A Systematic Review and Mixed Treatment Comparison of the Efficacy of Pharmacological Treatments for Fibromyalgia

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A Systematic Review and Mixed Treatment Comparison of the Efficacy of Pharmacological Treatments for Fibromyalgia Ernest Choy, MD,* David Marshall, MD,† Zahava L. Gabriel, PhD,‡ Stephen A. Mitchell, PhD,§ Elizabeth Gylee, MSc,§ and Helen A. Dakin, MSc¶

Objectives: To review the literature on pharmacological treatments for fibromyalgia. Methods: Relative efficacy was estimated in terms of outcome measures highlighted by the Outcome Measures in Rheumatology Network using a Bayesian mixed treatment comparison (MTC) meta-analysis. Randomized controlled trials reporting treatments for fibromyalgia were identified by systematically reviewing electronic databases (Cochrane Library, Medline, EMBASE; accessed February 2008) and conducting manual bibliographic searches. Results: Forty-five randomized controlled trials met the prespecified inclusion criteria for the systematic review. There were limited robust clinical data for some therapeutic classes (tricyclic antidepressants, analgesics, sedative hypnotics, monoamine oxidase inhibitors) and only 21 studies met the more stringent criteria for inclusion in the MTC. The majority of studies included in the MTC assessed the anticonvulsant pregabalin (n ⫽ 5) or the serotonin norepinephrine reuptake inhibitors (SNRIs) duloxetine (n ⫽ 3) and milnacipran (n ⫽ 3). Licensed doses of pregabalin and duloxetine were significantly (P ⬍ 0.05) more efficacious than placebo in terms of absolute reduction in pain, number of “responders” (ⱖ30% reduction in pain), or change in Fibromyalgia Impact Questionnaire score (pregabalin 450 mg/d only). There was no significant difference between licensed doses of pregabalin and duloxetine for these outcomes. However licensed doses of pregabalin produced significantly greater improvements in sleep compared with milnacipran (as measured by Medical Outcomes Study Sleep Scale). Conclusions: The current study confirms the therapeutic efficacy of pregabalin and the SNRIs, duloxetine and milnacipran, in the treatment of fibromyalgia. Given their different modes of action, combination therapy with pregabalin plus an SNRI should be investigated in future research. © 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:335-345 Keywords: fibromyalgia, mixed treatment comparison, systematic review, meta-analysis

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ibromyalgia is the most common cause of chronic widespread pain globally, with a prevalence of 2% (1). The diagnosis is most commonly based on American College of Rheumatology classification criteria,

*Cardiff University School of Medicine, Cardiff, UK. †Inverclyde Royal Hospital, Greenock, UK. ‡Pfizer Ltd, Surrey, UK. §Abacus International, Oxfordshire, UK. ¶Health Economics Research Centre, University of Oxford, Oxford, UK. This review was funded by Pfizer Ltd. Zahava Gabriel is a paid employee of Pfizer Ltd. Ernest Choy, David Marshall, Stephen Mitchell, Elizabeth Gylee, and Helen Dakin undertook paid consultancy work for Pfizer Ltd. Address reprint requests to Stephen Mitchell, PhD, Abacus International, 6 Talisman Business Centre, Talisman Road, Bicester, Oxfordshire, OX26 6HR, United Kingdom. E-mail: [email protected]

0049-0172/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2011.06.003

which require the presence of widespread pain in all 4 quadrants of the body for at least 3 months and pain on digital palpation in at least 11 of 18 characteristic tender point sites (2). Fibromyalgia is approximately 7 times more prevalent in women than men (1). Although pain is the dominant feature, fibromyalgia is also associated with other symptoms such as fatigue, problems sleeping, stiffness, problems with concentration, depression, anxiety, headaches, migraine, and paresthesia (3). The symptoms cause significant physical disability and reduced quality of life (4,5). A number of pharmacological and nonpharmacological treatments have been studied in subjects with fibromyalgia (6,7). Early interventional studies in fibromyalgia tended to be of poor quality and only enrolled small num335

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bers of patients (8 –10). Over the last decade, the number of high-quality large randomized controlled trials (RCTs) has increased substantially. Although the precise pathogenesis of fibromyalgia remains unknown, there is increasing evidence to implicate central sensitization as an important pathophysiological mechanism (11). As a result, a number of large, high-quality RCTs have been conducted in fibromyalgia to assess the efficacy and safety of medications that affect pain processing. Following these trials, pregabalin, duloxetine, and milnacipran have been approved by the Food and Drug Administration (FDA) for the treatment of fibromyalgia in the United States. None of these drugs have been approved by the European Medicines Agency for use in fibromyalgia to date and, as a result, there are no treatments specifically licensed for fibromyalgia in Europe. A number of systematic reviews in fibromyalgia have been previously published (7,12–16) but these tend to focus on individual drugs or single-drug classes (7,12,13). Several evidence-based guidelines on the management of fibromyalgia have also been published (including European League Against Rheumatism (17), American Pain Society (18), and German Association of Pain Therapy (19) guidelines) but these have not included some of the recent large RCTs that assessed pregabalin, milnacipran, and duloxetine (20 –22). Early systematic reviews were based on RCTs, which reported a variety of different outcome measures, resulting in large variations and inconsistencies in reporting of outcomes (23–26), rendering meta-analysis problematic. Recent RCTs have reported similar outcome measures (or visual analog scale (VAS) score, Fibromyalgia Impact Questionnaire (FIQ) domains), making more in-depth statistical analysis feasible (27). The present systematic review and meta-analysis aimed to assess the evidence base and the relative efficacy and safety of pharmacological treatments for fibromyalgia, including pregabalin, milnacipran, and duloxetine. Metaanalyses were conducted using mixed treatment comparison (MTC) techniques (28,29) in what we believe to be the first application of these techniques in fibromyalgia to assess the relative efficacy of the different medications in a Bayesian framework, taking account of all evidence, whether direct or indirect. METHODS Systematic Review A systematic review of electronic databases and conference proceedings was conducted to identify relevant studies. Medline, Embase, and the Cochrane Library were accessed on 28 February 2008. The search combined the terms “fibromyalgia” and “fibrositis” and publication type “controlled clinical trial” or “randomized controlled trial.” The following conference proceedings were handsearched (2003–2008 inclusive): World Congress of Pain, British Pain Society, World Institute of Pain, Amer-

Efficacy of pharmacological treatments for fibromyalgia

ican College of Rheumatology, the European League Against Rheumatism. Identified studies were independently assessed by 2 researchers to ascertain whether they met a set of predefined inclusion/exclusion criteria for inclusion in the systematic review (Table 1). A further set of more stringent inclusion criteria were applied to identify studies suitable for inclusion in the MTC analysis (Table 1). Cited references from included trials and reviews of similar trials were also searched. Two independent reviewers considered each publication and discrepancies were resolved through discussion. Reviewers extracted data in parallel from included publications into an Excel spreadsheet. Study quality was assessed independently by 2 reviewers using the Jadad scale (30). Any differences of opinion were resolved by discussion and consensus. Efficacy Outcome Measures The analysis focused on those outcomes considered most important by the Outcome Measures in Rheumatology Network (www.OMERACT.org), an international group that aimed to develop consensus on outcome measures reported in clinical trials of rheumatologic conditions (31): ● ● ● ● ●

Reduction in pain (assessed using 11-point numerical rating scale [NRS] or VAS) Responders (proportion of patients with a >30% reduction in pain on an 11-point NRS) FIQ total score Sleep (assessed using Medical Outcomes Study [MOS] sleep scale) Sleep quality (assessed using 11-point NRS)

The endpoints that were the main focus of our analyses are shown in bold. In all cases, a reduction in score equates to an improvement in symptoms. A secondary meta-analysis on the incidence of treatment-emergent adverse events (TEAEs) was also conducted, although assessment of safety was not the primary focus of the study. Statistical Methods for Meta-Analysis Standard meta-analytical techniques evaluate the relative efficacy of 1 treatment compared with a single comparator (32). More recently, MTC methods have been developed that provide a single combined analysis of the relative efficacy of a whole network of treatments of interest, including both direct and indirect evidence (28,29,32,33). MTC methods are often conducted in a Bayesian framework and are recommended by the National Institute for Health and Clinical Excellence (34). We conducted Bayesian MTC meta-analysis in WinBUGS Version 1.4.7 (MRC Biostatistics Unit, Cambridge, UK) (35), a statistical program that uses Bayesian Markov Chain Monte Carlo Gibbs sampling methods to fit user-defined models. We used statistical models developed by Bristol University for both fixed and random effects MTC, which allowed for studies with 3 or more

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Table 1 Inclusion and Exclusion Criteria Criterion Population

Perspective of study Study characteristics

Language Trial length Sample size Interventions/treatments

Control intervention/treatments Included trial outcomes

Included

Excluded

● Age: ⱖ18 yr ● Race: any ● Qualifying disease: fibromyalgia (according to ACR criteria) ● Any severity of disease at baseline ● Prospective (concurrent) ● Comparative ● RCT ● Parallel study design ● Cross-over trials with a wash-out period between treatments ● Studies employing the ACR criteria for inclusion of subjects ● ● ● ● ● ● ● ● ● ● ● ● ● ●

Any ⱖ4 wk Any 5-HT3 blockers Analgesics Anticonvulsant Dopaminergic agents Muscle relaxants NSAIDs SNRI Sedative hypnotics SSRI TCA Placebo or any of the included drugs ● Including, but not limited to, OMERACT key domains

● Age: ⬍18 yr ● Disease: myofascial pain

● ● ● ● ●

Retrospective Noncomparative Nonrandomized trials Open-label follow-up of RCT Cross-over study design

● Permitted concomitant use of antidepressants and/or anticonvulsants ● Jadad score ⬍3.0 ● ⬍4 wk ● Nonpharmacological treatment ● Flexible-dose regimen

The more stringent criteria for identification of studies for inclusion in the MTC are shown in italics. ACR, American College of Rheumatology; RCT, randomized clinical trial; OMERACT, Outcome Measures for Rheumatoid Arthritis Clinical Trials; NSAIDS, nonsteroidal anti-inflammatory drugs; SNRI, serotonin norepinephrine reuptake inhibitors; SSRI, selective serotonin re-uptake inhibitors; TCA, tricyclic antidepressants.

arms (36). Each outcome measure was analyzed using both fixed and random effects models; the model fit for both models was assessed based on residual deviance (37) and the model with the lowest residual deviance comprised the primary analysis. Placebo was used as the baseline treatment in all analyses since this comprised the treatment evaluated in the largest number of RCTs for the outcome measures considered. The log-odds ratios or weighted mean differences for each treatment relative to placebo that were calculated in the MTC were added to the absolute outcomes for placebo to give predictions of the mean outcomes for each treatment. For binary outcomes, the absolute log-odds of responding to placebo was calculated in WinBUGS using Bayesian random effects meta-analysis of the log-odds in the placebo arm. Similarly for continuous outcomes, the absolute mean change in outcome with placebo was calculated in WinBUGS using Bayesian random effects meta-analysis of the mean change in the placebo arm.

Differences between treatments were considered significantly significant at the 0.05 level if the 95% credible [Bayesian probability] interval around the log-odds ratio or weighted mean difference did not cross zero. Treatment effects based on head-to-head trials were estimated using pair-wise frequentist meta-analyses conducted in Stata Version 10 (StataCorp, College Station, TX) using the metan command. Consistency was assessed using methods described previously (38). Noninformative prior distributions were used for all parameters to ensure that the results were primarily driven by the data. For the main 3 outcome measures, the impact of using alternative priors and alternative initial values was evaluated in sensitivity analysis. As the base case analysis on reductions in pain assumed 11-point VAS and NRS to be equivalent, a sensitivity analysis that excluded VAS data was evaluated for this outcome. Additional sensitivity analyses evaluated the impact of 2 covariates on the main outcome measures: a dummy indicating whether or

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Efficacy of pharmacological treatments for fibromyalgia

Figure 1 Flowchart of inclusions/exclusions.

not the study allowed patients with major depression to enter the trial and a dummy indicating whether or not the trial scored 5/5 on the Jadad quality assessment scale. A total of 100,000 burn-in simulations were conducted for each MTC to ensure that results were robust. A further 100,000 simulations were then run and sampled using 2 chains with different initial values to accurately estimate the parameters of interest. Additional details of the methods used, data on model fit or convergence, and results of sensitivity analyses are available from the authors on request. RESULTS Systematic Review In total, 464 studies were identified (following removal of duplicates), of which 378 were excluded on the basis of title and abstract (Fig. 1). A further 34 relevant publications were identified from searching reference lists and conference proceedings. Seventy-five publications were excluded on examination of the full article, leaving a total of 45 RCTs that were included in the systematic review. Study characteristics for the included publications are reported in the online appendix. Across the 45 studies included in the systematic review, there was considerable variation in study quality. Overall, 13 of the 45 studies (29%) had a Jadad score of 1 or 2 (indicating poor quality). Four of 5 RCTs assessing anticonvulsants were of high quality (Jadad score of 4 or 5). By contrast, trials assessing the serotonin norepinephrine reuptake inhibi-

tors (SNRIs) (n ⫽ 13), tricyclic antidepressants (TCA, n ⫽ 11), selective serotonin reuptake inhibitors (n ⫽ 9), sedative hypnotics (n ⫽ 3), and analgesics (n ⫽ 3) were spread more evenly across the Jadad scores. Twenty-one studies met the more stringent criteria for inclusion in the MTC analysis (Table 1, Table A) and examined the following classes of therapeutic intervention: ● ●

● ● ● ● ●

Monoamine oxidase inhibitors (pirlindole, n ⫽ 1 (39)) Selective serotonin re-uptake inhibitors, selective serotonin reuptake inhibitors (paroxetine, n ⫽ 2 (40,41); citalopram, n ⫽ 2 (42,43)) SNRIs (duloxetine, n ⫽ 3 (44 – 46); milnacipran, n ⫽ 3 (20,47,48)) Analgesics (tramadol, n ⫽ 1 (49)) Anticonvulsants (pregabalin, n ⫽ 5 (21,50 –53)) TCAs (amitriptyline/nortriptyline, n ⫽ 2 (54,55)) Combination therapy with NSAIDs and sedative hypnotics (n ⫽ 2 (56,57))

MTC Results Reduction in Pain Eleven studies meeting the inclusion criteria for the metaanalysis reported data on the mean reduction in pain measured on NRS or VAS (21,40,43– 46,48,50,51,53,56). Nine treatments were evaluated: alprazolam, citalopram, duloxetine, ibuprofen, milnacipran, paroxetine, placebo, pregabalin, and ibuprofen plus alprazolam. Figure 2 shows the head-to-head comparisons that have been made

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Figure 2 Network diagram for absolute reduction in pain on 11-point numerical rating scale or visual analog scale. Each line joining 2 treatments represents 1 or more randomized trial comparing those treatments.

between these treatments in RCTs reporting this endpoint; the resulting evidence network connects all treatments, enabling all studies and treatments meeting inclusion criteria to be included in the MTC. The random effects model fitted the data best and was used to metaanalyze data on this outcome. Tests for consistency found no statistically significant inconsistencies in the evidence network (P ⬎ 0.05). Based on the random effects MTC model, pregabalin 300, 450, and 600 mg/d, and duloxetine 20, 60, and 120 mg/d, produced significantly greater reductions in pain than placebo. Duloxetine 120 mg/d produced significantly greater reductions in pain than milnacipran 100 mg/d and citalopram 20 mg/d (P ⬍ 0.05, Fig. 3, Table 2). However, there were no significant differences between duloxetine and pregabalin (P ⬎ 0.05). Sensitivity analysis showed that the results of the MTC were robust to changes in initial values and prior distribu-

tions. When included as covariates, neither study quality nor inclusion of patients with depression was statistically significant (P ⬎ 0.05) and both had negligible effect on model fit.

Responders Nine studies reported data on responders suitable for inclusion in the MTC on the proportion of patients achieving a ⱖ30% reduction in NRS (20,21,44,46 – 48,50,52,53). These studies evaluated 4 treatments: duloxetine, milnacipran, placebo, and pregabalin. The random effects model fitted the data best and was used to meta-analyze data on this outcome. Pregabalin 300, 450, and 600 mg/d, duloxetine 60 and 120 mg/d, and milnacipran 100 and 200 mg/d significantly increased the odds of response compared with placebo. Pregabalin 450 mg/d, duloxetine

Figure 3 Absolute reduction in pain on 11-point numerical rating scale or visual analog scale.

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Efficacy of pharmacological treatments for fibromyalgia

Table 2 Absolute Reduction in Pain on 11-Point Numerical Rating Scale or Visual Analog Scale Weighted Mean Difference Weighted Mean from Random Effect MetaDifference from Absolute Mean Reduction Random Effects MTC Analyses of Head-to-Head Trials (95% CI) versus Number (95% CrI) versus in Pain from Random Placebo of Trials Placebo Effects MTC (95% CrI) Placebo Pregabalin 600 mg/d Pregabalin 450 mg/d Pregabalin 300 mg/d Milnacipran 100 mg/d Milnacipran 200 mg/d Duloxetine 120 mg/d Duloxetine 60 mg/d Duloxetine 20 mg/d Paroxetine 12.5 to 62.5 mg/d Citalopram 20 mg/d Ibuprofen 600 mg/d Alprazolam 0.5 mg to 3 mg/d Ibuprofen 600 mg ⫹ alprazolam 0.5 to 3 mg/d

1.06 (0.53, 1.59)* 1.76 (1.15, 2.37)* 1.78 (1.17, 2.39)* 1.60 (0.99, 2.21)* 1.32 (0.60, 2.05)* 1.50 (0.78, 2.21)* 2.05 (1.38, 2.72)* 1.91 (1.20, 2.64)* 2.00 (1.11, 2.89)* 1.39 (0.47, 2.31)* 0.76 (⫺0.45, 1.97) 1.36 (⫺0.30, 3.03) 1.54 (⫺0.45, 3.53) 1.76 (⫺0.31, 3.87)

— 0.70 (0.41, 1.01)* 0.73 (0.42, 1.03)* 0.54 (0.24, 0.85)* 0.27 (⫺0.23, 0.77) 0.44 (⫺0.06, 0.93) 0.99 (0.57, 1.41)* 0.86 (0.37, 1.34)* 0.94 (0.22, 1.66)* 0.33 (⫺0.41, 1.09) ⫺0.29 (⫺1.40, 0.79) 0.30 (⫺1.27, 1.88) 0.48 (⫺1.44, 2.40) 0.70 (⫺1.30, 2.74)

— 0.72 (0.32, 1.12)* 0.70 (0.42, 0.98)* 0.51 (0.28, 0.74)* 0.27 (⫺0.02, 0.56) 0.44 (0.15, 0.73)* 0.99 (0.64, 1.34)* 0.89 (0.22, 1.55)* 0.79 (0.10, 1.48)* 0.34 (⫺0.30,0.98) ⫺0.30 (⫺1.31, 0.71) 0.30 (⫺1.23, 1.83) 0.50 (⫺1.35, 2.35) 0.70 (⫺1.32, 2.72)

11 4 4 4 1 1 3 2 1 1 1 1 1 1

CrI, credible interval; CI, confidence interval; MTC, mixed treatment comparison. *Statistically significant (P ⬍ 0.05).

60 and 120 mg/d had significantly greater odds of response than pregabalin 150 mg/d (Table 3). Sensitivity analysis showed that the results of the MTC were robust to changes in initial values and prior distributions. No covariates were statistically significant (P ⬎ 0.05) or improved model fit. FIQ Total Score Seven studies reported data on FIQ total score suitable for inclusion in the MTC (21,44,45,47,48,50,53). Four treatments were evaluated: duloxetine, milnacipran, placebo, and pregabalin. The random effects model fitted the data best and was used to meta-analyze data on this outcome. Pregabalin 450 and 600 mg/d, duloxetine 20, 60

and 120 mg/d, and milnacipran 100 mg/d produced significantly greater reductions in FIQ total score (indicates improvement) than placebo. There were no other significant differences between treatments (Table 4). Sensitivity analysis showed that the results of the MTC were robust to changes in initial values and prior distributions. Neither covariate was statistically significant (P ⬎ 0.05) and both had negligible effect on model fit. Sleep: MOS Four studies reported data on sleep MOS suitable for inclusion in the MTC (21,44,48,50,52). These trials evaluated 3 treatments: milnacipran, placebo, and pregabalin. The fixed effects model fitted the data best and was used

Table 3 Proportion of Patients Responding to Treatment (defined as a ⱖ 30% reduction in pain on 11-point NRS) Log OR from Random Effect Absolute % Responders Log OR from Random Effects Meta-Analyses of Head-toHead Trials (95% CI) versus Number of from Random Effects MTC (95% CrI) versus Placebo Trials MTC (95% CrI) Placebo Placebo Milnacipran 200 mg/d Pregabalin 450 mg/d Pregabalin 300 mg/d Milnacipran 100 mg/d Pregabalin 600 mg/d Duloxetine 60 mg/d Duloxetine 120 mg/d Pregabalin 150 mg/d Duloxetine 20 mg/d

0.30 (0.25, 0.36) 0.44 (0.35, 0.53) 0.47 (0.38, 0.56) 0.42 (0.33, 0.51) 0.40 (0.31, 0.50) 0.43 (0.34, 0.52) 0.48 (0.36, 0.59) 0.48 (0.36, 0.60) 0.33 (0.22, 0.46) 0.42 (0.28, 0.58)

— 0.58 (0.33, 0.84)* 0.71 (0.47, 0.96)* 0.52 (0.27, 0.77)* 0.45 (0.18, 0.72)* 0.54 (0.27, 0.81)* 0.74 (0.37, 1.12)* 0.75 (0.38, 1.15)* 0.13 (⫺0.37, 0.61) 0.52 (⫺0.02, 1.08)

— 0.57 (0.36, 0.79)* 0.71 (0.44, 0.98)* 0.51 (0.28, 0.74)* 0.44 (0.21, 0.67)* 0.51 (0.26, 0.77)* 0.74 (0.39, 1.09)* 0.75 (0.39, 1.10)* 0.25 (⫺0.29, 0.79) 0.44 (⫺0.11, 1.00)

CrI, credible interval; CI, confidence interval; MTC, mixed treatment comparison; NRS, numerical rating scale; OR, odds ratio. *Statistically significant (P ⬍ 0.05).

9 3 4 4 2 3 2 2 1 1

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Table 4 Absolute Mean Reduction in FIQ Score Weighted Mean Difference from Random Effect MetaAbsolute Mean Reduction Weighted Mean Difference Analyses of Head-to-Head Trials (95% CI) versus Number of in Pain from Random from Random Effects MTC Placebo Trials Effects MTC (95% CrI) (95% CrI) versus Placebo Placebo Pregabalin 600 mg/d Pregabalin 450 mg/d Pregabalin 300 mg/d Milnacipran 200 mg/d Milnacipran 100 mg/d Duloxetine 120 mg/d Duloxetine 60 mg/d Duloxetine 20 mg/d

9.63 (7.12, 12.14) 12.32 (8.74, 15.92) 14.13 (10.54, 17.75) 11.87 (8.29, 15.47) 13.04 (8.64, 17.42) 14.22 (9.85, 18.61) 15.41 (11.59, 19.22) 14.56 (10.48, 18.67) 15.80 (10.47, 21.28)

— 2.69 (0.13, 5.30)* 4.50 (1.93, 7.10)* 2.24 (⫺0.33, 4.84) 3.40 (⫺0.20, 7.04) 4.59 (1.02, 8.19)* 5.78 (2.91, 8.61)* 4.93 (1.74, 8.18)* 6.17 (1.50, 11.01)*

— 2.71 (0.08, 5.33)* 4.53 (2.29, 6.76)* 2.23 (0.06, 4.40)* 3.40 (0.63, 6.17)* 4.60 (1.83, 7.37)* 5.75 (2.74, 8.76)* 5.08 (⫺1.30, 11.46) 4.35 (⫺0.32, 9.02)

7 3 3 3 1 1 3 2 1

CrI, credible interval; CI, confidence interval; MTC, mixed treatment comparison. *Statistically significant (P ⬍ 0.05).

to meta-analyze data on this outcome. Pregabalin 300, 450, and 600 mg/d produced significantly greater improvements in sleep (decrease in MOS score) compared with placebo. Pregabalin 450 and 600 mg/d produced significantly greater improvements in sleep than milnacipran 100 and 200 mg/d. In addition, pregabalin 600 mg/d was significantly better than pregabalin 300 mg/d and pregabalin 300 mg/d was significantly better than milnacipran 200 mg/d. Sleep Quality: 11-Point NRS Five studies reported data on an 11-point NRS of sleep quality suitable for inclusion in the MTC (21,43,46,50,52). These studies examined 4 treatment regimens: citalopram, duloxetine, placebo, and pregabalin. The fixed effects model fitted the data best and was used to meta-analyze data on this outcome. Pregabalin 300, 450, and 600 mg/d and duloxetine 60 and 120 mg/d produced significantly greater improvements in sleep (11point NRS) than placebo. Pregabalin 450 and 600 mg/d produced significantly greater improvements in sleep than pregabalin 300 mg/d. TEAEs Six studies reported data on the incidence of TEAEs suitable for inclusion in the MTC (40,45,46,48,51,53). These studies examined 5 treatment regimens: milnacipran, pregabalin, duloxetine, paroxetine, and placebo. The random effects model fitted the data best and was used to meta-analyze data on this outcome. Patients receiving pregabalin 450 and 600 mg/d and duloxetine 120 mg/d treated patients were all significantly more likely to report TEAEs compared with placebo-treated patients. There were no significant differences reported between active treatments.

DISCUSSION The present analysis extends previous research by comparing different treatments using MTC. The result of our analyses found few statistically significant differences between FDA-approved treatments. The absolute difference between pregabalin and duloxetine was very small and did not reach statistical significance at licensed doses. Pregabalin produced significantly greater improvements in sleep (MOS sleep scores) compared with milnacipran at licensed doses. Although pregabalin, milnacipran, and duloxetine showed clear superiority over placebo for all outcome measures, the meta-analysis found no evidence that other treatments, such as alprazolam, citalopram, ibuprofen, and paroxetine, are significantly different from placebo on any outcome measure, mainly due to the lack of suitable data for inclusion in the MTC and partly due to poorer quality studies, which failed to meet inclusion criteria of the review. The results of this systemic review are consistent with previous reviews (12,14 –17) and confirm the therapeutic efficacy of pregabalin and duloxetine and milnacipran in the treatment of fibromyalgia. Although Hauser and coworkers found amitriptyline to be superior to both duloxetine and milnacipran in reducing pain, sleep disturbances, and fatigue (16), 8 of the 10 amitriptyline studies included in the Hauser review were excluded from our meta-analysis due to poor methodological quality; this poor study quality led Hauser and coworkers to stress that the robustness of any conclusions with regard to the relative efficacy of amitriptyline was questioned by the high risk of potential bias in the published evidence base (16). Other differences in the results reported in the present review compared with previous analyses may result from differences in the number of included publications, the non-Bayesian method of analysis employed in previous reviews, and the fact that the 2 reviews by Hauser and

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coworkers (14,16) did not consider the treatment doses separately. With medical advances leading to an increasing number of effective interventions, regulators, health care providers, physicians, and patients need evidence on the relative efficacy of 1 intervention against another for decision-making. Head-to-head trials may be methodologically ideal but they are expensive and time-consuming and require a very large sample size. Hence, statistical methods to conduct “indirect comparisons” have been developed to compare the efficacy of 1 intervention against another. Common methods include adjusted indirect comparison (58) and MTC (59), and both of these analyses can be implemented using a range of statistical methods and aim to construct an indirect estimate of the relative efficacy of 2 interventions based on head-to-head trials against other comparators. A recent study comparing these methods suggested that MTC may be more appropriate for more complex comparisons (60) and we therefore used MTC in this study. Although MTC ensures that randomization is preserved and permits estimation of relative treatment effects with minimal bias (29), it raises several important issues, which mean that the result of this study should be interpreted judiciously. In particular, MTC (like all metaanalyses) implicitly assumes that all of the studies relate to the same patient population and that treatment effects are exchangeable between studies—ie, that any differences in study design, inclusion criteria, or baseline characteristics will not influence the relative efficacy of the various treatments (29). In the present meta-analyses, we observed relatively little heterogeneity and very little inconsistency in treatment effects between trials, which supports the exchangeability assumption in this situation. This may (at least in part) have resulted from the stringent inclusion criteria shown in Table 1 that we applied to ensure that only those studies using similar methods in comparable populations were included in the meta-analysis. The RCTs included in the wider systematic review were published between 1991 and 2009, during which time trial quality and patient populations changed substantially. Poor study quality is a particular problem among early RCTs in fibromyalgia (many of which assessed the efficacy of TCAs), particularly since many of these were preliminary exploratory studies enrolling a small number of patients. To attempt to control for study quality and ensure that the conclusions were based on trials less prone to bias, our meta-analysis excluded studies with Jadad scores ⬍3 and evaluated the effect of including Jadad score as a covariate, although this did not alter our main conclusion. Nevertheless, there are limited robust clinical data available for some therapeutic classes. For treatments such as paroxetine and citalopram, where no statistically significant results compared with placebo were found, these negative results may be due to the lack of sufficient high-quality data and should not be interpreted as firm evidence of lack of therapeutic effect.

Efficacy of pharmacological treatments for fibromyalgia

Patient populations may also vary between trials. Fibromyalgia is a heterogeneous condition and previous studies have suggested there are different patient subgroups (61). Furthermore the trials included in the systematic review used different inclusion and exclusion criteria, potentially resulting in different patient populations being recruited. Many early RCTs permitted concomitant treatment and included patients with major depression. The proportion of patients who had previously received antidepressants was not always reported. Recent large RCTs conducted for pregabalin, duloxetine, and milnacipran used more stringent inclusion/exclusion criteria and tended to exclude patients with moderate to severe depression, disallow concomitant antidepressants, and recruit a high proportion of patients who have failed to respond to TCAs. While recent large RCTs of pregabalin, duloxetine, and milnacipran have employed more comparable inclusion and exclusion criteria, a number of potentially important differences remain. Since pregabalin is in a different therapeutic class from the SNRIs (duloxetine and milnacipran), different patient subgroups may respond better to 1 treatment than another. All of the trials included in the MTC that evaluated pregabalin (n ⫽ 5) or milnacipran (n ⫽ 3) excluded patients who had severe depression/neurological disorders or major depressive episodes, whereas all of the RCTs examining duloxetine (n ⫽ 3) allowed patients with major depressive disorder to enter the study. Although we attempted to adjust for this difference using a covariate indicating whether or not depressed patients were excluded from the trial, this method is not optimal and may underestimate the impact of this confounding factor. However, we were unable to control for baseline depression scores directly as numerous different scales were used by these trials. Future metaanalyses and indirect comparisons would be facilitated by consistent use of the same outcome measures in future studies (27). However, despite these issues, the finding that our results are robust across numerous sensitivity analyses is reassuring. Currently no pharmacological agents are indicated specifically for the treatment of fibromyalgia in Europe. However, the present study confirms that pregabalin, duloxetine, and milnacipran are effective treatments for fibromyalgia. Although pregabalin was superior to milnacipran for sleep outcomes, the difference between pregabalin and duloxetine was small and not statistically significant. Since pregabalin and SNRIs have similar efficacy overall but have different modes of action and are optimal against different symptoms, combining these classes in the treatment of fibromyalgia may have the greatest therapeutic potential. Given their different modes of action, pregabalin and SNRIs may act synergistically. Their use in combination should be investigated in future RCTs. The results of this systemic review confirms the therapeutic efficacy of pregabalin and the SNRIs, duloxetine and milnacipran, in the treatment of fibromyalgia and

E. Choy et al.

extends previous research by comparing different treatments using MTC. The result of our analyses found few statistically significant differences between FDA-approved treatments. Given the different modes of action of these pharmacological agents, combination therapy with pregabalin plus an SNRI should be investigated in future research. APPENDIX A. SUPPLEMENTARY DATA Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.semarthrit.2011. 06.003.

343

16.

17.

18. 19. 20.

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345.e1

Efficacy of pharmacological treatments for fibromyalgia

Table A Study Characteristics of RCTs Included in Systematic Review Study MAOIs Ginsberg et al (1998) (39)

Dose Pirlindole 75 mg BID Placebo

Dopaminergic agents Holman and Myers (2005) (62) Pramipexole 0.25 to 4.5 mg Placebo NSAIDs Quijada Carrera et al (1996) Tenoxicam 20 mg (57) Bromazepam 3 mg Tenoxicam 20 mg ⫹ Bromazepam 3 mg Placebo Sedative hypnotics Moldofsky and Alvarez-Horine Sodium oxybate 4.5 mg (2008) (63) Sodium oxybate 6 mg Placebo Russell et al (1991) (56) Ibuprofen 600 mg QDS Alprazolam 0.5 to 3 mg Ibuprofen 600 mg QDS ⫹ Alprazolam 0.5 to 3 mg Placebo Scharf et al (2003) (64) Sodium oxybate 6 mg Placebo Selective serotonin re-uptake inhibitors Anderberg et al (2000) (42) Citalopram 10 to 40 mg Placebo Nørregaard et al (1995) (43) Arnold et al (2002) (65) Giordano et al (1999) (41) Patkar et al (2007) (40) Norepinephrine Serotonin Reuptake Inhibitors Branco et al (2008) (66) Gracely et al (2008) (67) Chappell et al (2009) (68) Erhan et al (2005) (69) Russell et al (2008) (44)

Borman et al (2004) (70) Mease et al (2009) (20)

Citalopram 20 to 40 mg Placebo Fluoxetine 20 to 80 mg Placebo Paroxetine 20 mg Placebo Paroxetine CR 12.5 to 62.5 mg Citalopram 10 to 40 mg

Milnacipran 200 mg Placebo Milnacipran 100 mg BID Placebo Duloxetine 60 mg OD Duloxetine 120 mg OD Mirtazapine 30 to 45 mg OD Placebo Duloxetine 20 mg Duloxetine 60 mg Duloxetine 120 mg Placebo Amitriptyline 25 mg Venlafaxine 75 mg Milnacipran 100 mg Milnacipran 200 mg Placebo

% Female

No. of Patients Randomized

87.9 82.2

50 50

51 (10.1) 46 (9.5)

94 95

39 21

43 (10)

93.3

41 41 41

Mean Age (SD) 39.7 (8.6) 39.8 (8.8)

41 Not reported

47.3 (1.2)

48.92 (20 to 69)

48.6 (7.5)

48 (9) 50 (9) 46 (11) 46 (12) 31.0 (72) 47.9 (9.1) 49.1 (11.2)

Not reported

Not reported

195

88.5

78

100

24

100

21 19

Not reported 100 100 100 95 93

100

48.97 (18.41 to 83.82)

95.7

Not reported

Not reported

50.9 (11.4) 51.8 (10.6) 51.1 (10.8) 50.3 (10.9) 31.2 (9.06) 36.7 (6.01) 49.9 (10.6) 49.2 (11.0) 49.4 (10.1)

97.5 90.7 97.3 95.1 100 95.1 95.9 95.5

21 21 30 30 20 20 58 58

435 449 92 104 203 10 10 79 150 147 144 16 16 224 441 223

E. Choy et al.

345.e2

Table A Continued No of Patients Completed

Duration of FM, yr

33 28

43.1 (68.2) 26.2 (22.4)

4 wk

Paracetamol

33 16

8.9 (9.2) 7.9 (6.8)

14 wk

No specific medications excluded.

24 25 35

7.7 (5) 10.5 (8.7) 12.6 (9.5)

8 wk

Paracetamol permitted during the 3-week washout period

26

11.6 (9.5)

151

Not reported

8 wk

Not reported

63

8.9 (1.0)

6 wk

Acetaminophen. Medications for unrelated conditions, eg, hypertension were continued.

18

Not reported

32 d

Not reported

17 18

11.9 (7.0)

4 mo

12 21 19 17 17 12 38 48

10 (8) 10 (11) 11 (9) 11 (8) Not reported

4 wk

Paracetamol (500 mg BID) acetylsalicylic acid (1 g BID). Stronger analgesics allowed in exceptional cases. Acetaminophen, codeine, NSAID

12 wk

NSAIDS, Acetaminophen

12 wk

No analgesics/anxiolytics permitted.

49 5

12 wk

Acetoaminophen (ⱕ4 g/d), ibuprofen (ⱕ1200 mg/d). Antihypertensives required ⱖ4 weeks stable dose.

Duration of Study

Permitted Concomitant Medication

12 wk Not reported

Not reported

13 wk

Not reported

71 124 10 10 44 82 79 72 Not reported

Not reported

52 wk

Not reported

Not reported

8 wk

Not reported

Not reported

6 mo

Aspirin (ⱕ325 mg/d), acetaminophen (ⱕ2 g/d). Sedating antihistamines and drug therapy to facilitate sleep

Not reported

8 wk

Not reported

128 238 145

5.6 (5.3) 5.5 (5.1) 6.0 (5.9)

27 wk

Acetaminophen, aspirin, stable dose of NSAIDS

345.e3

Efficacy of pharmacological treatments for fibromyalgia

Table A Continued Study

Dose

Clauw et al (2008) (48,71)

Milnacipran 100 mg Milnacipran 200 mg Placebo Goldenberg et al (2007) (72)— Milnacipran 100 mg Milnacipran 200 mg Extension of Clauw et al (2007) (73) Chappell et al (2008) (74,75) Duloxetine 60 to 120 mg Placebo Arnold et al (2004) (45) Duloxetine 60 mg BID Placebo Gendreau et al (2005) (47), Milnacipram 200 mg OD Vitton et al (2004) (76) Milnacipram 100 mg BID Placebo Arnold et al (2005) (46) Duloxetine 60 mg OD Duloxetine 60 mg BID Placebo Analgesics Gur et al (2006) (77) Tramadol 100 mg Tramadol 50 to 400 mg Placebo Russell et al (2000) (49) Bennett et al (2003, 2005) (78,79)

Anticonvulsants Rowbotham et al (2007) (80) Arnold et al (2008) (50,81)

Crofford et al (2008) (51,82) FREEDOM RCT

Mease et al (2008) (21)

Crofford et al (2005) (52)

Pauer et al (2008) (53)

Arnold et al (2007) (83)

Tramadol 37.5 mg ⫹ Acetaminophen 325 mg Placebo Ketamine 0.3 mg/kg Placebo Levetiracetam 500 to 3000 mg Placebo Pregabalin 300 mg BID Pregabalin 450 mg BID Pregabalin 600 mg BID Placebo Pregabalin 300 mg BID Pregabalin 450 mg BID Pregabalin 600 mg BID Placebo Pregabalin 300 mg Pregabalin 450 mg Pregabalin 600 mg Placebo Pregabalin 150 mg Pregabalin 300 mg Pregabalin 450 mg Placebo Pregabalin 300 mg BID Pregabalin 450 mg BID Pregabalin 600 mg BID Placebo Gabapentin 1200 to 2400 mg Placebo

Mean Age (SD)

% Female

No. of Patients Randomized

49.5 (10.9) 50.4 (10.6) 50.7 (10.4) Not reported

97.0 97.0 94.8 Not reported

401 401 405 48 401

Not reported

Not reported

162 168 104 103 46 51 28 118 116 68

49.9 (12.3) 48.3 (11.3) 46.2 (12.2) 47.4 (11.6) 48.0 (8.4) 49.6 (10.9)

Not stated

48.8 (9.19) 49 (11) 51 (10) 39 (23 to 53)

Not reported 49.1 (11.2) 50.8 (11.8) 50.9 (11.1) 49.0 (11.4) 49.6 (12.2) 49.0 (12.7) 48.4 (11.4) 49.6 (10.5) 50.1 (10.4) 47.4 (10.8) 48.7 (11.2) 48.6 (11.3) 48.0 (10.4) 47.7 (10.1) 48.9 (11.3) 49.7 (10.7) 48.4 (10.8) 48.0 (11.3) 49.6 (11.3) 48.1 (11.3) 49.2 (10.6) 47.3 (11.8)

88.5 89.3 98 98 96 100

100

40

94 34 93 95 100

35 156 157 12

Not reported

67

94.5 96.3 95.2 91.8 95 95 91 94 94.1 92.3 94.7 96.3 95.5 89.6 90.2 90.8 90.7 92.9 90.9 91.3 93.3 86.7

183 190 188 184 63 73 143 287 185 183 190 190 132 134 132 131 183 182 186 184 75 75

E. Choy et al.

345.e4

Table A Continued No of Patients Completed

Duration of FM, yr

264 257 290 301

9.5 (8.0) 9.9 (8.2) 9.8 (8.5) Not reported

15 wk

Hydrocodone (ⱕ60 mg/d)

6 mo

Not reported

101 103 58 66 32 37 21 71 76 68

Not reported

6 mo

Not reported

Not reported

12 wk

Acetaminophen (ⱕ2 g/d); aspirin (ⱕ325 mg/d)

4.3 (4.8) 4.0 (3.8) 3.8 (3.7) Not reported

12 wk

Stable doses of NSAID, aspirin, and acetaminophen

12 wk

Acetaminophen (ⱕ2 g/d); aspirin for cardiac prophylaxis (ⱕ325 mg/d)

3 mo

Not reported

Not stated

Not stated

Duration of Study

Permitted Concomitant Medication

35 34 79 59 11

4.7 (3.97)

6 wk

No rescue pain medication permitted

Not reported

91 d

Low dose SSRI or St. John’s wort for depression. Zolpidem/flurazepam for sleep

Not reported

Not reported

9 wk

Not reported

123 125 113 125 30 24 53 55 123 121 111 130 99 111 103 97 123 133 121 141 57 62

9.6 (7.0) 10.3 (7.7) 9.9 (8.3) 10.3 (9.0) 118.0 (101.0) 123.8 (96.1) 135.8 (120.5) 114.0 (90.2) 115.4 (103.5) 114.7 (101.5) 111.0 (91.4) 105.7 (82.8) 102.3 (101.1) 109.8 (97.4) 114.8 (113.3) 103.7 (89.4) 83.5 (80.0) 88.6 (82.5) 115.2 (107.6) 107.6 (98.7) Not reported

14 wk

Acetaminophen (ⱕ4 g/d) Aspirin (ⱕ325 mg/d for cardiac prophylaxis)

26 wk

Acetaminophen (ⱕ4 g/d)

13 wk

Aspirin for cardiac prophylaxis and acetaminophen as pain rescue medication weeks prior to entry)

8 wk

Aspirin, acetaminophen, and symptomatic migraine treatment

14 wk

Aspirin (ⱕ325 mg/d) Acetaminophen (ⱕ4 g/d)

12 wk

Acetaminophen and over-the-counter NSAIDS

3 (2 to 28)

345.e5

Efficacy of pharmacological treatments for fibromyalgia

Table A Continued Study Drugs used in nausea and vomiting Skrabek et al (2008) (84) TCA Çapaci and Hepgüler (2002) (85) Heymann et al (2001) (54)

Ataog ˘ lu et al (1997) (86) Borman et al (2004) (70) Nicolodi and Sicuteri (1996) (87)

Hannonen et al (1998) (88)

Ozgocmen et al (2006) (89) Nishikai and Akiya (2003) (90) Ginsberg et al (1996) (55) Goldenberg et al (1996) (91)

Carette et al (1994) (92)

Dose

Mean Age (SD)

% Female

No. of Patients Randomized

Nabilone 1 mg BID Placebo

47.6 (9.13) 50.11 (5.96)

0 15

20 20

Amitriptyline 10 to 20 mg Paroxetine 20 to 40 mg Amitriptyline 25 mg Nortriptyline 25 mg Placebo Amitriptyline 50 to 100 mg Paroxetine 20 mg Amitriptyline 25 mg Venlafaxine 75 mg Amitriptyline 10 to 50 mg Pargyline 5 to 10 mg or Phenelzine 10 to 15 mg 5-hydroxytryptophan (5-HTP) Pargyline 5 to 10 mg or Phenelzine 10 to 15 mg ⫹ 5HTP Amitriptyline 10 to 37.5 mg Moclobemide 150 to 600 mg Placebo Amitriptyline 20 mg Sertraline 50 to 100 mg Amitriptyline 20 mg Fluvoxamine 25 mg Amitriptyline 25 mg Placebo Amitriptyline 25 mg ⫹ fluoxetine 20 mg Amitriptyline 25 mg Fluoxetine 20 mg Placebo Amitriptyline 10 to 50 mg Cyclobenzaprine 10 to 30 mg Placebo

42.10 (11.01) 45.70 (4.45) 53.4 (31 to 75) 48.8 (18 to 76) 49.4 (22 to 75) 36.4 (25 to 62) 35.8 (24 to 63) 31.2 (9.06) 36.7 (6.01) Not reported

90%

40

OD, once daily; BID, twice daily; MDD, major depressive disorder.

49.7 (8.2) 47.6 (8.7) 48.9 (8.9) 37.7 (8.9)

100

100

40 38 40 34 34 16

Not reported

200

100

100

39.1 45.3 46 (11) 46 (12) 43.2 (9.1)

78 81 83 82 90

42 43 45 12 18 30 38 26 25 31

44.1 (9.71) 43.4 (10.5) 47.1 (8.9)

92.9 95.1 92.9

84 82 42

100

E. Choy et al.

345.e6

Table A Continued No of Patients Completed

Duration of FM, yr

15 18

Not reported

4 wk treatment ⫹ follow-up at week 8

Not reported

40

Not reported

8 wk

Not reported

37 36 33 29 32 Not reported 16 200

Not reported

8 wk

Acetaminophen

34.7 36.6 Not reported

6 wk

Not reported

8 wk

Not reported

Not reported

1 yr

Not reported

32 30 30 12 18 18 32 24

8.2 (3.9) 8.6 (4.0) 7.9 (4.1) Not reported

12 wk

Paracetamol 500 mg (ⱕ4 tablets/d)

8 wk

None permitted

4 wk

Not reported

8 wk

Paracetamol

19

3.7 3.3 2.5 (2.7) Range: 0.3 to 10.8 3.9 (5.5) Range: 0.3 to 20.4 72.6 (48.1)c

6 wke

Acetaminophen

70 58 28

101.0 (103.0) 84.3 (104.9) 92.7 (98.2)

6 mo

Acetaminophen

22

Duration of Study

Permitted Concomitant Medication