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

In the paper

“The main symptoms of fibromyalgia syndrome (FMS) are chronic widespread pain, nonrestorative sleep, physical fatigue, and cognitive disturbances.”

What the sources say

• Supported

  The Results (Symptoms and functionality; page unavailable) identify fatigue, poor sleep, pain, and memory and concentration problems as prominent symptoms. The Discussion (page unavailable) calls pain a hallmark of fibromyalgia and specifically describes non-restorative sleep. These passages support the citing sentence’s broad symptom summary. (LLM, conf=0.88)

  cites [5] Bennett, 2007, An internet survey of 2,596 people with fibromyalgia, BMC Musculoskelet Disord source
• ?Not checked — no full text of the sourcecites [34] Häuser, 2008, What are the key symptoms of fibromyalgia syndrome? Results of a survey of the German Fibromyalgia Association, Schmerz source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [25] Fietta, 2007, Fibromyalgia and psychiatric disorders, Acta BiomedExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [35] Henningsen, 2003, Medically unexplained physical symptoms, anxiety, and depression: A meta-analytic review, Psychosom Med source

In the paper

“DLX and MLN are serotonin (5HT) and norepinephrine (NE) reuptake inhibitors.”

What the sources say

• Partly supported

  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)

  cites [64] Vaishnavi, 2004, Milnacipran: A comparative analysis of human monoamine uptake and transporter binding affinity, Biol Psychiatry sourceExperimental — accuracy not yet measured

In the paper

“DLX has a 5:1 5HT/NE ratio and MLN has a 3:1 NE/5HT ratio.”

What the sources say

• Partly supported

  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)

  cites [64] Vaishnavi, 2004, Milnacipran: A comparative analysis of human monoamine uptake and transporter binding affinity, Biol Psychiatry sourceExperimental — accuracy not yet measured

In the paper

“The levels of reduced physical functioning of FMS patients are comparable to the ones of patients with osteoarthritis of the hip or rheumatoid arthritis.”

What the sources say

• Supported

  Table 2 reports SF-36 physical-functioning scores of 55.0 for fibromyalgia, 62.4 for hip osteoarthritis, and 62.3 for rheumatoid arthritis. The Results also groups all three among the conditions with the worst physical-functioning scores, supporting the comparison. No page number is available in our copy. (LLM, conf=0.90)

  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

In the paper

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

What the sources say

• Supported

  The Discussion states the claimed principle almost verbatim: the validity of indirect comparisons depends on the assumption of consistent treatment effects across trials. It also explains that combining trials from different eras may violate that assumption. (LLM, conf=0.95)

  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

In the paper

“This assumption can be violated by methodological shortcomings in the trials, differences in populations, interventions (eg, dosing), assessment of outcomes, or other factors.”

What the sources say

• Supported

  The Discussion (page unavailable in our copy) identifies consistent treatment effects across trials as a critical assumption of indirect comparisons and says differences in patient characteristics, treatment regimens, outcome assessment, and trial design or conduct can undermine it. The Introduction also identifies methodological shortcomings and differences in populations and interventions as factors affecting estimates; the Data Synthesis and Analysis section specifically mentions dosing. (LLM, conf=0.92)

  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

In the paper

“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”

What the sources say

• Supported

  The Abstract Background and Background state that including grey literature in systematic reviews may help overcome publication bias arising from the selective availability of data. The citing authors’ description of their own review as strengthened by that inclusion is their framing, not a finding attributed to this source. (LLM, conf=0.94)

  cites [37] Hopewell, 2007, Grey literature in meta-analyses of randomized trials of health care interventions, Cochrane Database Syst Rev. 18;MR000010 source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Busch, 2008, Exercise for fibromyalgia: A systematic review, J Rheumatol
• Partly supported

  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)

  cites [8] Carville, 2008, EULAR evidence based recommendations for the management of fibromyalgia syndrome, Ann Rheum Dis sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [30] Häuser, 2009, Efficacy of multicomponent treatment in fibromyalgia syndrome: A meta-analysis of randomized controlled clinical trials, Arthritis Rheum source
• Partly supported

  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)

  cites [33] Häuser, 2009, Fibromyalgia syndrome: Classification, diagnosis, and treatment, Dtsch Arztebl Int sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [41] Langhorst, 2009, Efficacy of hydrotherapy in fibromyalgia syndrome–a meta-analysis of randomized controlled clinical trials, Rheumatology (Oxford) source

In the paper

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

In the paper

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

In the paper

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

In the paper

“DLX was superior to MLN and PGB in reducing depressed mood.”

In the paper

“The studies with DLX and PGB excluded patients undergoing disability reviews.”

In the paper

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

In the paper

“All studies excluded patients <18 years and with unstable somatic diseases (including inflammatory rheumatic disorders).”

In the paper

“fatigue (-.13 [-.21, -.06]; .006)”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“Two studies with DLX were extension phases of RCTs.”

In the paper

“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).”

In the paper

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

In the paper

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

In the paper

“All studies with PGB excluded patients with creatinin clearance ≤60 mL/minute.”

In the paper

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

In the paper

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

In the paper

“Most studies did not report comorbidities of the patients and if nonpharmacological cotherapies were allowed.”

In the paper

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

In the paper

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

In the paper

“These side effects were inconsistently reported in the studies.”

In the paper

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

In the paper

“HRQOL (-.17 [-.25, -.10]; <.001)”

In the paper

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

In the paper

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

What the sources say

• ?Not matched

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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“and the panel voted against a black box warning.”

What the sources say

• ?Not matched

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

In the paper

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

What the sources say

• ?Not matched

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Discontinuation syndrome can occur with all 3 drugs.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [68] Wohlreich, 2008, Answers to the most common questions about the hepatic safety profile of duloxetine, Postgrad Med source

In the paper

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

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [27] Gartlehner, 2006, A simple and valid tool distinguished efficacy from effectiveness studies, J Clin Epidemiol source

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [68] Wohlreich, 2008, Answers to the most common questions about the hepatic safety profile of duloxetine, Postgrad Med source

In the paper

“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.”

In the paper

“Effective pharmacotherapy of FMS includes medications that inhibit pronociceptive input and augment modulatory signaling.”

What the sources say

• ?Not checked — no full text of the sourcecites [69] Wood, 2007, Novel pharmacotherapy for fibromyalgia, Expert Opin Investig Drugs source

In the paper

“Two authors (CS, WH) independently extracted data (study characteristics, study results) using standard extraction forms.”

In the paper

“Pregabalin is a structural analog of the neurotransmitter γ-aminobutyric acid (GABA).”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Lyseng-Williamson, 2008, Pregabalin: A review of its use in fibromyalgia, Drugs source

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Lyseng-Williamson, 2008, Pregabalin: A review of its use in fibromyalgia, Drugs source

In the paper

“A comparison of the efficacy and harms of the 3 drugs has not yet been published.”

In the paper

“Meta-analysis was performed according to the QUORUM guidelines (quality of reporting meta-analyses).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [6] Bucher, 1997, The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials, J Clin Epidemiol source

In the paper

“In case of 10 RCT's for each drug, the symmetry of funnel plots was examined to check for a potential publication bias.”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Egger, 1997, Bias in meta-analysis detected by a simple, graphical test, BMJ source
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [49] Page, 2008, Possible heart failure exacerbation associated with pregabalin: Case discussion and literature review, J Cardiovasc Med source

In the paper

“With the search strategy used, it is unlikely that we missed a RCT.”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [27] Gartlehner, 2006, A simple and valid tool distinguished efficacy from effectiveness studies, J Clin Epidemiol source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [28] Gartlehner, 2009, Inadequate reporting of trials compromises the applicability of systematic reviews, Int J Technol Assess Health Care source

In the paper

“Fifth, there is a certain risk inherent in offering conventional operational definitions such as the relevance of magnitude of effect sizes.17”

What the sources say

• ?Not matched

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

  cites [17] Cohen, 1988

In the paper

“Fourth, there is no gold standard of the methods used in meta-analysis.22”

What the sources say

• ?Not checked — no full text of the sourcecites [22] Engels, 2000, Heterogeneity and statistical significance in meta-analysis: An empirical study of 125 meta-analyses, Stat Med source

In the paper

“Therefore, concerns can be raised on our indirect formal comparison of harms.”

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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