to patients with FM only if used in combination with cyclobenzaprine. In contrast, Goldenberg et al 24 showed that both fluoxetine and amitriptyline, compared to placebo, produced significantly greater improvements in patients' reports of their overall disability levels (ie, Fibromyalgia Impact Questionnaire) and VAS ratings of pain, global well-being and sleep disturbances. Moreover, the two pharmacologic interventions produced greater improvements when used in combination with each other than when used alone (ie, 20 mg fluoxetine in the morning and 25 mg amitriptyline at bedtime). It was surprising, however, that neither ofthe interventions altered the patients' tender point scores. A small number of investigations have examined the efficacy of other psychopharmacologic compounds for patients with FM. Studies of SSRIs other than fluoxetine (eg, citalopram) have produced negative results. 1,25 Nevertheless, the 7-year study of health services utilization by Wolfe et al showed that 11 % of the FM patients at six centers were prescribed an SSRI during the course of the investigation. 21 A preliminary study of ondansetron, a 5-hydroxytryptamine type 3 receptor antagonist, has documented improvements in pain distribution and intensity and in overall function among a subset of FM patients whose blood serum serotonin levels remained unchanged during treatment. In contrast, those patients in whom serotonin increased from baseline levels failed to respond to this compound. Similar results were obtained in a small number of patients treated with low doses of a related compound, tropisetron. 26 The only anxiolytic that produces positive effects in FM patients is alprazolam, a benzodiazepine. Russell et al showed that the combination of alprazolam and ibuprofen produced significantly greater improvement than placebo in the tender point index and patients' ratings of disease severity.27 However, a recent study of bromazepam and tenoxican revealed that this combination was only marginally superior to placebo in reducing patients' ratings of pain and other symptoms. 28 Despite the paucity of data to support the use of benzodiazepines other than alprazolam, they frequently are prescribed for patients with FM, primarily for the treatment of anxiety disorders common in these patients. 29 Indeed, Wolfe et al 21 showed that 43% of the patients June 1998 Volume 315 Number 6
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seen in six rheumatology centers used anxiolytics over the 7-year study period. In summary, the tricyclic antidepressants and the combination of fluoxetine and amitriptyline are superior to placebo in producing subjective improvements providing in pain, sleep quality, and fatigue. However, the factors which mediate these improvements are not understood. Moreover, the positive effects of the tricyclic medications tend to diminish over time. It is necessary to study systematically whether these effects may be prolonged by rotating the compounds with one another or with either fluoxetine or the combination of alprazolam and ibuprofen, similar to current practice with disease modifying antirheumatic drugs for patients with rheumatoid arthritis. Muscle Relaxants. The only muscle relaxant which has proven to be beneficial in FM is cyclobenzaprine, used alone or in combination with ibuprofen. 2o,30-32 Similar to amitriptyline, however, the effects of cyclobenzaprine are not superior to those of placebo with prolonged use. 20 Nevertheless, Wolfe et al 21 found that 26% of the FM patients treated at six rheumatology centers used cyclobenzaprine during the 7-year investigation. Other centrally active muscle relaxants such as metaxalone and carisoprodol are indicated for the treatment of acute musculoskeletal pain (primarily trauma) and are not recommended for patients with FM. Anesthetics. It has been shown that the parenteral (intravenous) daily administration of anesthetics (such as lignocaine) leads to improved pain levels and mood scores in FM patients for 30 days after administration. 33 Similar results have been reported with other anesthetics such as lidocaine. 34 However, it is unlikely that this therapeutic modality will be used for a large number of patients unless its beneficial efforts prove to be more prolonged. No data are currently available regarding the frequency with which anesthetics are used with FM patients. Analgesics. Patients with FM frequently are prescribed analgesic medications despite the fact that no data are available regarding their efficacy for pain control in this population. Wolfe et al 21 reported that 50% of the patients seen in six rheumatology centers over 7 years used nonnarcotic analgesics; 20% ofthe patients used narcotic analgesics. Indeed, it is not at all unusual to encounter patients with FM who simultaneously use more than one analgesic medication. Considering the high levels ofpsychopathology present in patients with FM who are treated at tertiary care facilities,29 the prescription of narcotic analgesics for these patients should be avoided because in the long run it is likely to be detrimental. In our experience and that of other clinicians, FM patients who receive narcotic analgesics for the control of their pain do not report improvement in the quality or severity of their pain and, in fact, are THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
likely to escalate the use of these compounds, to request more potent drugs, or to combine them with benzodiazepines and other psychopharmacologic agents. Anti-inflammatories. Wolfe et al 21 found that 91% of all FM patients seen at six rheumatology centers over 7 years reported use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. Nevertheless, ibuprofen, the only NSAID that has been systematically studied, has been shown to be beneficial only if used in combination with alprazolam. 27 ,35 Consistent with the results ofthese investigations, our experience suggests that the usefulness of NSAIDs in the treatment of FM is limited. However, patients who present with a defined regional pain syndrome superimposed on their generalized musculoskeletal pain may benefit from the shortterm use of ibuprofen or other NSAID. Patients with FM and joint hypermobility, who are prone to sustain soft-tissue injuries, may also benefit from the short-term use of NSAIDs; otherwise, they should be used on a trial basis, only for a limited time, and with due knowledge of the spectrum of their side effects, especially in older adults. 36 - 38 Greater restraint in the prescription of NSAIDs for FM patients may lead to a reduction in the high use of antacids and H2 antagonists by these individuals. 21 Only one investigation has examined the effects of prednisone on pain, sleep disturbance, morning stiffness, and fatigue in patients with FM.39 It was found that prednisone did not differ from placebo with regard to change in the variables of interest. In fact, both prednisone and placebo tended to produce deteriorations in patient ratings of pain, fatigue, and morning stiffness during the course of the study. Despite the negative findings, Wolfe et al21 found that 24% of the FM patients seen in six rheumatology centers reported use of prednisone over the 7year study period. Other Compounds. A number of other compounds, which do not quite fit within the other categories, have been tried in FM. Most, however, have not been tested in a systematic and scientific fashion, with the exceptions of Super Malic, diencephalon, S-adenosylmethionine, zolpidem, and growth hormone. Super Malic is a proprietary tablet consisting of malic acid and magnesium. The effects of this compound have been examined with mixed results. Super Malic was found to be safe at low doses when used for a relatively short time, but its effects on VAS pain ratings and tender point measures were not superior to those ofplacebo. 40 However, a subsequent open-label trial with a higher dosage of Super Malic produced significant improvements on both measures. 40 Nevertheless, it is impossible to determine to what extent these improvements were due to the higher dosage or to nonspecific effects of the open-label methodology.
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Antidiencephalon immune serum has been tested against placebo and amitriptyline in a relatively small number of women with FM; patients treated with this compound showed definite improvement in sleep relative to the other two groups, but no longterm data on its effects are available. 41 S-adenosylmethionine (SAMe) has been studied in two placebocontrolled trials. 42 ,43 Both investigations found that SAMe was superior to placebo in reducing depression, but there were conflicting results with respect to tender point scores. A recent study of zolpidem revealed that this hypnotic agent produced significant improvements, relative to placebo, in patients' quality and quantity of sleep as well as in their energy levels, without altering levels ofpain.44 Finally, growth hormone (GH) supplementation has been evaluated in FM patients with low IGF-llevels. 45 It was found that, compared to placebo, GH produced significant improvements in IGF-l levels, myalgic scores, and ratings of quality of life over a 9-month treatment period. Nonsystemic Pharmacologic Agents. There is little justification for the use of corticosteroids and anesthetics as injections into tender points, with the possible exception of their use when there is a defined regional problem such as localized tendonitis or bursitis. In this case, injections are helpful; likewise, injections into "trigger" rather than tender points may be justifiable and indeed beneficial, although hard data regarding the effects of these investigations are not available. 46 It should be noted that atrophy ofthe underlying skin may occur, especially with the injection of fluorinated corticosteroid compounds, and thus they should be avoided. The use of topical capsaicin, an inhibitor of substance P, or analog substances, has not been studied systematically in FM. Given the chronic and diffuse nature of the musculoskeletal pain in patients with FM, it may be preferable to limit its empirical use to defined anatomic areas where a regional problem is clearly present. Nonpharmacologic Interventions
Given the complexity and chronicity of the clinical manifestations of FM patients and their relatively poor response to. pharmacologic agents, it is not surprising that several non pharmacologic treatment interventions have been tested in these patients with variable success. The outcomes of these interventions have been assessed using many of the same measures which have been employed in studies of the pharmacologic therapies. The following discussion will review the literature concerning the following types of nonpharmacologic interventions: cognitive-behavioral and behavioral therapies, exercise-based programs, and other nonpharmacologic treatments. Cognitive-Behavioral
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and
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Therapies.
Bradley47 first suggested the use of these therapies for patients with FM because of the initial findings of their benefits for patients with rheumatoid arthritis 48 and back pain. 49 Indeed, these therapies may be especially beneficial in reducing the high costs of medical services for FM given that they have been shown to reduce these costs among patients with rheumatoid arthritis and recurrent back pain. 5o,51 At present, the cognitive-behavioral and behavioral therapies usually are provided to patients with FM as part of interdisciplinary treatment programs which also include physical therapy, pharmacologic interventions, and fitness training. Both the cognitive-behavioral and behavioral interventions encompass training in relaxation and other coping strategies as well as positive reinforcements for increasing healthy behavior and reducing pain behavior. However, the cognitive-behavioral therapies place relatively greater emphasis on helping patients reduce perceptions of helplessness, restructure negative patterns of thoughts that may lead to frequent pain behaviors, and to develop preventive strategies for coping with situations which are likely to produce increased perceptions of pain and pain behavior. Several investigators have examined the outcomes produced by cognitive-behavioral and behavioral interventions with FM patients. Most have reported that these interventions produced significant reductions in patients' ratings of pain, other clinical symptoms, and functional disability as well as in pain behavior and tender point measures. 12 ,52-55 However, none of these investigators employed attentionplacebo comparison groups to control for the nonspecific effects of prolonged or frequent contact with concerned healthcare professionals. Thus, it is not possible to attribute the treatment gains to the interventions, although it is promising that two investigatorsreported that patient improvements in observed pain behavior, reports of functional ability, and the tender point count were maintained for periods ranging from 6 months to 30 months after treatment termination. 52,55 Two groups of investigators have performed wellcontrolled studies of behaviorally based treatment for patients with FM. Both groups examined the effects of cognitive-behavioral interventions, including electromyographic (EMG) biofeedback, relaxation training, and training in cognitive coping strategies. 56,57 Vlaeyen et al reported that patients who received the cognitive-behavioral intervention did not show greater improvement on any measure of pain or suffering than patients who received an education-based, attention-placebo intervention. 56 As one might expect, the per patient cost of the cognitive-behavioral intervention ($980) was not justified by the outcomes produced. 58 It should be noted, however, that there was poor compliance among the cognitive-behavioral patients with home practice of the June 1998 Volume 315 Number 6
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pain control and coping skills 56 ; thus, the intervention may have failed because many patients did not attempt to fully learn these skills or to incorporate their use in their home and work environments. Buckelew et al 57 compared the effects of a cognitive-behavioral intervention, exercise training, and a combination of the two treatments with an education-based, attention-placebo condition. All treatments were provided in 6 weekly sessions. At 2-year follow-up, all of the active treatments had produced significant improvements in the tender point index relative to the attention-placebo condition. Only exercise training and the combination of exercise and cognitive-behavioral therapy produced significant improvements in physical activity relative to attention-placebo. There were no other group differences on any measure of pain or suffering. However, the investigators suggested that the effects of the cognitive-behavioral and exercise interventions might have been enhanced if the treatments had not been limited to only 6 training sessions. In summary, well-controlled studies of the effects of behaviorally based interventions have produced modest effects that generally are not superior to those of attention-placebo conditions. We believe, however, that the potential power of these interventions has not been adequately assessed due to difficulties with patient compliance 56 and the use of training periods that were much shorter than those used for patients with rheumatoid arthritis (6 weeks vs. 15 weeks).48,57 These methodologic problems must be resolved before the value of cognitive-behavioral and behavioral interventions for patients with FM may be determined. Exercise-Based Programs. Interest in the therapeutic efficacy of physical exercise in patients with FM began with the report by Bennett et al that 80% to 84% of a group ofFM patients fell below the average level of physical fitness established by the American Heart Association. 59 Indeed, McCain et al 60 demonstrated that a 20-week cardiovascular fitness training program was superior to training in flexibility exercise in producing improvements in pain thresholds, subjective ratings of disease activity, and cardiovascular fitness indices. Unfortunately, subsequent investigators have not produced uniformly positive results about the effects of physical exercise on FM patients. Martin et al 61 reported that an exercise program emphasizing cardiovascular fitness and training in strength and flexibility was superior to relaxation training in improving tender point and myalgic scores as well as aerobic fitness. As noted earlier, Buckelew et al found that exercise training produced significant improvement in physical activity, although its effects on the tender point index did not differ from those produced by cognitive-behavioral therapy. 57 Similar exercise programs, however, generally have proTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
duced improvements only in perceptions of self-efficacy or in global ratings of outcome. 62 ,63 At present, then, it appears that the most effective exercise programs for FM are those that closely resemble the program originally developed by McCain et al. 60 However, the effects of these programs will be diminished if patients do not actively participate and comply with the training. 56 Other Nonpharmacologic Treatments. A small number of studies have examined the effectiveness of hypnotherapy,64 frontal EMG biofeedback training,65 and bright-light and hydrogalvanic therapy.66 The hypnotherapy and biofeedback therapies produced some positive results, but these may have been due to the inclusion of relaxation training components in the treatment packages. Bright-light and hydrogalvanic therapy, however, were not beneficial to FM patients. Conclusions
The evidence reviewed in this article indicates that cardiovascular fitness training and several medications (eg, amitriptyline, fluoxetine, and amitriptyline combined with cyclobenzaprine) produce short-term improvements in patients' reports of pain and other symptoms of FM. Cognitive-behavioral and behavioral therapies may also be helpful to patients with FM, but these interventions have not been adequately evaluated in controlled clinical trials. Indeed, none of the treatments examined in this article has been shown to be superior to appropriate placebo interventions over prolonged periods of time (eg, 6 to 12 months). It is not surprising, then, that patients with FM frequently seek alternatives to traditional medical therapies,67 but it is surprising that some physicians prescribe medications for these patients which have not been appropriately evaluated in patients with FM (eg, narcotic analgesics) or which may be appropriate for only a small number of FM patients (eg, prednisone). The modest effectiveness of our current treatments for FM should be considered in light of the fact that our understanding of the etiopathogenesis of this disorder is still quite limited. 1 Nevertheless, as the articles in this issue of the Journal indicate, great gains have been made in the past 5 years in identifying the role of abnormal peripheral (eg, muscle tissue) and central factors (eg, functional activity of the HPA axis and basal ganglia brain structures) in symptom production among patients with FM. Scientific breakthroughs in FM research are likely to occur soon due to the combined efforts of multiple investigators from different disciplines working on what now appear to be isolated phenomena or events, but which may prove to be intertwined. As our understanding ofthe etiopathogenesis ofFM improves, more rational and effective therapeutic programs will be developed. 401
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However, before new therapies are embraced by clinicians and their patients, systematic, controlled outcome studies of these therapies will be needed. We suggest that future investigators of FM treatments adopt an approach similar to that of Carette et al,20 that is, investigators should perform outcome evaluations in which large numbers of subjects are assigned to treatment or appropriate placebo conditions and clinically meaningful outcomes are evaluated with specific criteria for defining positive treatment response. We believe that outcomes should be assessed using measures of both pain and suffering. Moreover, it is essential to evaluate the outcomes of both pharmacologic and nonpharmacologic treatments at posttreatment and follow-up (eg, 6 and 12 months) to determine whether patient improvement tends to diminish over time. It also is necessary to begin to evaluate variables which may mediate the effects of treatment. For example, it would be useful to know whether the beneficial effects of tricyclic antidepressants are associated with changes in functional activity in brain structures involved in processing the sensory or the emotional dimensions of the pain experience. Similarly, it would be beneficial to learn whether any of our treatments affect patients' pain sensitivity under controlled laboratory conditions. 68,69 These evaluations, however, must be performed in a rigorous manner to rule out the influence of extraneous factors on patient performance or functional brain activity.70 Investigators also should assess clinically meaningful measures of change in addition to traditional measures of statistical significance. 71 One especially promising approach is the use of the Reliable Change Index (RCI)12,73 to determine whether or not each subject in a clinical trial produces a posttreatment score which represents a return to normal or near normal functioning. An RCI score may be calculated for each subject by dividing the difference between the individual's pretreatment and posttreatment scores by the standard error of the difference between the two scores. An RCI score greater than 1.96 is considered to be both statistically and clinically meaningful. Demonstration of clinically meaningful change with the RCI would be enhanced by additional evidence that treatment also produces significant reductions in the use of healthcare resources. Finally, it is necessary for investigators to demonstrate that the effects produced in their outcome studies generalize to settings beyond those in which the studies are initially conducted. 3 This requires evidence that the results of treatment outcome studies performed with patients and resources in university-based centers generalize to community settings. For example, it has been shown that cognitivebehavioral interventions for patients with back pain
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are effective both in university-based treatment centers and in local hospital clinics. 49 To summarize, our ability to effectively treat patients with FM currently is limited by our lack of understanding of the etiopathogenesis of the disorder and by the methodologic shortcomings the outcome studies published to date. However, we believe that with advances in basic and clinical FM research described in this issue of the Journal, it will be possible to document statistically and clinically meaningful improvements in patient outcomes in the early stages of the 21st century. Acknowledgments
Preparation of this article was supported by National Institute of Arthritis, Musculoskeletal and Skin Diseases grants lRO l-AR-43136-04 and PO-AR20164, National Center for Research Resources grant 5-MOI-00032, and grants from the American Fibromyalgia Syndrome Association. The authors thank Ella Henderson for her assistance with the technical aspects of this manuscript. References 1. Bradley LA, Alarcon GS. Fibromyalgia. In: Koopman WJ, eq. Arthritis and Allied Conditions: A Textbook ofRheumatology. Baltimore: Williams & Wilkins; 1997:1619. 2. Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum. 1993;36:72940. 3. Simms RW, Felson DT, Goldenberg DL. Development of preliminary criteria for response to treatment in fibromyalgia syndrome. J Rheumatol. 1991; 18:1558-63. 4. Hewett JE, Buckelew SP, Johnson JC, Shaw SE, Huyser B, Fu YZ. Selection of measures suitable for evaluating change in fibromyalgia clinical trials. J Rheumatol. 1995;22:2307-12. 5. Melzack R. The McGill Pain Questionaire: major properties and scoring methods. Pain. 1975; 1:277 -99. 6. Chapman CR, Gavrin J. Suffering and its relationship to pain (review). J Palliat Care. 1993;9:5-13. 7. Burckhardt CS, Clark SR, Bennett RM. The fibromyalgia impact questionnaire: development and validation. J Rheumatol. 1991; 18:728-33. 8. Geisser ME, Robinson ME, Henson CD. The coping strategies questionnaire and chronic pain adjustment: a conceptual and empirical reanalysis. Clin J Pain. 1994; 10:98-106. 9. Hidding A, van Santen M, De Klerk E, Gielen X, Boers M, Geenen R, et al. Comparison between self-report measures and clinical observations offunctional disability in ankylosing spondylitis, rheumatoid arthritis and fibromyalgia. J Rheumatol. 1994;21:818-23. 10. Jensen MP, Turner JA, Romano JM. Correlates of improvement in multidisciplinary treatment of chronic pain. J Consult Clin Psychol. 1994;62:172-9. 11. Simms RW. Controlled trials oftherapy in fibromyalgia syndrome (review). Baillieres Clin Rheumatol. 1994;8:917-34. 12. Bennett RM, Campbell S, Burckhardt C, Clark S, O'Reilly C, Weins A. Balanced approach provides small but significant gains. A multidisciplinary approach to fibromyalgia management. J Musculoskeletal Med. 1991;8:21-32. 13. Bennett RM. Multidisciplinary group programs to treat fibromyalgia patients. Rheum Dis Clin N Am. 1996;22:35167. June 1998 Volume 315 Number 6
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