Pain and Therapy

, Volume 2, Issue 1, pp 65–71 | Cite as

Interpreting Effect Sizes and Clinical Relevance of Pharmacological Interventions for Fibromyalgia

  • Lesley M. Arnold
  • Joseph C. Cappelleri
  • Andrew Clair
  • Elizabeth T. Masters
Open Access


Duloxetine, milnacipran, and pregabalin are approved by the United States Food and Drug Administration for the management of fibromyalgia. A number of meta-analyses, pooled analyses, and systematic reviews have been published in recent years involving the efficacy of these three medications for pain in fibromyalgia. Despite being based on the same clinical data, some analyses found these treatments to have a clinically relevant effect on pain, while others concluded that the advantages were small or of questionable clinical relevance. This commentary discussed possible reasons behind these differing conclusions and explored ways of evaluating the clinical relevance of pharmacological treatments for fibromyalgia. In particular, we considered: (1) the importance of judicious and careful interpretation of average treatment effect size and the recognition that average treatment effect sizes do not always tell the whole story; (2) the utility of individual patient response data to assess clinical relevance; and (3) the importance of considering pain reduction within the context of other benefits due to the presence of associated symptoms in patients with fibromyalgia.


Clinical relevance Duloxetine Effect size Fibromyalgia Milnacipran Pain Patient response Patient-reported outcomes Pregabalin 


Fibromyalgia (FM) is a common chronic pain condition with multiple associated symptom domains. While FM is diagnosed based on the presence of chronic pain and tenderness [1], patients also frequently experience other symptoms, including fatigue, poor sleep, anxiety, and depression [2]. Three medications (duloxetine [3], milnacipran [4], and pregabalin [5]) have been approved by the United States Food and Drug Administration (FDA) for the management of FM. Several well-controlled, high-quality clinical trials have demonstrated the efficacy of these treatments for the management of FM [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. A number of meta-analyses, pooled analyses, and systematic reviews of pharmacological interventions for FM have been published in recent years [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35]. However, these analyses have not always reached the same conclusions regarding the clinical meaningfulness of trial results, despite often involving data from the same studies. This is likely due, in part, to differences in how a clinically meaningful result was defined, as there is no definitive definition of what constitutes a clinically relevant or meaningful improvement in symptoms in FM.

In this commentary, we highlight some key points we believe should be considered when determining the clinical relevance of pharmacological treatments for FM: (1) the importance of judicious and careful interpretation of average treatment effect size and the recognition that average treatment effect sizes do not always tell the whole story; (2) the utility of individual patient response data to assess clinical relevance; and (3) the importance of considering pain reduction within the context of other benefits due to the presence of associated symptoms in patients with FM.

Use of Average Treatment Effect Size to Determine Clinical Relevance

Average treatment effect sizes have been used by several meta-analyses and systematic reviews [19, 23, 27, 32, 34] to evaluate the efficacy of interventions for FM based on thresholds defined by Cohen, which categorize effect sizes as small [standardized mean difference (SMD) of 0.2], medium (SMD of 0.5), and large (SMD of 0.8) [36] (SMD is the difference in means between active and control groups divided by their pooled standard deviation). Among these is a recent analysis by Nuesch et al. [19], the most comprehensive meta-analysis of pharmacological and non-pharmacological interventions for FM published to date. Nuesch et al. concluded that current evidence best supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs; specifically, duloxetine or milnacipran) or pregabalin in combination with non-pharmacological therapies as treatment for FM, an approach supported by recent guidelines and recommendations for FM management [37, 38, 39]. However, regarding the efficacy of individual interventions for FM, Nuesch et al. [19] remarked that the “benefits for SNRIs and pregabalin compared with placebo were statistically significant but small and not clinically relevant”.

While the observed effect sizes of FM medications were not large according to Cohen’s classification [36], we question whether use of these categories as a stand-alone gauge of clinical meaningfulness is appropriate, since they are based solely on statistical distributions and not on clinical criteria per se. Categorization of effect sizes can help to summarize the signal-to-noise magnitude of therapeutic effects; however, we believe more can be done to assess fully the therapeutic benefit to patients. Many approved treatments are expected to have average effect sizes in the small-to-moderate range, which explains why larger sample sizes are needed in clinical trials, but that is not to say that treatment effects are not clinically significant. It is important to consider, for example, that average treatment effect sizes do not fully characterize the spectrum of treatment responses observed in chronic pain patients. It is also worthwhile to distinguish between responders and non-responders by evaluating individual patient data, based on predefined thresholds that are relevant to the condition [20, 29, 40, 41].

IMMPACT Recommendations and Use of Patient Response Thresholds to Determine Clinical Relevance

The initiative on methods, measurement, and pain assessment in clinical trials (IMMPACT) has recommended classifying pain responses in chronic pain patients as minimally important (10–20% pain reduction from baseline), moderately important (≥30%), and substantial (≥50%), based on three chronic pain studies that assessed changes in pain scores (on a numerical rating scale from 0 to 10) along with patient impressions of overall improvement [42]. A threshold of 30% change from baseline in the Brief Pain Inventory average pain and severity scores has been confirmed in a recent study as a minimally clinically relevant response in an FM population [43]. Responder analysis is a useful way to complement and supplement an analysis based on means, and has been recommended by regulatory bodies as a way to establish clinically relevant benefits [44, 45]. Responder analysis can also be extended to show the cumulative proportion of responders and of all patients over a range of possible cutoff points [44, 46, 47], further enhancing the interpretation of patient responses.

Several meta-analyses and pooled analyses of clinical trials of the FDA-approved FM medications have used the IMMPACT ≥30% threshold to define a clinically relevant response [20, 24, 25, 26, 29, 30, 33, 34, 35]. These analyses have estimated response rates (≥30% improvement in pain score) of up to 49% for 60–120 mg/day duloxetine (compared with up to 32% for placebo) [26, 33, 35], up to 61% for 100–200 mg/day milnacipran (compared with up to 36% for placebo) [20, 24], and up to 43% for 150–450 mg/day pregabalin (compared with up to 29% for placebo) [25, 29, 30, 34]. These data indicate that a substantial proportion of patients experience a clinically meaningful response to active treatment of pain associated with FM. Even after accounting for a placebo effect, differences in responder rates between active and placebo treatments are noteworthy.

Additional Benefits

Patients with FM identify several symptoms in addition to chronic pain that have a negative impact on their quality of life, including sleep disturbance, fatigue, depression, anxiety, and cognitive impairment [48]. A recent analysis of FM responder definitions suggested that inclusion of assessments of symptom and functional domains in addition to pain could significantly improve the ability of clinical trials to identify clinically meaningful improvements [49]. In addition, improvements in fatigue, physical function, and sleep, as well as pain, have individually been shown to correlate well with improvements on the patient global impression of change scale [24, 49, 50, 51], which provides an indication of overall patient improvement.

Duloxetine, milnacipran, and pregabalin have been shown to have positive effects not only on pain but also on secondary symptom domains of FM [27]. Specifically, duloxetine was shown to be effective for sleep disturbance, depressed mood, and health-related quality of life (HR-QoL); milnacipran for fatigue, depressed mood, and HR-QoL; and pregabalin for fatigue, sleep disturbance, and HR-QoL. Pregabalin-mediated pain relief has also been shown to reduce the number of work days lost by FM patients by more than 1 day per week [52]. We suggest that all potential effects of an intervention, benefits, and harms, should be considered when evaluating the net clinical benefit, particularly for a condition such as FM. This assessment should also take into account the potential for adverse events, contraindications, and patient comorbid conditions. The most common adverse reactions to these medications (occurring in at least 5% of treated patients and at least twice the incidence of placebo patients) are nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis for duloxetine [3]; nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpitations, increased heart rate, dry mouth, and hypertension for milnacipran [4]; and dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and abnormal thinking (primarily difficulty with concentration or attention) for pregabalin [5]. All three medications were generally well tolerated in clinical trials of patients with FM, with the majority of patients successfully completing the trials [3, 4, 5].

Conclusions and Future Perspectives

It is important for clinicians and patients with FM to have a realistic idea of the potential net clinical benefit of pharmacological FM treatments. Clinical trials and meta-analyses of FM treatments should evaluate not only the statistical significance of a study outcome, but also its clinical significance. Studies should attempt to clearly define, when possible, a clinically important change for key measures at their outset, and examine patient-level responses in addition to average treatment effects in order to enhance the clinical interpretation of treatment benefit. The fact that standards and practices in evidence-based health care depend on conversion from the research to clinical setting should not be underestimated. Finally, it is important to consider the benefits of treatments for FM beyond their effect on pain, taking into account their effects on other related comorbidities and symptoms, and overall patient function and quality of life.

This commentary has focused on pharmacological interventions for FM; however, several studies have showed the positive effects of non-pharmacological interventions, including exercise [53], hydrotherapy [54], and cognitive-behavioral therapy [55]. Multi-modal treatment, including at least one educational treatment and one exercise therapy, has also been shown to have short-term benefits [56]. While it may not be feasible for trials of non-pharmacological therapies to achieve the same high methodological and regulatory standards as trials of pharmacological therapies (for instance, in exercise trials it is not possible to blind participants to their treatment), we believe that the points raised in this commentary could be also worthy of consideration for trials of non-pharmacological interventions.



Medical writing support was provided by Lorna Forse, PhD, of UBC Scientific Solutions and funded by Pfizer Inc. Elizabeth Masters is the guarantor for this article, and takes responsibility for the integrity of the work as a whole.

Conflict of interest

Lesley Arnold has consulted with Eli Lilly and Company (past), Sanofi-Synthelabo (past), Forest Laboratories (past), Sepracor (past), Allergan (past), Vivus (past), Boehringer Ingelheim (past), Organon (past), Johnson and Johnson (past), AstraZeneca (past), Takeda (past), Grunenthal (past), Pfizer Inc, Daiichi Sankyo, Theravance, Dainippon Sumitomo Pharma, and Purdue; has received research funding from Sanofi-Synthelabo (past), Boehringer Ingelheim (past), Allergan (past), Novartis (past), Pfizer Inc, Forest Laboratories, Eli Lilly and Company, Takeda, AstraZeneca, and Theravance; and has been on speakers bureaus for Eli Lilly and Company (past), Forest Laboratories (past) and Pfizer Inc. Joseph Cappelleri is an employee of Pfizer Inc. and holds stock options with Pfizer Inc. Andrew Clair is an employee of Pfizer Inc. and holds stock options with Pfizer Inc. Elizabeth Masters is an employee of Pfizer Inc. and holds stock options with Pfizer Inc.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


  1. 1.
    Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160–72.PubMedCrossRefGoogle Scholar
  2. 2.
    Russell IJ, Raphael KG. Fibromyalgia syndrome: presentation, diagnosis, differential diagnosis, and vulnerability. CNS Spectr. 2008;13:6–11.PubMedGoogle Scholar
  3. 3.
    Eli Lilly and Company. Cymbalta® US prescribing information. Available at: Accessed 8 Feb 2013.
  4. 4.
    Forest Pharmaceuticals. Savella® US prescribing information. Available at Accessed 16 Jan 2013.
  5. 5.
    Pfizer Inc. LYRICA® US prescribing information. Available at Accessed 16 Jan 2013.
  6. 6.
    Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50:2974–84.PubMedCrossRefGoogle Scholar
  7. 7.
    Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain. 2008;136:432–44.PubMedCrossRefGoogle Scholar
  9. 9.
    Chappell AS, Bradley LA, Wiltse C, Detke MJ, D’Souza DN, Spaeth M. A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia. Int J Gen Med. 2008;1:91–102.PubMedCrossRefGoogle Scholar
  10. 10.
    Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG. A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. Hum Psychopharmacol. 2004;19(Suppl 1):S27–35.PubMedCrossRefGoogle Scholar
  11. 11.
    Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther. 2008;30:1988–2004.PubMedCrossRefGoogle Scholar
  12. 12.
    Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36:398–409.PubMedCrossRefGoogle Scholar
  13. 13.
    Branco JC, Zachrisson O, Perrot S, Mainguy Y. A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia. J Rheumatol. 2010;37:851–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Arnold LM, Gendreau RM, Palmer RH, Gendreau JF, Wang Y. Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62:2745–56.PubMedCrossRefGoogle Scholar
  15. 15.
    Crofford LJ, Rowbotham MC, Mease PJ, Pregabalin 1008–105 Study Group, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264–73.PubMedCrossRefGoogle Scholar
  16. 16.
    Arnold LM, Russell IJ, Diri EW, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain. 2008;9:792–805.PubMedCrossRefGoogle Scholar
  17. 17.
    Mease PJ, Russell IJ, Arnold LM, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol. 2008;35:502–14.PubMedGoogle Scholar
  18. 18.
    Pauer L, Winkelmann A, Arsenault P, A0081100 Investigators, et al. An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia. J Rheumatol. 2011;38:2643–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Nuesch E, Hauser W, Bernardy K, Barth J, Juni P. Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis. Ann Rheum Dis. 2012 (epub ahead of print).Google Scholar
  20. 20.
    Derry S, Gill D, Phillips T, Moore RA. Milnacipran for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;3:CD008244.PubMedGoogle Scholar
  21. 21.
    Choy E, Marshall D, Gabriel ZL, Mitchell SA, Gylee E, Dakin HA. A systematic review and mixed treatment comparison of the efficacy of pharmacological treatments for fibromyalgia. Semin Arthritis Rheum. 2011;41:335–345.e6.PubMedCrossRefGoogle Scholar
  22. 22.
    Roskell NS, Beard SM, Zhao Y, Le TK. A meta-analysis of pain response in the treatment of fibromyalgia. Pain Pract. 2011;11:516–27.PubMedCrossRefGoogle Scholar
  23. 23.
    Hauser W, Petzke F, Uceyler N, Sommer C. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Rheumatology (Oxford). 2011;50:532–43.CrossRefGoogle Scholar
  24. 24.
    Geisser ME, Palmer RH, Gendreau RM, Wang Y, Clauw DJ. A pooled analysis of two randomized, double-blind, placebo-controlled trials of milnacipran monotherapy in the treatment of fibromyalgia. Pain Pract. 2011;11:120–31.PubMedCrossRefGoogle Scholar
  25. 25.
    Siler AC, Gardner H, Yanit K, Cushman T, McDonagh M. Systematic review of the comparative effectiveness of antiepileptic drugs for fibromyalgia. J Pain. 2011;12:407–15.PubMedCrossRefGoogle Scholar
  26. 26.
    Bradley LA, Wohlreich MM, Wang F, et al. Pain response profile of patients with fibromyalgia treated with duloxetine. Clin J Pain. 2010;26:498–504.PubMedCrossRefGoogle Scholar
  27. 27.
    Hauser W, Petzke F, Sommer C. Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome. J Pain. 2010;11:505–21.PubMedCrossRefGoogle Scholar
  28. 28.
    Chwieduk CM, McCormack PL. Milnacipran: in fibromyalgia. Drugs. 2010;70:99–108.PubMedCrossRefGoogle Scholar
  29. 29.
    Straube S, Derry S, Moore RA, Paine J, McQuay HJ. Pregabalin in fibromyalgia-responder analysis from individual patient data. BMC Musculoskelet Disord. 2010;11:150.PubMedCrossRefGoogle Scholar
  30. 30.
    Straube S, Derry S, Moore RA, McQuay HJ. Pregabalin in fibromyalgia: meta-analysis of efficacy and safety from company clinical trial reports. Rheumatology (Oxford). 2010;49:706–15.CrossRefGoogle Scholar
  31. 31.
    Tzellos TG, Toulis KA, Goulis DG, et al. Gabapentin and pregabalin in the treatment of fibromyalgia: a systematic review and a meta-analysis. J Clin Pharm Ther. 2010;35:639–56.PubMedCrossRefGoogle Scholar
  32. 32.
    Hauser W, Bernardy K, Uceyler N, Sommer C. Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis. JAMA. 2009;301:198–209.PubMedCrossRefGoogle Scholar
  33. 33.
    Arnold LM, Clauw DJ, Wohlreich MM, et al. Efficacy of duloxetine in patients with fibromyalgia: pooled analysis of 4 placebo-controlled clinical trials. Prim Care Companion J Clin Psychiatry. 2009;11:237–44.PubMedCrossRefGoogle Scholar
  34. 34.
    Hauser W, Bernardy K, Uceyler N, Sommer C. Treatment of fibromyalgia syndrome with gabapentin and pregabalin-a meta-analysis of randomized controlled trials. Pain. 2009;145:69–81.PubMedCrossRefGoogle Scholar
  35. 35.
    Arnold LM, Pritchett YL, D’Souza DN, Kajdasz DK, Iyengar S, Wernicke JF. Duloxetine for the treatment of fibromyalgia in women: pooled results from two randomized, placebo-controlled clinical trials. J Womens Health (Larchmt). 2007;16:1145–56.CrossRefGoogle Scholar
  36. 36.
    Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale: L. Erlbaum Associates; 1988.Google Scholar
  37. 37.
    Fitzcharles MA, Ste-Marie PA, Goldenberg DL, et al. 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome. Available at Accessed 16 Jan 2013.
  38. 38.
    Arnold LM, Clauw DJ, Dunegan LJ, Turk DC. A framework for fibromyalgia management for primary care providers. Mayo Clin Proc. 2012;87:488–96.PubMedCrossRefGoogle Scholar
  39. 39.
    Carville SF, Arendt-Nielsen S, Bliddal H, EULAR, et al. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis. 2008;67:536–41.PubMedCrossRefGoogle Scholar
  40. 40.
    Moore RA, Edwards JE, McQuay HJ. Acute pain: individual patient meta-analysis shows the impact of different ways of analysing and presenting results. Pain. 2005;116:322–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Moore RA, Moore OA, Derry S, Peloso PM, Gammaitoni AR, Wang H. Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice. Ann Rheum Dis. 2010;69:374–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9:105–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Mease PJ, Spaeth M, Clauw DJ, et al. Estimation of minimum clinically important difference for pain in fibromyalgia. Arthritis Care Res (Hoboken). 2011;63:821–6.PubMedCrossRefGoogle Scholar
  44. 44.
    US Food and Drug Administration. Guidance for industry: patient reported outcome measures: use in medical product development to support labeling claims. 2009. Available at Accessed 13 Mar 2013.
  45. 45.
    European Medicines Agency. Committee for Proprietary Medicinal Products. Points to consider on multiplicity issues in clinical trials. 2002. Available at Accessed 13 Mar 2013.
  46. 46.
    Farrar JT, Dworkin RH, Max MB. Use of the cumulative proportion of responders analysis graph to present pain data over a range of cut-off points: making clinical trial data more understandable. J Pain Symptom Manage. 2006;31:369–77.PubMedCrossRefGoogle Scholar
  47. 47.
    McLeod LD, Coon CD, Martin SA, Fehnel SE, Hays RD. Interpreting patient-reported outcome results: US FDA guidance and emerging methods. Expert Rev Pharmacoecon Outcomes Res. 2011;11:163–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Arnold LM, Crofford LJ, Mease PJ, et al. Patient perspectives on the impact of fibromyalgia. Patient Educ Couns. 2008;73:114–20.PubMedCrossRefGoogle Scholar
  49. 49.
    Arnold LM, Williams DA, Hudson JI, et al. Development of responder definitions for fibromyalgia clinical trials. Arthritis Rheum. 2012;64:885–94.PubMedCrossRefGoogle Scholar
  50. 50.
    Arnold LM, Zlateva G, Sadosky A, Emir B, Whalen E. Correlations between fibromyalgia symptom and function domains and patient global impression of change: a pooled analysis of three randomized, placebo-controlled trials of pregabalin. Pain Med. 2011;12:260–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Hudson JI, Arnold LM, Bradley LA, et al. What makes patients with fibromyalgia feel better? Correlations between patient global impression of improvement and changes in clinical symptoms and function: a pooled analysis of 4 randomized placebo-controlled trials of duloxetine. J Rheumatol. 2009;36:2517–22.PubMedCrossRefGoogle Scholar
  52. 52.
    Straube S, Moore RA, Paine J, et al. Interference with work in fibromyalgia: effect of treatment with pregabalin and relation to pain response. BMC Musculoskelet Disord. 2011;12:125.PubMedCrossRefGoogle Scholar
  53. 53.
    Busch AJ, Schachter CL, Overend TJ, Peloso PM, Barber KA. Exercise for fibromyalgia: a systematic review. J Rheumatol. 2008;35:1130–44.PubMedGoogle Scholar
  54. 54.
    Langhorst J, Musial F, Klose P, Hauser W. Efficacy of hydrotherapy in fibromyalgia syndrome—a meta-analysis of randomized controlled clinical trials. Rheumatology (Oxford). 2009;48:1155–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Bennett R, Nelson D. Cognitive behavioral therapy for fibromyalgia. Nat Clin Pract Rheumatol. 2006;2:416–24.PubMedCrossRefGoogle Scholar
  56. 56.
    Hauser W, Bernardy K, Arnold B, Offenbacher M, Schiltenwolf M. Efficacy of multicomponent treatment in fibromyalgia syndrome: a meta-analysis of randomized controlled clinical trials. Arthritis Rheum. 2009;61:216–24.PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2013

Authors and Affiliations

  • Lesley M. Arnold
    • 1
  • Joseph C. Cappelleri
    • 2
  • Andrew Clair
    • 3
  • Elizabeth T. Masters
    • 3
  1. 1.Department of Psychiatry and Behavioral NeuroscienceUniversity of Cincinnati College of MedicineCincinnatiUSA
  2. 2.Pfizer Inc.GrotonUSA
  3. 3.Pfizer Inc.New YorkUSA

Personalised recommendations