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Cited by 216Fibromyalgia and Chronic Fatigue Syndrome ResearchPain Mechanisms and TreatmentsMusculoskeletal pain and rehabilitation

Comparative Efficacy and Harms of Duloxetine, Milnacipran, and Pregabalin in Fibromyalgia Syndrome

Open access
Häuser, Winfried, Petzke, Frank, Sommer, Claudia·2010·The Journal of Pain
DOI 10.1016/j.jpain.2010.01.002
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Abstract

Unlabelled Duloxetine (DLX), milnacipran (MLN), and pregabalin (PGB) are the only drugs licensed by the US Food and Drug Administration (FDA) for fibromyalgia syndrome (FMS). Evidence on the comparative benefits and harms is still accruing. The authors searched MEDLINE, SCOPUS, Cochrane Central Register of Controlled Trials, and sought unpublished data from the databases of FDA, US National Institutes for Health, and Industry through May 2009 for randomized controlled trials. Outcomes of interest were symptom reduction (pain, fatigue, sleep disturbance, depressed mood, reduced health-related quality of life), and adverse events. 17 studies with 7,739 patients met the inclusion criteria. The 3 drugs were superior to placebo except DLX for fatigue, MLN for sleep disturbance, and PGB for depressed mood. Adjusted indirect comparisons indicated no significant differences for 30% pain relief and dropout rates due to adverse events between the 3 drugs. Significant differences in average symptom reduction were found: DLX and PGB were superior to MLN in reduction of pain and sleep disturbances. DLX was superior to MLN and PGB in reducing depressed mood. MLN and PGB were superior to DLX in reducing fatigue. The risk of headache and nausea with DLX and MLN was higher compared with PGB. The risk of diarrhea was higher with DLX compared to MLN and PGB. There is evidence for the short-term (up to 6 months) efficacy of DLX, MLN, and PGB. Differences with regard to the occurrence of the key symptoms of FMS and to drug-specific adverse events may be relevant for the choice of medication. Perspective This article presents comparative data on the efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome. The results can help clinicians in choosing medication since the 3 drugs have different effects on the key symptoms of fibromyalgia syndrome and differences in side effects, contraindications, and warnings.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review with adjusted indirect comparisons found that duloxetine, milnacipran, and pregabalin are all superior to placebo for short-term (up to 6 months) fibromyalgia symptom relief, with no significant differences between them for 30% pain relief or dropout due to adverse events. The three drugs differ in which key symptoms they improve and in their adverse event profiles, which the authors argue should guide medication choice.

Key findings

  • 17 studies with 7,739 patients met inclusion criteria; the 3 drugs were superior to placebo except DLX for fatigue, MLN for sleep disturbance, and PGB for depressed mood.
  • Adjusted indirect comparisons showed no significant differences for 30% pain relief or dropout due to adverse events, but significant differences in average symptom reduction: DLX and PGB were superior to MLN for pain and sleep disturbance; DLX was superior to MLN and PGB for depressed mood; MLN and PGB were superior to DLX for fatigue.
  • NNTs for 30% pain reduction were DLX 7.2 (95% CI 5.2, 11.4), MLN 19 (95% CI 7.4, 20.5), and PGB 8.6 (95% CI 6.4, 12.9); NNHs for dropout due to side effects were DLX 14.9 (95% CI 9.1, 41.4), MLN 7.6 (95% CI 6.2, 9.9), and PGB 7.6 (95% CI 6.3, 9.4).
  • Headache and nausea risk was higher with DLX and MLN than PGB; diarrhea risk was higher with DLX than MLN and PGB. Drug-specific harms included increased heart rate with MLN (NNH 20.6, 95% CI 15.1, 29.1), and neurocognitive harms (pooled NNH 16.3, 95% CI 13.4, 20.8) and blurred vision (NNH 18.3, 95% CI 15.5, 26.7) with PGB.

Methods

  • Systematic review and meta-analysis (QUORUM guidelines) of RCTs and uncontrolled open-label extension studies of DLX, MLN, or PGB in FMS, searched in MEDLINE, SCOPUS, and Cochrane Central Register of Controlled Trials through May 2009, plus FDA, NIH, and PhRMA databases and drug sponsor data.
  • 11 parallel-design RCTs enrolled 6,388 patients (4,508 active drug, 1,880 placebo); median randomized phase duration 24 weeks (range 6–28); median age 49 years, 95% women, 90% Caucasian. All studies used ACR diagnostic criteria and were rated high methodological quality (van Tulder score).
  • Pooled relative risks (Mantel-Haenszel, random-effects) and standardized mean differences (Hedges g) were calculated; adjusted indirect comparisons used the Bucher method, with NNT/NNH computed from pooled observations.

Limitations

  • Stated by the authors: no head-to-head trials existed, so indirect comparisons were used, whose validity depends on consistent treatment effects across trials; populations, dosing, outcome instruments, and comorbidity reporting differed, and adverse events were assessed without standardized methods and reported inconsistently.
  • Stated: some HRQOL data from PGB studies and data from 2 MLN RCTs and 1 long-term MLN open-label study were unavailable; all studies were manufacturer-sponsored, raising potential bias; there is no gold standard for meta-analytic methods and effect-size interpretation is context dependent.
  • Evident from the text: applicability is limited because trials excluded patients <18 and >70 years, those with severe somatic comorbidities, and (except DLX trials) those with mental disorders; long-term efficacy data for DLX and PGB were inconclusive and MLN long-term data were unpublished.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jpain.2010.01.002

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

12 of 61 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Findingcitation
    § Abstract

    In the 1-year study, 1.1% of patients on DLX had suicide-related behavior.

    “In the 1-year study, 1.1% of the patients on DLX had suicide-related behavior.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [15] Choy, 2009, Safety and tolerability of duloxetine in the treatment of patients with fibromyalgia: Pooled analysis of data from five clinical trials, Clin Rheumatol source
    • cites [46] Mease, 2009, Long-term safety, tolerability and efficacy of duloxetine in the treat- ment of fibromyalgia, Semin Arthritis Rheum epub source
  • Interpretationreasoning
    § Discussion

    Conflicts of interest and prejudice may have increased bias.

    “Conflicts of interest and prejudice may have increased bias.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Ioannidis, 2005, Why most published research findings are false, PLoS Med source
  • Findingown data
    § Abstract

    Milnacipran and pregabalin were superior to duloxetine in reducing fatigue.

    “MLN and PGB were superior to DLX in reducing fatigue.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    The risk of diarrhea was higher with duloxetine than with milnacipran and pregabalin.

    “The risk of diarrhea was higher with DLX compared to MLN and PGB.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Seventeen studies with 7,739 patients met the inclusion criteria of this systematic review.

    “17 studies with 7,739 patients met the inclusion criteria.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 50
  • May combine two claims. 38

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Introduction

    The main symptoms of fibromyalgia syndrome are chronic widespread pain, nonrestorative sleep, physical fatigue, and cognitive disturbances.

    “The main symptoms of fibromyalgia syndrome (FMS) are chronic widespread pain, nonrestorative sleep, physical fatigue, and cognitive disturbances.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [5] Bennett, 2007, An internet survey of 2,596 people with fibromyalgia, BMC Musculoskelet Disord source
    • cites [34] Häuser, 2008, What are the key symptoms of fibromyalgia syndrome? Results of a survey of the German Fibromyalgia Association, Schmerz source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Introduction

    Most fibromyalgia syndrome patients suffer from additional somatic and psychological symptoms, resulting in a high prevalence of comorbid functional somatic syndromes such as irritable bowel syndrome and mental disorders.

    “Most patients suffer from additional somatic and psychological symptoms resulting in a high prevalence of comorbid functional somatic syndromes such as irritable bowel syndrome and mental disorders.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [25] Fietta, 2007, Fibromyalgia and psychiatric disorders, Acta Biomed

      The Introduction (page unavailable) says additional symptoms, including psychological distress and irritable bowel syndrome, are usually present in fibromyalgia. The Results (page unavailable) report increased rates of psychiatric disorders. The paper does not establish that the additional symptoms cause the comorbidities or identify irritable bowel syndrome as a comorbid functional somatic syndrome rather than a symptom. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [35] Henningsen, 2003, Medically unexplained physical symptoms, anxiety, and depression: A meta-analytic review, Psychosom Med source

  • May combine two claims.

    Premisecitation
    § Introduction

    Duloxetine and milnacipran are serotonin (5HT) and norepinephrine (NE) reuptake inhibitors.

    “DLX and MLN are serotonin (5HT) and norepinephrine (NE) reuptake inhibitors.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [64] Vaishnavi, 2004, Milnacipran: A comparative analysis of human monoamine uptake and transporter binding affinity, Biol Psychiatry source

      The copy’s unlabelled ligand–target affinity entries list milnacipran binding to both human serotonin and noradrenaline transporters, supporting that part of the claim. No passage addresses duloxetine (searched: duloxetine, duloxetin), so the claim about both drugs is not fully supported by this copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Introduction

    Duloxetine has a 5:1 5HT/NE ratio and milnacipran has a 3:1 NE/5HT ratio.

    “DLX has a 5:1 5HT/NE ratio and MLN has a 3:1 NE/5HT ratio.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [64] Vaishnavi, 2004, Milnacipran: A comparative analysis of human monoamine uptake and transporter binding affinity, Biol Psychiatry source

      The indexed copy has no section or page labels. Its binding-affinity entries give milnacipran values of 68 nM for the noradrenaline transporter and 151 nM for the serotonin transporter, consistent with greater noradrenaline affinity but not a 3:1 ratio. Other milnacipran entries give 22 nM and 8.44 nM, respectively; no retrieved passage mentions duloxetine or supports its stated 5:1 ratio. (LLM, conf=0.68)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Introduction

    The levels of reduced physical functioning of fibromyalgia syndrome patients are comparable to those of patients with osteoarthritis of the hip or rheumatoid arthritis.

    “The levels of reduced physical functioning of FMS patients are comparable to the ones of patients with osteoarthritis of the hip or rheumatoid arthritis.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [55] Picavet, 2004, Health related quality of life in multiple musculoskeletal diseases: SF-36 and EQ-5D in the DMC3 study, Ann Rheum Dis source

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    The validity of indirect comparisons depends on how well they meet the critical assumption of consistent treatment effects across all of the trials.

    “The validity of indirect comparisons depends on how well they meet the critical assumption of consistent treatment effects across all of the trials.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Chou, 2009, Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: Discrepancies between direct and indirect meta-analyses of randomized controlled trials, J Gen Intern Med source

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    The assumption of consistent treatment effects can be violated by methodological shortcomings in the trials, differences in populations, interventions (eg, dosing), assessment of outcomes, or other factors.

    “This assumption can be violated by methodological shortcomings in the trials, differences in populations, interventions (eg, dosing), assessment of outcomes, or other factors.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Chou, 2009, Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: Discrepancies between direct and indirect meta-analyses of randomized controlled trials, J Gen Intern Med source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation
    § Discussion

    The strength of the review is that we included grey literature to overcome some of the problems of publication bias, which can arise due to the selective availability of data.

    “The strength of the review is that we included “grey literature” (ie, literature that has not been formally published) to overcome some of the problems of publication bias, which can arise due to the selective availability of data.37”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Hopewell, 2007, Grey literature in meta-analyses of randomized trials of health care interventions, Cochrane Database Syst Rev. 18;MR000010 source

  • May combine two claims.

    Premisecitation
    § Discussion

    Aerobic exercise, hydrotherapy, and multicomponent therapy have shown efficacy in alleviating fibromyalgic symptoms without harms.

    “Aerobic exercise, hydrotherapy, and multicomponent therapy have shown efficacy in alleviating fibromyalgic symptoms without harms, and can be offered to the patient either as alternative or used adjunctively with pharmacological therapy.7,8,30,33,41”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [7] Busch, 2008, Exercise for fibromyalgia: A systematic review, J Rheumatol
    • cites [8] Carville, 2008, EULAR evidence based recommendations for the management of fibromyalgia syndrome, Ann Rheum Dis source

      The Assessment of recommendations (page not available) reports improvements with heated-pool treatment and some aerobic-exercise trials; it also describes multidisciplinary care as often needed, while noting limited high-quality trial evidence. It says adverse-event drop-out was very low for heated-pool treatment and describes exercise as safe, but does not establish that all three therapies are without harms. The recommendations table (Discussion, page not available) supports tailoring a combination of non-pharmacological and pharmacological treatments, though it does not establish that each therapy can be used as an alternative to medication. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [30] Häuser, 2009, Efficacy of multicomponent treatment in fibromyalgia syndrome: A meta-analysis of randomized controlled clinical trials, Arthritis Rheum source
    • cites [33] Häuser, 2009, Fibromyalgia syndrome: Classification, diagnosis, and treatment, Dtsch Arztebl Int source

      The Results (Table 5; page not available) give aerobic endurance training, balneotherapy or pool-based exercise, and multimodal therapy strong recommendations for short-term fibromyalgia treatment. The Results also recommend monitoring potential side effects; they do not establish that these treatments are without harms. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [41] Langhorst, 2009, Efficacy of hydrotherapy in fibromyalgia syndrome–a meta-analysis of randomized controlled clinical trials, Rheumatology (Oxford) source

  • May combine two claims.

    Findingown data
    § Abstract

    Duloxetine and pregabalin were superior to milnacipran in average reduction of pain and of sleep disturbances.

    “Significant differences in average symptom reduction were found: DLX and PGB were superior to MLN in reduction of pain and sleep disturbances.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Duloxetine, milnacipran, and pregabalin were each superior to placebo for the outcomes studied, except that duloxetine was not superior for fatigue, milnacipran was not superior for sleep disturbance, and pregabalin was not superior for depressed mood.

    “The 3 drugs were superior to placebo except DLX for fatigue, MLN for sleep disturbance, and PGB for depressed mood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Adjusted indirect comparisons found no significant differences between duloxetine, milnacipran, and pregabalin for 30% pain relief or for dropout rates due to adverse events.

    “Adjusted indirect comparisons indicated no significant differences for 30% pain relief and dropout rates due to adverse events between the 3 drugs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Duloxetine was superior to milnacipran and to pregabalin in reducing depressed mood.

    “DLX was superior to MLN and PGB in reducing depressed mood.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given
    § Abstract

    The duloxetine (DLX) and PGB studies excluded patients undergoing disability reviews.

    “The studies with DLX and PGB excluded patients undergoing disability reviews.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Weight gain and peripheral edema were only reported in PGB trials.

    “Weight gain and peripheral edema were only reported in PGB trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § Abstract

    All included studies excluded patients younger than 18 years and patients with unstable somatic diseases, including inflammatory rheumatic disorders.

    “All studies excluded patients <18 years and with unstable somatic diseases (including inflammatory rheumatic disorders).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    MLN had a statistically significant but not substantial effect on fatigue (SMD -0.13, 95% CI -0.21 to -0.06, p=.006).

    “fatigue (-.13 [-.21, -.06]; .006)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § Abstract

    All included studies allowed comedication: acetaminophen and aspirin in the DLX and PGB studies, hydrocodone in the milnacipran (MLN) studies, and the MLN studies additionally allowed stable doses of acetyl salicylic acid, acetaminophen, and NSAIDs.

    “All studies allowed comedication: acetaminophen and aspirin in the DLX and PGB studies, hydrocodone in the MLN studies, which additionally allowed stable doses of acetyl salicylic acid, acetaminophen, and NSAIDs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Eleven randomized controlled trials (RCTs) with a parallel design enrolled 6,388 patients (range 125-1200).

    “Eleven RCTs with a parallel design enrolled 6,388 patients (range 125–1200).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given
    § Abstract

    Patients were referred to DLX and PGB studies by physician referral and advertisement for medication trial, and to MLN studies by referral of rheumatologists, pain therapists, and primary physicians.

    “Patients were referred to DLX and PGB studies by physician referral and advertisement for medication trial and for MLN studies by referral of rheumatologists, pain therapists, and primary physicians.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given
    § Abstract

    Patients were recruited from different continents (America, Europe, Asia, Australia), with Americans in the majority.

    “The patients were recruited from different continents (America, Europe, Asia, Australia) with Americans in the majority.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given
    § Abstract

    Two studies with DLX were extension phases of RCTs.

    “Two studies with DLX were extension phases of RCTs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § Abstract

    The median mean age was 49 years (range 47-51), the median percentage of women was 95% (range 88-100), and the median percentage of Caucasians was 90% (range 76-94).

    “The median mean age was 49 years (range 47–51), the median percentage of women was 95% (range 88–100), and of Caucasians 90% (range 76–94).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given
    § Abstract

    All included studies excluded patients with severe mental disorders except the DLX studies, which included patients with major depression.

    “All studies excluded patients with severe mental disorders except the studies with DLX, which included patients with major depression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    PGB had a statistically significant but not substantial effect on fatigue (SMD -0.16, 95% CI -0.23 to -0.09, p<.001).

    “The effect on fatigue was not substantial, but statistically significant (-.16 [-.23, -.09]; <.001).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given
    § Abstract

    All pregabalin (PGB) studies excluded patients with creatinine clearance ≤60 mL/minute.

    “All studies with PGB excluded patients with creatinin clearance ≤60 mL/minute.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § Abstract

    The median percentage of patients on active drug completing the studies was 64% (range 55-78), and 68% on placebo (range 50-77).

    “The median percentage of patients on active drug completing the studies was 64% (range 55–78) and 68% on placebo (range 50–77).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Abstract

    The median duration of the randomized phase of the trials was 24 weeks (range 6-28).

    “The median duration of the randomized phase of the trials was 24 (range 6–28) weeks.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Most included studies did not report patient comorbidities or whether nonpharmacological cotherapies were allowed.

    “Most studies did not report comorbidities of the patients and if nonpharmacological cotherapies were allowed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § Abstract

    4,508 patients were on active drug and 1,880 on placebo.

    “4,508 patients were on active drug, 1,880 on placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    MLN had a statistically significant but not substantial effect on pain (SMD -0.19, 95% CI -0.26 to -0.11, p<.001).

    “The effects of MLN on pain (-.19 [-.26, -.11]; <.001)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given
    § Abstract

    These side effects were inconsistently reported in the studies.

    “These side effects were inconsistently reported in the studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Abstract

    The median percentage of patients who were randomized was 55% (range 37-75).

    “The median percentage of patients who were randomized was 55% (range 37–75).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    MLN had a statistically significant but not substantial effect on HRQOL (SMD -0.17, 95% CI -0.25 to -0.10, p<.001).

    “HRQOL (-.17 [-.25, -.10]; <.001)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Abstract

    The frequency of blurred vision (amblyopia) was reported by 3 studies.

    “The frequency of blurred vision (amblyopia) was reported by 3 studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Abstract

    The manufacturer of MLN informed the public of rare fulminant hepatitis and hyponatremia.

    “The manufacturer of MLN informed the public of rare fulminant hepatitis and hyponatremia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Forest Laboratories, Inc. and Cypress Bioscience Announce Revised Timing for Commercial Availability of Savella.™ Accessed http://www.cypressbio.com/news/20090306.pdf, March 31.2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation
    § Abstract

    The prescribing information on PGB includes information on infrequent (1:100-1:1000) cardiac problems (heart failure), gastrointestinal inflammation (eg, cholecystitis, pancreatitis), and bone-marrow toxicity (eg, thrombocytopenia).

    “The prescribing information on PGB includes information on infrequent (1:100-1:1000) cardiac problems (heart failure), gastrointestinal inflammation (eg, cholecystitis, pancreatitis), and bone-marrow toxicity (eg, thrombocytopenia).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] US Food and Drug Administration. Prescribing information pregabalin. Accessed at http://www.fda.gov/cder/foi/label/2007/021446s010lbl.pdf. Accessed on March 31, 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Abstract

    The panel voted against a black box warning.

    “and the panel voted against a black box warning.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] US Food and Drug Administration. Suicidal Behavior and Ideation and Antiepileptic Drugs. http://www.fda.gov/cder/drug/infopage/antiepileptics/default.htm. Accessed March 31, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    Suicidal behavior or ideation was reported in .37% of patients who received an anticonvulsant and in .22% of those who received placebo.

    “Suicidal behavior or ideation was reported in .37% of patients who received an anticonvulsant and in .22% of those who received placebo.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] US Food and Drug Administration. Suicidal Behavior and Ideation and Antiepileptic Drugs. http://www.fda.gov/cder/drug/infopage/antiepileptics/default.htm. Accessed March 31, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    The FDA report stated 7/1,236 dropouts because of hepatic-related adverse events (no dropout due to hepatic side effects in placebo) in DLX trials.

    “The FDA report stated 7/1,236 dropouts because of hepatic-relatic adverse events (no dropout due to hepatic side effects in placebo) in DLX trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] US Food and Drug Administration. Prescribing information duloxetine. Accessed at http://www.fda.gov/cder/foi/label/2009/021427s021s027s028lbl.pdf. Accessed on March 31, 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given
    § Abstract

    Discontinuation syndrome can occur with all 3 drugs.

    “Discontinuation syndrome can occur with all 3 drugs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation
    § Abstract

    Postmarketing reports on the use of DLX for other indications have demonstrated that a small fraction of patients treated with DLX developed elevations in liver enzymes, which generally resolved spontaneously without any change in treatment.

    “Postmarketing reports on the use of DLX for other indications have demonstrated that a small fraction of patients treated with DLX developed elevations in liver enzymes, which generally resolved spontaneously without any change in treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Wohlreich, 2008, Answers to the most common questions about the hepatic safety profile of duloxetine, Postgrad Med source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given
    § Discussion

    Subgroup analyses for the efficacy of DLX and MLN in men were available, but not for PGB.

    “Subgroup analyses for the efficacy of DLX and MLN in men were available, but not for PGB.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given
    § Discussion

    The most frequent adverse events in DLX and MLN, respectively, were gastrointestinal problems and headache; in PGB, neurocognitive side effects, weight gain, and peripheral edema.

    “The most frequent adverse events in DLX and MLN, respectively, were gastrointestinal problems and headache; in PGB, neurocognitive side effects, weight gain, and peripheral edema.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Discussion

    All trials were "efficacy studies," initiated by pharmaceutical companies for the approval of DLX, MLN, and PGB by regulatory agencies.

    “All trials were “efficacy studies,” initiated by pharmaceutical companies for the approval of DLX, MLN, and PGB by regulatory agencies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Gartlehner, 2006, A simple and valid tool distinguished efficacy from effectiveness studies, J Clin Epidemiol source

  • May combine two claims.

    Findingown data
    § Discussion

    Because we found no head-to-head comparisons of DLX, MLN, and PGB, we performed an indirect comparison.

    “First, because we found no head-to-head comparisons of DLX, MLN, and PGB, we performed an indirect comparison.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given
    § Discussion

    There were some differences in the instruments used for the assessment of symptoms between the trials of the 3 drugs.

    “There were some differences in the instruments used for the assessment of symptoms between the trials of the 3 drugs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Discussion

    The studies applied numerous inclusion and exclusion criteria.

    “The studies applied numerous inclusion and exclusion criteria, were conducted in academic and speciality settings, and were —given the fact that FMS symptoms persist in most patients their whole life—relatively short-term.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation
    § Abstract

    Very rare cases (estimated 1 to 2 per 100,000 exposures) of idiosyncratic hepatic toxicity have been reported in patients, particularly in those with substantial alcohol use and/or preexisting liver disease.

    “Very rare cases (estimated 1 to 2 per 100,000 exposures) of idiosyncratic hepatic toxicity have been reported in patients, particularly in those with substantial alcohol use and/or preexisting liver disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Wohlreich, 2008, Answers to the most common questions about the hepatic safety profile of duloxetine, Postgrad Med source

  • May combine two claims.

    Findingnone given
    § Discussion

    The data of 2 RCTs and 1 long-term open-label study with MLN were not published as full papers and were not included in our analysis.

    “The data of 2 RCTs and 1 long-term open-label study with MLN were not published as full papers and were not included in our analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Introduction

    Effective pharmacotherapy of fibromyalgia syndrome includes medications that inhibit pronociceptive input and augment modulatory signaling.

    “Effective pharmacotherapy of FMS includes medications that inhibit pronociceptive input and augment modulatory signaling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Wood, 2007, Novel pharmacotherapy for fibromyalgia, Expert Opin Investig Drugs source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data
    § Methods

    Two authors independently extracted study characteristics and results using standard extraction forms, with discrepancies re-checked and resolved by consensus.

    “Two authors (CS, WH) independently extracted data (study characteristics, study results) using standard extraction forms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Introduction

    Pregabalin is a structural analog of the neurotransmitter gamma-aminobutyric acid (GABA).

    “Pregabalin is a structural analog of the neurotransmitter γ-aminobutyric acid (GABA).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Lyseng-Williamson, 2008, Pregabalin: A review of its use in fibromyalgia, Drugs source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § Methods

    Two authors independently screened the titles and abstracts of potentially eligible studies identified by the search strategy.

    “Two authors (CS, WH) independently screened the titles and abstracts of potentially eligible studies identified by the search strategy detailed above.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Introduction

    Pregabalin is a ligand to the alpha-2-delta subunit on voltage-gated calcium channels, which reduces calcium influx at nerve terminals and decreases the release of several neurotransmitters, including glutamate, norepinephrine, and substance P.

    “This second-generation antiepileptic is a ligand to the alpha-2-delta subunit on voltage-gated calcium channels, which reduces calcium influx at nerve terminals resulting in a decreased release of several neurotransmitters, including glutamate, norepinephrine, and substance P.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Lyseng-Williamson, 2008, Pregabalin: A review of its use in fibromyalgia, Drugs source

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Introduction

    A comparison of the efficacy and harms of duloxetine, milnacipran, and pregabalin has not yet been published.

    “A comparison of the efficacy and harms of the 3 drugs has not yet been published.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation
    § Methods

    Meta-analysis was performed according to the QUORUM guidelines for the quality of reporting of meta-analyses.

    “Meta-analysis was performed according to the QUORUM guidelines (quality of reporting meta-analyses).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Moher, 1999, Improving the quality of reports of meta-analyses of randomised controlled trials: The QUOROM statement. Quality of Reporting of Meta-analyses, Lancet source

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Methods

    Adjusted indirect comparisons were performed using the method described by Bucher and coworkers.

    “We performed adjusted indirect comparisons using the method described by Bucher and coworkers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Bucher, 1997, The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials, J Clin Epidemiol source
    • Rests on an assumption: The trials of duloxetine, milnacipran, and pregabalin are sufficiently similar in populations and methods that adjusted indirect comparisons yield valid estimates of their comparative effects.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation
    § Abstract

    When 10 randomized controlled trials were available for each drug, the symmetry of funnel plots was examined to check for potential publication bias.

    “In case of 10 RCT's for each drug, the symmetry of funnel plots was examined to check for a potential publication bias.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Egger, 1997, Bias in meta-analysis detected by a simple, graphical test, BMJ source
    • cites [36] Higgins JPT, Green S (eds): Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]: The Cochrane Collaboration, 2008. Available from, www.cochrane-handbook.org source

  • May combine two claims.

    Interpretationown data
    § Discussion

    As to short-term (up to 6 months) efficacy, the 3 drugs were superior to placebo for all outcomes except DLX for fatigue, MLN for sleep disturbances, and PGB for depressed mood.

    “As to short-term (up to 6 months) efficacy, the 3 drugs were superior to placebo for all outcomes except DLX for fatigue, MLN for sleep disturbances, and PGB for depressed mood.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation
    § Abstract

    The relevance of heart failure in patients with preexisting heart disease is highlighted by a recent case series.

    “The relevance of heart failure in patients with preexisting heart disease is highlighted by a recent case series.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Page, 2008, Possible heart failure exacerbation associated with pregabalin: Case discussion and literature review, J Cardiovasc Med source

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given
    § Abstract

    With the search strategy used, it is unlikely that we missed an RCT.

    “With the search strategy used, it is unlikely that we missed a RCT.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Abstract

    For clinical practice, the development of a potentially life-threatening serotonin syndrome on DLX or MLN, particularly with concomitant use of serotonergic drugs (including triptans and tramadol) and with drugs that impair metabolism of serotonin (including MAOIs), is relevant.

    “For clinical practice, the development of a potentially life-threatening serotonin syndrome on DLX or MLN, particularly with concomitant use of serotonergic drugs (including triptans and tramadol) and with drugs that impair metabolism of serotonin (including MAOIs), is relevant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    There is uncertainty if the 3 drugs are effective in FMS patients with comorbid dysthymia, anxiety, or posttraumatic stress disorders, and whether MLN and PGB are effective in patients with comorbid major depression.

    “Therefore, there is uncertainty if the 3 drugs are effective in FMS patients with comorbid dysthymia, anxiety, or posttraumatic stress disorders, and whether MLN and PGB are effective in patients with comorbid major depression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § Abstract

    The small number of studies included in the funnel plot limited meaningful interpretation.

    “The small number of studies included in the funnel plot limited meaningful interpretation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    Given the high prevalence of comorbid mental disorders in FMS, the major obstacle for the applicability of the studies is the exclusion of patients with mental disorders in all studies except major depression in DLX trials.

    “Given the high prevalence of comorbid mental disorders in FMS, the major obstacle for the applicability of the studies is the exclusion of patients with mental disorders in all studies except major depression in DLX trials.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Other factors, such as patient preferences, costs, or risk factors for serious adverse events, such as overdose, may be relevant for making treatment choices, but are not well studied in randomized trials.

    “Finally, other factors, such as patient preferences, costs, or risk factors for serious adverse events, such as overdose, may be relevant for making treatment choices, but are not well studied in randomized trials.27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Gartlehner, 2006, A simple and valid tool distinguished efficacy from effectiveness studies, J Clin Epidemiol source

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Discussion

    The major methodological problem was the absence of standardized methods to assess subjective adverse events (eg, nausea).

    “The major methodological problem in our opinion was the absence of standardized methods to assess subjective adverse events (eg, nausea).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Gartlehner, 2009, Inadequate reporting of trials compromises the applicability of systematic reviews, Int J Technol Assess Health Care source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation
    § Discussion

    There is a certain risk inherent in offering conventional operational definitions such as the relevance of magnitude of effect sizes.

    “Fifth, there is a certain risk inherent in offering conventional operational definitions such as the relevance of magnitude of effect sizes.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Cohen, 1988

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation
    § Discussion

    There is no gold standard of the methods used in meta-analysis.

    “Fourth, there is no gold standard of the methods used in meta-analysis.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Engels, 2000, Heterogeneity and statistical significance in meta-analysis: An empirical study of 125 meta-analyses, Stat Med source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § Discussion

    Concerns can be raised on our indirect formal comparison of harms.

    “Therefore, concerns can be raised on our indirect formal comparison of harms.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The treatment effects are consistent across all trials included in the indirect comparison.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation
    § Discussion

    Qualitative interpretation of effect sizes could be problematic because the patient's perception of the importance of a finding is context dependent and not amenable to generic statements.

    “Qualitative interpretation of effect sizes could be problematic because the patient's perception of the importance of a finding is context dependent and not amenable to generic statements.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Higgins JPT, Green S (eds): Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]: The Cochrane Collaboration, 2008. Available from, www.cochrane-handbook.org source
72 of 72

  • The paper relies on this without support.

    The trials of duloxetine, milnacipran, and pregabalin are sufficiently similar in populations and methods that adjusted indirect comparisons yield valid estimates of their comparative effects.

    “We performed adjusted indirect comparisons using the method described by Bucher and coworkers.”

  • The authors state this as an assumption.

    The treatment effects are consistent across all trials included in the indirect comparison.

    “The validity of indirect comparisons depends on how well they meet the critical assumption of consistent treatment effects across all of the trials.”
    “This assumption can be violated by methodological shortcomings in the trials, differences in populations, interventions (eg, dosing), assessment of outcomes, or other factors.”

  • The paper relies on this without support.

    This is the first study with formally adjusted indirect analyses of drugs in FMS.

    “To our knowledge, this is the first study with formally adjusted indirect analyses of drugs in FMS.”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Milnacipran NNT falls outside its reported confidence interval

    Minor

    The reported NNT of −31.1 is outside its stated 95% confidence interval of −23.7 to −16.7.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. The Nordic Cochrane Centre, 2009, Review Manager (RevMan) [Computer program]

Cited by

Sorted by citations

Related

Authors
Häuser, W., Petzke, F., & Sommer, C.
Affiliations
  • Klinikum Saarbrücken (DE)
  • University of Cologne (DE)
  • University of Würzburg (DE)
ORCID
Venue
The Journal of Pain
Publisher
Elsevier BV
Published
2010-06
Volume
11
Issue
6
Pages
505-521
ISSN
1526-5900 (ISSN-L)
DOI
10.1016/j.jpain.2010.01.002
OpenAlex
W2022815318
Semantic Scholar
8e163ab5928389602edd5851627b5bda1b55f460
Cited by
216
References
51
Citations by year
2026: 9 · 2025: 6 · 2024: 40 · 2023: 2 · 2022: 8 · 2021: 8 · 2020: 3 · 2019: 8 · 2018: 11 · 2017: 8 · 2016: 12 · 2015: 16 · 2014: 12 · 2013: 24 · 2012: 22
FWCI
14.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Pain (publishedVersion)
  • PubMed (publishedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion)
Funders
  • Eli Lilly and Company
  • Les Laboratories Pierre Fabre
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Pharmacology › Musculoskeletal pain and rehabilitation
Keywords
fibromyalgia, duloxetine, milnacipran, pregabalin, drug efficacy comparison, adverse drug reactions, analgesia, fatigue, sleep disorders, depressive mood, health-related quality of life, headache, nausea, diarrhea, antidepressants, antiepileptic drugs
MeSH terms
Duloxetine Hydrochloride, Pregabalin, Milnacipran, Analgesics, Cyclopropanes, Fibromyalgia, gamma-Aminobutyric Acid, Humans, Thiophenes, Randomized Controlled Trials as Topic, Treatment Outcome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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