Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia
Referencias
References to studies included in this review
References to studies excluded from this review
References to studies awaiting assessment
Additional references
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Study setting: multicenter study with 18 outpatient research centers in USA Study period: July 2001‐March 2002 Study design: parallel Trial duration: 3‐30 days' screening, 1 week single‐blind placebo run in, 12 weeks' therapy | |
| Participants | DLX: N = 104; 88.5% female; 88.5% white; mean age 49.9 (SD 12.3) years; pain baseline (0‐10) 6.1 (SD 1.8); 35.6% current major depression Placebo: N = 103; 89.3% female; 85.4% white; mean age 48.3 (SD 11.3) years; pain baseline (0‐10) 6.1 (SD 1.7); 40.8% current major depression Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain intensity item of the FIQ; age ≥ 18 years; with and without MDD Exclusion criteria: pain from traumatic injury or structural or regional rheumatic disease; rheumatoid arthritis, inflammatory arthritis, or autoimmune disease; unstable medical or psychiatric illness; current dysthymia, which is more resistant to treatment than major depression, or primary psychiatric disorder other than MDD; substance abuse in the last year; history of psychosis; pregnancy or breast feeding; unacceptable contraception in those of childbearing potential; involvement in disability reviews that might compromise treatment response; use of an investigational drug within 30 days; prior participation in a study of DLX; severe allergic reactions to multiple medications; intolerance to 3 psychoactive drugs or 1 SSRI; and failure to respond to 2 adequate regimens of 2 different classes of antidepressants for depression or FM. Concomitant medication exclusions included use of medications or herbal agents with CNS activity (antidepressants required a 7‐day washout prior to visit 2 except for monoamine oxidase inhibitors, which required a 14‐day washout, and fluoxetine, which required a 30‐day washout); regular use of analgesics with the exception of acetaminophen up to 2 g/d and aspirin up to 325 mg/d; chronic use of sedatives, antiemetics, or antispasmodics; episodic use of anticoagulants; 3 months' stable therapy with antihypertensives, hormones, anti‐arrhythmics, antidiarrhoeals, antihistamines, cough/cold preparations (excluding dextromethorphan), or laxatives; and initiation of or change in unconventional or alternative therapies | |
| Interventions | DLX 120 mg. Titration from 20 mg/d to 60 mg twice/day during first 2 weeks of the therapy phase, as follows: 20 mg every day for 5 days, 20 mg twice/day for at least 3 days, 40 mg twice/day for at least 2 days, and 60 mg twice a day for the remainder of the study Placebo (N = 103) Rescue and/or allowed medication: acetaminophen (paracetamol) up to 2 g/d and aspirin up to 325 mg/d | |
| Outcomes | Pain: BPI average pain severity (NRS 0‐10); pain relief of ≥ 30% and ≥ 50% reported PGIC much or very much improved: not reported; average scores of PGIC (1‐7) reported Fatigue: FIQ single item (VAS 0‐10) Sleep problems: BPI (NRS 0‐10): not reported HRQoL: FIQ total score (0‐80) AEs: physical examination, ECGs, and laboratory analysis. Further details of assessment of AEs not reported. Frequency of nausea, somnolence and insomnia insufficiently reported (not suited for meta‐analysis) Depression: BDI ‐II total score (NRS 0‐63) Anxiety: BAI total score (NRS 0‐63) Disability: BPI interference from pain (NRS 0‐10) Cognitive disturbances: not assessed Sexual function: not assessed Tenderness: mean tender point threshold (kg/cm²) | |
| Notes | Conflicts of interest: Drs Crofford and Arnold have received consulting fees or honoraria in the last 2 years from Eli Lilly and Company (Dr.Crawford USD 10,000, Dr. Arnold USD 10,000). In addition to the authors employed by Eli Lilly and Company listed above, Dr. Goldstein’s wife is employed by Eli Lilly and Company. Funding: Eli Lilly | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence using an interactive response system |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details reported on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar, details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | High risk | Outcomes: sleep problems, 30% pain reduction and SAEs not reported |
| Group similarity at baseline | Low risk | No significant group differences in demographic and clinical data at baseline |
| Sample size bias | Unclear risk | 50‐199 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 21 outpatient research centers in USA Study design: parallel Study period: November 2002‐October 2003 Duration therapy: screening duration not reported: 12 weeks' therapy | |
| Participants | Total sample: 100% female; 89.5% white; mean age 49.6 (SD 10.9) years; 26% current major depression "No significant differences among treatment groups were observed in any of the patient demographics or clinical characteristics including origin, age, gender, height, weight, primary diagnoses of major depressive disorder, or secondary diagnosis of anxiety" DLX 60 mg/d: N = 118; pain baseline (0‐10) 6.4 (SD 1.4) DLX 120 mg/d: N = 116; pain baseline (0‐10) 6.4 (SD 1.4) Placebo: N = 120; pain baseline (0‐10) 6.5 (SD 1.5) Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain intensity item of the FIQ; age ≥ 18 years; with and without MDD Exclusion criteria: pain from traumatic injury or structural or regional rheumatic disease; rheumatoid arthritis, inflammatory arthritis, or autoimmune disease; unstable medical or psychiatric illness; current primary psychiatric diagnosis other than MDD, a primary anxiety disorder within the past year (specific phobias allowed); substance abuse within the past year; serious suicide risk; pregnancy or breast‐feeding; women who, in the opinion of the investigator, were treatment refractory or may have had an involvement in disability reviews that might compromise treatment response; severe allergic reactions to multiple medications; or prior participation in a study of DLX. Concomitant medication exclusions included use of medications or herbal agents with CNS activity; regular use of analgesics with the exception of acetaminophen up to 2 g/d and aspirin for cardiac prophylaxis up to 325 mg/d; chronic use of sedatives, antiemetics, or antispasmodics; and initiation of or change in unconventional or alternative therapies | |
| Interventions | DLX 1‐week, double‐blind, study‐drug tapering phase at which time dosage of study drug was reduced to DLX 30 mg/d for DLX 60 mg/d‐treated participants and DLX 60 mg/d for DLX120 mg/d‐treated participants; forced titration from 60 mg/d to 120 mg/d within 3 days Placebo Rescue and or allowed medication: acetaminophen up to 2 g/d and aspirin up to 325 mg/d | |
| Outcomes | Pain: (BPI average pain severity (NRS 0‐10) PGIC much or very much improved: not reported; average scores of PGIC (1‐7) reported Fatigue: FIQ (VAS 0‐10): not reported Sleep problems: BPI sleep interference (NRS 0‐10) HRQoL: FIQ total score (0‐80) AEs: physical examination, ECGs, and laboratory analysis. Details of assessment of AEs not reported. Frequency of nausea and somnolence reported; frequency insomnia not reported Depression: HDRS (NRS 0‐52) Anxiety: FIQ (VAS 0‐10): not reported Disability: BPI interference from pain (NRS 0‐10) Sexual function: not assessed Cognitive disturbances: not assessed Tenderness: mean tender point threshold (kg/cm²) Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: not reported Funding: Eli Lilly | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence using an interactive response system (details reported on request) |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details reported on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar, details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | High risk | Outcomes of anxiety and fatigue not reported |
| Group similarity at baseline | Low risk | No significant group differences in demographic and clinical data at baseline |
| Sample size bias | Unclear risk | 50‐199 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 48 outpatient research centers in USA and Puerto Rico Study period: June 2008‐July 2009 Study design: parallel Trial duration: 5‐30‐day screening phase, the acute phase was 12 weeks’ duration, double‐blind, and placebo‐controlled. After Week 12, participants in the placebo group were transitioned to active treatment and all participants continued for an additional 12 weeks of double‐blind treatment. An optional 2‐week drug‐tapering phase was offered at the end of the 12‐week continuation phase or for participants who discontinued early after receiving at least 2 weeks of study medication. | |
| Participants | DLX: N = 263; 92.8% women; 77.6% white; mean age 50.7 (SD 11.3); pain baseline (0‐10) 6.5 (SD 1.5); 16.7% current major depression; 7.2% current GAD Placebo: N = 267; 93.6% women; 77.2% white; mean age 49.6 (SD 10.8); pain baseline (0‐10) 6.5 (SD 1.6); 19.9% current major depression; 9.0% current GAD Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain intensity item of the FIQ; age ≥ 18 years; with and without MDD/GAD Exclusion criteria: current or diagnosed within the past year with any primary psychiatric disorder other than MDD or GAD defined by DSM‐IV; clinically judged to be at serious risk of suicide; had any unstable medical illness likely to require intervention or hospitalization; pain symptoms unrelated to FM that could interfere with interpretation of outcome measures; regional pain syndromes; multiple surgeries or failed back syndrome; a confirmed current or previous diagnosis of rheumatoid arthritis, inflammatory arthritis, or other autoimmune disease; severe liver disease; pregnant or breast‐feeding; or history of substance abuse within the past year. Participants were also excluded if they had been treated with an adequate trial of DLX and did not respond or could not tolerate DLX; were judged by the opinion of the investigator to be treatment‐refractory in FM; or whose treatment response might be compromised by disability compensation issues. | |
| Interventions | DLX was initiated at 30 mg and escalated to 60 mg after 1 week. At week 4 and week 8 visits, DLX dose was automatically escalated via IVRS by 30 mg daily for those participants who had < 50% reduction from baseline in their BPI 24‐h pain score and the investigator had endorsed a dose increase. If the participant could not tolerate the dose increase, it was reduced to the pre‐escalation dose via IVRS Placebo Rescue and/or allowed medication: acetaminophen up to 2 g/d and aspirin up to 325 mg/d | |
| Outcomes | Pain: BPI 24‐h average pain severity (NRS 0‐10) PGIC much or very much improved: not reported; average scores of PGIC (1‐7) reported Fatigue: MFI general fatigue (NRS 4‐20) Sleep problems: bothered by sleep difficulties (NRS 0‐10): data extracted from figure HRQoL: SF‐36 physical component summary score (100‐0) AEs: physical examination, ECGs, and laboratory analysis. Details of assessment of adverse symptoms not reported. Frequency of nausea, dizziness and insomnia reported Depression: BDI total score (NRS 0‐63) Anxiety: BAI total score (NRS 0‐63) Disability: BPI pain interference pain (NRS 0‐10) Sexual function: not assessed Cognitive disturbances: MFI mental fatigue (NRS 4‐20) Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: not declared Funding: the study authors thank the Clinical Operations and Data Management teams of Lilly USA | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence using an interactive response system |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details reported on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar‐details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; patients were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described. |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
| Group similarity at baseline | Low risk | No significant group differences in demographic and clinical data at baseline |
| Sample size bias | Low risk | > 200 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 68 outpatient research centers in USA and Canada Study period: April 2006‐June 2008 Study design: parallel Trial duration: screening and washout (1‐4 weeks),baseline assessment (2 weeks), randomization/flexible dose escalation (4‐6 weeks), stable dose (12 weeks), and randomized discontinuation (2 weeks) | |
| Participants | MLN: N = 516; 96.6% female; 91.9% white; mean age 49.1 (SD 10.8) years; pain baseline (0‐100) 63.1 (SD 12.5) Placebo: N = 509; 93.7% female; 90.0% white; mean age 48.7 (SD 10.6) years; pain baseline (0‐10) 64.4 (SD 12.7) Inclusion criteria: 1990 ACR criteria, 18‐70 years, raw score of ≥ 4 on the FIQ Exclusion criteria: previous exposure to MLN; treatment with an investigational drug within 30 days of screening; BDI score > 25 at screening or randomization; current major depressive episode as determined by MINI; significant risk of suicide according to investigator’s judgment or results of the MINI or BDI; lifetime history of psychosis, hypomania, or mania; substance abuse; other severe psychiatric illness as determined by investigator judgment; history of behavior that would, in the investigator’s judgment, prohibit compliance for the duration of the study; active or pending disability claim, workman’s compensation claim, or litigation; pregnancy or breastfeeding; unacceptable contraception; active or unstable medical illness; prostate enlargement or other genitourinary disorder | |
| Interventions | MLN flexible up to 100 mg/d (516 participants): MLN 12.5 mg on days 1‐3; MLN 25 mg (12.5 mg twice daily) for 4 days; MLN 50 mg (25 mg twice daily) for 7 days; MLN 75 mg (37.5 mg twice daily) for 7 days; and MLN 100 mg (50 mg twice daily) for 7 days. If side effects developed, the dose of MLN could be temporarily reduced. Placebo Rescue and allowed medication: tramadol or hydrocodone between randomization and week 4 (end of dose escalation). Permitted analgesic medications were acetaminophen, aspirin, and NSAIDs | |
| Outcomes | Pain: PED 24‐h recall pain score (VAS 0‐100) PGIC much or very much improved: reported Fatigue: MFI total (NRS 20‐100) Sleep problems: BPI sleep interference: not reported HRQoL: FIQ total score AEs: physical examination, ECGs, and laboratory analysis. Details of assessment of adverse symptoms not reported. Frequency of nausea, dizziness and insomnia reported Depression: BDI total score (NRS 0‐63) Anxiety: BAI total score (NRS 0‐63) Disability: BPI pain interference pain (NRS 0‐10) Sexual function: not assessed Cognitive disturbances: MASQ cognitive function (NRS 38‐190) Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: not declared Funding: the study was financially supported by Forest Laboratories, Inc. Forest Laboratories, Inc. and | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence using an interactive response system |
| Allocation concealment (selection bias) | Low risk | Central independent unit |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar, details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described. |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | High risk | Outcomes of sleep and anxiety not reported |
| Group similarity at baseline | Low risk | No significant differences in clinical and demographic variables at baseline |
| Sample size bias | Low risk | > 200 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 29 outpatient research centers in USA, Mexico, Israel and Argentina Study period: September 2009‐November 2010 Study design: parallel Trial duration: 5‐30 days' screening and wash out; 12 weeks' therapy | |
| Participants | DLX (N = 155): 94% women, 94% white, mean age 50.9 (SD 11.9) years, pain baseline (0‐10) 6.5 (SD 1.5); 20.6% with major depressive disorder Placebo (N = 153): 96% women, 89% white, mean age 50.7 (SD 12.5) years; pain baseline (0‐10) 6.4 (SD 1.7); 24.2% with major depressive disorder Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain severity item of the BPI; age ≥ 18 years; with and without MDD Exclusion criteria: prior treatment with DLX; prior participation in a DLX study; a history of substance abuse within the past year; a primary psychiatric disorder other than MDD or GAD within the last year; a history of psychosis or bipolar disorder; clinically judged to be at risk of suicide; pregnant or breast‐feeding; pain symptoms unrelated to FM that could interfere with interpretation of outcome measures; regional pain syndromes; failed back syndrome; chronic localized pain related to any past surgery, and a confirmed current or previous diagnosis of rheumatoid arthritis; inflammatory arthritis, or infectious arthritis; or an autoimmune disease. Participants who, in the opinion of the investigator, were judged to be treatment‐refractory or whose response might be compromised by disability compensation, or had an unstable medical condition were also excluded. Concomitant medication exclusions included use of medications or herbal agents with primarily cCNS activity; regular use of analgesics other than acetaminophen up to 2 g/d and aspirin up to 325 mg for cardiac prophylaxis; topical lidocaine or capsaicin, antidepressants, anticonvulsants, barbiturates, muscle relaxants; chronic use of anti‐emetics, hypnotics and sedatives; < 3 months stable therapy of antihypertensives, anti‐arrhythmics, diuretics, and hormones; steroids other than episodic treatment of symptoms unrelated to FM; and benzodiazepine use for FM pain | |
| Interventions | DLX 30 mg Placebo Rescue and/or allowed medication: some analgesics, such as non‐steroidal antiinflammatory | |
| Outcomes | Pain: BPI) average pain severity (NRS 0‐10) PGIC much or very much improved: not reported; average PGI assessed and reported Fatigue: FIQ single item (VAS 0‐10): not reported Sleep problems: not assessed Health‐related Quality of life: FIQ total score (0‐80) AEs: vital signs, laboratory analyses, and the C‐SSRS. Frequency of nausea, somnolence and insomnia reported Depression: BDI ‐II total score (NRS 0‐63) Anxiety: BAI total score (NRS 0‐63) Disability: BPI interference from pain (NRS 0‐10) Sexual function: not assessed Cognitive disturbances: MFI mental fatigue (NRS 4‐20) Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: BAP and SZ are full time employees and stockholders at Eli Lilly and Company. LMA has received grants from and/or is a consultant for Eli Lilly and Company, Pfizer Inc, Cypress Bioscience Inc, Forest Laboratories, Boehringer Ingelheim, Novartis, Takedo,Grunenthal and Daiichi Sankyo. Funding: Eli Lilly | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐ generated random sequence by IVRS |
| Allocation concealment (selection bias) | Unclear risk | No details reported |
| Blinding of participants and personnel (performance bias) | Low risk | Capsules were identical in appearance |
| Blinding of outcome assessment (detection bias) | Unclear risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described |
| Incomplete outcome data (attrition bias) | Unclear risk | Modified BOCF for ITT‐analysis (participants who discontinued because of an AE, the baseline value was used as the endpoint, and for all other participants, the last non‐missing, post‐baseline observation before rescue therapy (if any) was used as the endpoint) |
| Selective reporting (reporting bias) | High risk | Study protocol available at clinicaltrials.gov; NCT00965081. All predefined outcomes except fatigue reported |
| Group similarity at baseline | Low risk | No significant differences in demographic and clinical variables at baseline |
| Sample size bias | Unclear risk | 100‐199 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 29 outpatient research centers in USA, Mexico, Israel and Argentina Study period: March‐December 2010 Study design: parallel Trial duration: 2‐week, open‐label run‐in, 10 weeks' therapy | |
| Participants | MLN (N = 79): 92% women, 94% white, mean age 48.6 (SD 10.2) years; pain baseline (0‐100) 65.4 (13.2) Placebo (N = 21): 91% women, 95% white, mean age 48.5 (SD 11.3) years; pain baseline (0‐100) 65.2 (12.2) Inclusion criteria: female and male outpatients, aged 18–70 years, with a diagnosis of FM who had been receiving the recommended dosage of DLX 60 mg/d (ie, the maximum dosage recommended by the US Food and Drug Administration)17 at stable doses for at least 4 weeks prior to screening. DLX prescriptions had to be for the management of FM and not for the treatment of depression or another pain syndrome. Participants with a 1‑week VAS pain recall score ≥ 40 mm to ≤ 90 mm at screening were entered into the open‐label, run‑in period of this study and continued receiving DLX 60 mg/d for an additional 2 weeks in order to confirm that they were not having an adequate response to DLX under study conditions. After this 2‐week run‐in period, participants who continued to have a VAS pain score ≥ 40 mm and who still expressed dissatisfaction with treatment were eligible for randomization. A deliberately general question was used to evaluate treatment satisfaction (ie, “Are you satisfied with DLX treatment?”) in order to allow for any potential dissatisfaction (e.g. unsatisfactory improvement in pain or non‐pain symptoms, poor tolerability, simple desire to try a new medication), as might occur in clinical practice.) Exclusion criteria: history or current diagnosis of serious psychiatric disorder; substantial alcohol use or abuse; behavior that would, in the investigator’s judgment, prohibit participation in the study; serious suicide risk; BDI 22‐25; pregnancy or breastfeeding; unacceptable contraception in those of childbearing potential; untreated hypertension; cardiovascular disease, including myocardial infarction or stroke within the past 6 months; sitting mean systolic BP .160 mmHg or diastolic BP.100 mmHg; active or unstable medical illness; evidence of active liver disease; prostate enlargement or other genitourinary disorders; renal impairment (creatinine clearance, 30 mL/min); uncontrolled narrow‐angle glaucoma; body mass index ≥ 45 kg/m2. Excluded concomitant medications included drugs with CNS activity, such as antidepressants, anorectics, antiepileptic agents, opiates, and related analgesics (e.g. oxycodone, codeine, tramadol, narcotic patches), dopamine agonists, stimulants, and sodium oxybate | |
| Interventions | MLN 100 mg Placebo Rescue and/or allowed medication: acetaminophen, aspirin, and NSAIDs. Participants requiring short‐term pain rescue medication were allowed opioid analgesics, but opioids were not permitted within days of scheduled study visits. Triptans were permitted for acute migraine treatment. Nonbenzodiazepine hypnotics were also allowed for participants requiring treatment of insomnia. | |
| Outcomes | Pain: 1‐week recall pain intensity (VAS 0‐100) PGIC much or very much improved: reported Fatigue: FIQ single item (0‐10): not reported Sleep problems: not assessed HRQoL: FIQ total score (0‐100) AEs: no details reported. Frequency of nausea, dizziness and insomnia reported Depression: BDI ‐II total score; SD not reported Anxiety: FIQ single item (0‐10) not reported Disability: FIQ single item (VAS 0‐10) Sexual function: Arizona Sexual Experience Scale (5‐30) Cognitive disturbances: MASQ (38‐190) Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: LB has received research support and speaker fees from Forest Laboratories, Inc. and Forest Research Institute, Inc. RHP, JMT, and YL are full‐time employees of Forest Research Institute, Inc., a wholly owned subsidiary of Forest Laboratories, Inc., and hold stock in the parent company. Funding: Forest Research Institute | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No details reported |
| Allocation concealment (selection bias) | Unclear risk | No details reported |
| Blinding of participants and personnel (performance bias) | Unclear risk | No details reported |
| Blinding of outcome assessment (detection bias) | Unclear risk | No details reported |
| Incomplete outcome data (attrition bias) | Unclear risk | ITT analysis by LOCF |
| Selective reporting (reporting bias) | High risk | All predefined outcomes of study protocol NCT01077375 reported except fatigue and anxiety |
| Group similarity at baseline | Low risk | No significant differences in clinical and demographic variables |
| Sample size bias | High risk | < 50 participants in placebo arm, 79 in active treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 89 outpatient research centers in 13 European countries Study period: February 2006‐September 2007 Study design: parallel Trial duration: 1‐ to 4‐week washout period from disallowed medications, eligible participants entered a 2‐week period in which they were trained in the use of the PED; 16 weeks' therapy; 2‐week follow‐up phase without treatment | |
| Participants | MLN: N = 430; 95.1% female; ethnicity not reported; mean age 48.3 (SD 9.3) years; pain baseline (0‐100) 65.5 (SD 12.9) Placebo: N = 446; 93.5% female; ethnicity not reported; mean age 49.2 (SD 10.3) years; pain baseline (0‐100) 65.0 (SD 12.7) Inclusion criteria: 1990 ACR criteria; raw score ≥ 3 on physical function component of FIQ; baseline VAS pain intensity rating between 40‐90 (0‐100 scale) Exclusion criteria: severe psychiatric illness including GAD or current major depressive episode (assessed by MINI, BDI‐27 score > 25), alcohol/substance abuse; significant cardiovascular, respiratory, rheumatoid, rheumatic, hepatic, renal, or other medical condition; systemic infection; epilepsy; active cancer; severe sleep apneas; unstable endocrine disease; active peptic ulcer or inflammatory bowel disease; prostatic enlargement or other genitourinary disorders (in male participants); pregnancy or breastfeeding; and history or behavior that would prohibit compliance for the duration of the study | |
| Interventions | MLN: 25 mg once daily (evening dose, days 1 and 2); 25 mg twice daily (days 3–7); 50 mg (days 8–14); 50 mg (morning dose) and 100 mg (evening dose, days 15–21); and 100 mg (days 22–28). Participants then entered the 12‐week stable‐dose treatment period, followed by a 9‐day down‐titration phase and a 2‐week follow‐up phase without treatment. Placebo Rescue or allowed medication: not reported | |
| Outcomes | Pain: PED 24‐h recall pain score (VAS 0‐100); 50% response rates not reported and not provided on request; calculated by imputation method PGIC much or very much improved: reported Fatigue: MFI total (NRS 20‐100) Sleep problems: MOS‐Sleep Index II (NRS 0‐100) HRQoL: FIQ total score (VAS 0‐100) AEs: physical examination, ECGs, and laboratory analysis. AEs were assessed throughout the study based on spontaneous reporting by participants, investigators’ use of non‐leading questions, and clinical evaluation. Frequency of nausea, dizziness and insomnia reported Depression: BDI total score (NRS 0‐63) Anxiety: State‐Trait Anxiety Inventory (NRS 20‐80) Disability: BPI pain interference pain (NRS 0‐10) Sexual function: not assessed Cognitive disturbances: MASQ cognitive function (NRS 38‐190) Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: Dr. Branco has received grant support as an investigator and consultant for Pierre Fabre Médicament. Drs. Zachrisson and Perrot have served as speakers and consultants for Pierre Fabre Médicament. Dr. Mainguy is an employee and shareholder of Pierre Fabre Médicament. Funding: Supported by Pierre Fabre Médicament, Boulogne, France | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence using an interactive response system (details provided on request) |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details provided on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar‐details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Outcome assessors of safety were adequately blinded to the intervention |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | High risk | 50% pain reduction not reported and not provided on request; The FDA report on MLN stated that a female participant committed suicide and that this death was possibly related to MLN |
| Group similarity at baseline | Low risk | No significant differences in demographic and clinical variables at baseline |
| Sample size bias | Low risk | > 200 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 36 outpatient research centers in Western Europe (Germany, Spain, Sweden, UK) and USA Study period: September 2005‐December 2006 Study design: parallel Trial duration: 1 week's screening, 27 weeks' therapy | |
| Participants | DLX: N = 162; 92.0% female; 92.6% white; mean age 50.8 (SD 10.1) years; pain baseline (0‐10) 6.6 (SD 1.5); 22.2% current major depression Placebo: N = 168; 94.6% female; 89.3% white; mean age 50.2 (SD 11.3) years; pain baseline (0‐10) 6.4 (SD 1.5); 22.6% current major depression Inclusion criteria: ACR 1990 criteria; age ≥ 18 years; with and without MDD Exclusion criteria: current or previous treatment with DLX; any current primary Axis I diagnosis other than MDD; pain symptoms related to traumatic injury, structural rheumatic disease, or regional rheumatic disease (such as osteoarthritis, bursitis, tendonitis); regional pain syndrome; multiple surgeries or failed back syndrome; confirmed current or previous diagnosis of rheumatoid arthritis, inflammatory arthritis, infectious arthritis, or an autoimmune disease; and serious medical illness | |
| Interventions | DLX 60 mg/d or 120 mg/d: participants randomly assigned to the DLX 60 mg treatment group underwent a titration in which they received DLX 30 mg for 1 week before receiving DLX 60 mg for 12 weeks. At visit 8 (week 13) participants who did not have 50% reduction in the BPI‐Modified Short Form average pain score were blindly escalated to 120 mg. Those that could not tolerate this dose were allowed to return to the 60 mg dose. Participants were allowed to increase their dose to 120 mg at any time between visits 8 and 10 (weeks 13 and 23), based upon whether they had 50% reduction in their BPI average pain score. If at any time between visits 9 and 11 (weeks 18 and 27) participants had tolerability issues with the higher dose (120 mg), they were allowed to go back to the lower dose (60 mg). Placebo Rescue or allowed medication: not reported | |
| Outcomes | Pain: BPI 24‐h average pain severity (NRS 0‐10) PGIC much or very much improved: not reported; mean scores of PGIC (NRS 1‐7) reported Fatigue: MFI general fatigue (NRS 4‐20) Sleep problems: BPI sleep interference (NRS 0‐10): not reported HRQoL: FIQ total score (VAS 0‐80) AEs: physical examination, ECGs, and laboratory analysis. AEs were assessed throughout the study based on spontaneous reporting by participants. Frequency of nausea, somnolence and insomnia reported Depression: BDI‐II total score (NRS 0‐63) Anxiety: FIQ anxiety (VAS 0‐10): not reported Disability: BPI pain interference (NRS 0‐10) Sexual function: not assessed Cognitive disturbances: MFI mental fatigue (NRS 4‐20) Tenderness: mean tender point threshold (kg/cm²) Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: Drs. Chappell, Detke, and D’Souza are employees and stockholders of Eli Lilly and Company. Dr Wiltse is a former employee of Eli Lilly and Company. Dr Spaeth is a consultant to Allergan, Eli Lilly, Jazz, and Pierre Fabre Medicament, and is on the speaker bureaus of Eli Lilly and Pierre Fabre Medicament. Dr Bradley is a consultant for Eli Lilly, Pfizer, and Forest; has received grant/research support from the National Institutes of Health, the Agency for Healthcare Research and Quality, Eli Lilly, Pfizer, and the American Fibromyalgia Syndrome Association; has received honoraria from Eli Lilly, Pfizer, Forest, and the Society for Women’s Health Research; is a member of the speaker/advisory board for Pfizer; and has received royalties from UpToDate Rheumatology | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence stratified by major depression status within each study center |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details reported on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar, details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | High risk | Outcomes of sleep and anxiety not reported |
| Group similarity at baseline | Low risk | No significant differences in clinical and demographic variables at baseline |
| Sample size bias | Unclear risk | 50‐199 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 86 outpatient research centers in USA Study period: November 2004‐December 2006 Study design: parallel Trial duration: After a 1‐ to 4‐week period for washout of prohibited medications, participants were trained in the use of the electronic study diary and entered a 2‐week baseline period, during which baseline efficacy and safety values were recorded; 15 weeks' therapy | |
| Participants | MLN 100 mg/d: N = 399; 97.0% female; 94.0% white; mean age 49.5 (SD 13.5) years; pain baseline (0‐100) 64.6 (SD 13.5) MLN 200 mg/d: N = 396; 97.0% female; 92.9% white; mean age 50.4 (SD 10.6) years; pain baseline (0‐100) 64.5 (SD 13.8) Placebo: N = 401; 94.8% female; 93.5% white; mean age 50.7 (SD 10.4) years; pain baseline (0‐100) 65.7 (SD 13.3) Inclusion criteria: 1990 ACR criteria; raw score ≥ 4 on the physical function component of the FIQ; baseline VAS pain intensity rating between ≥ 40 (0‐100 scale) Exclusion criteria: severe psychiatric illness including GAD or current major depressive episode (assessed by MINI), BDI‐27 score > 25; alcohol/substance abuse; significant cardiovascular, respiratory, rheumatoid, rheumatic, hepatic, renal, or other medical condition; systemic infection; epilepsy; active cancer; severe sleep apneas; unstable endocrine disease; active peptic ulcer or inflammatory bowel disease; prostatic enlargement or other genitourinary disorders (in male participants); pregnancy or breastfeeding; and history or behavior that would prohibit compliance for the duration of the study | |
| Interventions | MLN 100 mg/d or 200 mg/d: dose escalation within 3 weeks Placebo Rescue medication: hydrocodone up to 60 mg/d | |
| Outcomes | Pain: PED 24‐h recall pain score (VAS 0‐100); 50% response rates not reported and not provided on request; calculated by imputation method PGIC much or very much improved: reported (NRS 1‐7)* Fatigue: MFI total (NRS 20‐100) HRQoL: FIQ total score (VAS 0‐100) AEs: physical examination, ECGs, and laboratory analysis. AEs were assessed throughout the study based on spontaneous reporting by participants and investigators’ observation. Frequency of nausea, dizziness and insomnia reported Sleep problems: MOS‐Sleep Index II (NRS 0‐100) Depression: BDI total score (NRS 0‐63) Anxiety: FIQ anxiety (VAS 0‐10): not reported Disability: MDHAQ disability subscale score Sexual function: Arizona Sexual Function Scale (5‐50) Cognitive disturbances: MASQ cognitive function (NRS 38‐190) Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | *Completer analysis Conflicts of interest: Dr. Clauw has received grant supports by Bioscience, Inc., and serves as a consultant to Cypress Bioscience, Forest Laboratories, and Pierre Fabre Medicament,all of which are involved in the development of MLN for FM. He also acts as a consultant to Eli Lilly and Company, Pfizer Inc., Procter & Gamble, and Wyeth Pharmaceuticals. He has owned stock in Cypress Bioscience. Dr. Mease has received research grant support from Allergan, Inc.; Cypress Bioscience; Forest Laboratories; Fralex Therapeutics Inc.; Jazz Pharmaceuticals; Eli Lilly; Pfizer; and Wyeth. Drs. Palmer and Wang are employees of Forest Research Institute and own stock in Forest November 2008 Laboratories. Dr. Gendreau is an employee of Cypress Bioscience and owns stock in that company. Funding: Forest Research Institute and Cypress Bioscience | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence using an interactive response system (details provided on request) |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details provided on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar, details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; patients were adequately blinded to intervention. Outcome assessors of safety were adequately blinded to the intervention |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using baseline and LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | High risk | Anxiety scores not reported and not provided on request |
| Group similarity at baseline | Low risk | No significant group differences in clinical and demographic variables |
| Sample size bias | Low risk | > 200 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: 58 study centers, USA Study period: November 2009‐June 2010 Study design: enriched enrolment randomized withdrawal Trial duration: 4 weeks open‐label, 12 weeks of therapy of participants randomized to MLN or placebo, double‐blind) and 1 week of tapering (double blind) | |
| Participants | MLN (N = 100): 96% women, 95.3% white, mean age 54.5 (SD 9.5) years; pain baseline (0‐100) 65.4 (SD 13.0) Placebo (N = 50): 96% women, 94% white, mean age 54.0 (SD 8.5) years; pain baseline (0‐100) 65.7(SD 13.6) Inclusion criteria: adults meeting the 1990 ACR criteria for FM who entered directly from a long‐term, open‐label, flexible‐dose, lead‐in study in which they received MLN 50 mg/d to 200 mg/d for up to 3.25 years. Prior to this lead‐in study, participants had received up to 15 months of treatment with MLN 100 mg/d or 200 mg/d during double‐blind studies, resulting in up to 4.5 years of MLN exposure prior to entering into the current discontinuation study. Exclusion criteria: significant risk of suicide, history of serious psychiatric disorder, substantial alcohol use or abuse, pregnancy or breastfeeding, cardiovascular disease within the past 12 months, mean systolic BP > 180 mmHg or diastolic BP > 110 mmHg, uncontrolled narrow‐angle glaucoma, active liver disease, severe renal impairment and any other medical disorder that might preclude participation as judged by the principal investigator | |
| Interventions | MLN 100 or 200 mg/d Placebo Rescue and/or allowed medication: monoamine oxidase inhibitors, stimulant medications, anorectic agents, daily opiates, sodium oxybate and anesthetic and/or opiate patches were prohibited. Although daily opiates were prohibited, intermittent use was allowed as needed, except during the 7 days before scheduled study visits. | |
| Outcomes | Pain: 24‐h recall pain intensity (VAS 0‐100). Data for mean pain reduction extracted from figures. Time to loss of therapeutic response: < 30% reduction in VAS pain from pre‐MLN exposure or worsening of FM requiring alternative treatment: < 50% reduction in VAS pain from pre‐MLN exposure or worsening of FM requiring alternative treatment not assessed. PGIC much or very much worse from randomization: reported Fatigue: MFI Total Score (20‐100); worsening was defined as a 10‐point increase from randomization Sleep problems: not assessed HRQoL: FIQ‐R total score (0‐100). Data extracted from figures AEs: AEs, vital signs and clinical laboratory tests were monitored for safety. Frequency of nausea reported, of somnolence and insomnia not reported Depression: FIQ‐R depression (0‐10): not reported Anxiety: FIQ‐R depression (0‐10): not reported Disability: SF‐36 physical summary component score (50‐0); worsening was defined as a 6‐point decrease from randomization Sexual function: not assessed Cognitive disturbances: not assessed Tenderness: not assessed Dropout due to lack of efficacy: insufficiently reported (not suited for meta‐analysis) | |
| Notes | Conflicts of interest: DJC has received grants and research support from Pfizer Inc and Forest Laboratories. He has been a consultant for and has served on advisory boards for Pfizer Inc, Eli Lilly and Co, Forest Laboratories, Inc, Cypress Bioscience, Inc (now Royalty Pharma), Pierre Fabre Pharmaceuticals, UCB and AstraZeneca. PJM has received research and grant funding as well as consultation fees from Forest Laboratories, Inc, Cypress Bioscience, Inc, Eli Lilly and Co, Pfizer Inc, Allergan, Inc, Wyeth Pharmaceuticals, Jazz Pharmaceuticals and Fralex Therapeutics. In addition to being full‐time employees of Forest Research Institute, Inc, a wholly owned subsidiary of the study sponsor (Forest Laboratories, Inc), RHP, JMT and YW hold stock in the parent company. Funding: Pierre Fabre | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomization codes were generated and securely stored by Forest Research Institute, Inc (Jersey City, NJ, USA) |
| Allocation concealment (selection bias) | Low risk | IVRS and/or web response system |
| Blinding of participants and personnel (performance bias) | Unclear risk | No details reported |
| Blinding of outcome assessment (detection bias) | Unclear risk | Participant‐reported outcomes; no details reported about whether participants and outcome assessors of safety were adequately blinded to intervention. |
| Incomplete outcome data (attrition bias) | Unclear risk | ITT by LOCF |
| Selective reporting (reporting bias) | High risk | Protocol NCT01014585. Outcomes depression and anxiety not reported |
| Group similarity at baseline | Low risk | No significant group differences in clinical and demographic variables |
| Sample size bias | Unclear risk | 50‐199 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: single center (interdisciplinary FM outpatient department); Italy Study period: 2011‐2012 Study design: parallel Trial duration: no details on washout period reported; 12 weeks of therapy | |
| Participants | DLX (N = 29 ) L‐carnitine (N = 22) Total sample: 100% female; ethnicity not reported; mean age 54.0 (SD 8.5) years; duration FM 7.6 (SD 6.8) years. "There were no demographic or clinical differences between the two groups at baseline" Inclusion criteria: female adults meeting the 1990 ACR criteria for FM as assessed by an experienced rheumatologist pain intensity > 3 on a VAS Exclusion criteria: concomitant DSM‐IV TR axis I psychiatric syndrome including mood and anxiety disorders; pain due to trauma; rheumatic disease; autoimmune disease; contraindications to the use of DLX or acetylcarnitine; current antidepressant treatment | |
| Interventions | DLX 30 or 60 mg/d Acetyl‐carnitine: 3x500 mg/d Rescue and/or allowed medication: no information provided | |
| Outcomes | Pain: VAS 0‐10 (current pain); 30% and 50% and more pain relied calculated by imputation method PGIC much or very much improved: Clinical Global Impression Improvement: Only average scores reported Fatigue: FIQ subscale score not reported Sleep problems: not assessed HRQoL: FIQ total score not reported AEs: "Side effects were assessed by the same psychiatrist". Frequency of nausea, somnolence and insomnia insufficiently reported (not suited for meta‐analysis). Depression: HADS Depression Subscale 0‐21 Anxiety: HADS Anxiety Subscale 0‐21 Disability: SF‐36 physical summary component score (100‐0) Sexual function: not assessed Cognitive disturbances: not assessed Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: not reported Funding: no details provided | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No details reported |
| Allocation concealment (selection bias) | Unclear risk | No details reported |
| Blinding of participants and personnel (performance bias) | Unclear risk | No details reported |
| Blinding of outcome assessment (detection bias) | Unclear risk | No details reported |
| Incomplete outcome data (attrition bias) | High risk | Completer analysis |
| Selective reporting (reporting bias) | High risk | No study protocol available. FIQ scores not reported |
| Group similarity at baseline | Low risk | No significant differences in demographic and clinical variables at baseline |
| Sample size bias | High risk | < 50 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: single‐center study, university hospital, Switzerland Study period: September 2006‐September 2009 Study design: parallel Trial duration: 1‐4 weeks' screening and washout; 7 weeks' therapy; down‐titration phase of 3‐9 days | |
| Participants | MLN (N = 38): 100% women, ethnicity not reported, mean age 48.5 (SD 11.4) years; pain baseline (0‐100) 61.2 (SD 14.5) Placebo (N = 39): 100% women, ethnicity not reported, mean age 50.9 (SD 11.4) years; pain baseline (0‐100) 63.5 (SD 15.1) Inclusion criteria: Women ≥ 18 years old who met the 1990 ACR FMS criteria were included if the following criteria were met: signed informed consent, negative urine pregnancy test at screening and use of adequate contraception or absence of childbearing potential, willingness to withdraw from CNS‐active therapies, willingness to discontinue treatment with trigger point injections and anesthetics, and reported baseline weekly recall pain over 40 on a 0–100 mm VAS. Exclusion criteria: severe psychiatric illness, current major depressive episode or screening BDI > 25, history of substance abuse, epilepsy, active cardiac disease, severe chronic obstructive pulmonary disease, active liver disease, renal impairment, documented autoimmune disease, current systemic infection, active cancer, active peptic ulcer or inflammatory bowel disease (irritable bowel syndrome excepted), unstable endocrine disorder, pregnancy or breastfeeding, concomitant use of psychotropic drugs (including antidepressants or phytotherapy), sympathicomimetics, long‐acting benzodiazepines, anticoagulants, antiepileptic drugs, centrally‐acting muscle relaxants, opioids, smoking (> 25 cigarettes a day) | |
| Interventions | MLN with stepwise increase starting from 25 mg/d to 200 mg/d Placebo Rescue and/or allowed medication: no details reported | |
| Outcomes | Pain: 1‐week recall pain intensity (VAS 0‐100). 30% and 50% and more pain reduction rates calculated by imputation method PGIC much or very much improved: reported as odds ratio (not suited for meta‐analysis) Fatigue: MFI Total Score (20‐100) Sleep problems: MOS Sleep Index I (50‐0) Quality of life: FIQ total score (0‐80) AEs: no details reported. Frequency of nausea, somnolence and insomnia not reported. No reports on SAEs Depression: BDI ‐II total score (0‐63) Anxiety: State‐Trait Anxiety Inventory (20‐80) Disability: FIQ single item (VAS 0‐10): not reported Sexual function: not assessed Cognitive disturbances: not assessed Tenderness: pressure pain threshold Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: each author certifies that he or she, or a member of his or her immediate family, has Funding: Pierre Fabre | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated list by sponsor |
| Allocation concealment (selection bias) | Low risk | Chronological order of the occurring visit 2 by sponsor |
| Blinding of participants and personnel (performance bias) | Unclear risk | No details reported |
| Blinding of outcome assessment (detection bias) | Unclear risk | No details reported about whether participants and outcome assessors of safety were adequately blinded to intervention |
| Incomplete outcome data (attrition bias) | Unclear risk | ITT by LOCF method |
| Selective reporting (reporting bias) | High risk | All predefined outcomes of study protocol NCT00757679 except FIQ disability reported |
| Group similarity at baseline | Low risk | No significant group differences in clinical and demographic variables at baseline |
| Sample size bias | High risk | < 50 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 59 outpatient research centers in USA Study period: October 2003‐July 2005 Study design: parallel Trial duration: washout period (weeks 1‐4), 2‐week baseline period, 27 weeks' therapy (3 weeks' titration, 24 weeks' stable dose); down‐titration 3‐9 days | |
| Participants | MLN 100 mg/d: N = 224: 95.1% women, 95.9% white, mean age 49.9 (SD 10.6) years; pain baseline (0‐100) 68.3 (SD 11.5) MLN 200 mg/d: N = 441: 95.9% women, 93.4% white, mean age 49.2 (SD 11.0) years; pain baseline (0‐100) 69.4 (SD 11.9) b N = 223: 95.5% women, 93.4% white, mean age 49.4 (SD 10.1) years; pain baseline (0‐100) 68.3 (SD 11.9) Inclusion criteria: 1990 ACR criteria; baseline VAS pain intensity rating between ≥ 50 (0‐100 scale) Exclusion criteria: severe psychiatric illness; current major depressive episode (as assessed by MINI); significant risk of suicide according to the investigator’s judgment; alcohol or other drug abuse; a history of significant cardiovascular, respiratory, endocrine, genitourinary, liver, or kidney disease; autoimmune disease; systemic infection; cancer or current chemotherapy; significant sleep apnoea; active peptic ulcer or inflammatory bowel disease | |
| Interventions | MLN 100 mg/d or 200 mg/d Placebo Rescue medication: hydrocodone up to 60 mg/d | |
| Outcomes | Pain: PED 24‐h recall pain score (VAS 0‐100); missing means and SDs provided on request PGIC much or very much improved: Reported (NRS 1‐7)* Fatigue: MFI total (NRS 20‐100); missing SDs reported on request Sleep problems: MOS‐Sleep Index I (NRS 0‐100); missing SDs provided on request HRQoL: FIQ total score (VAS 0‐100): missing SDs provided on request AEs: physical examination, ECGs, and laboratory analysis. AEs were assessed throughout the study based on spontaneous reporting by participants and investigators’ observation. Frequency of nausea, somnolence and insomnia reported Depression: BDI total score (NRS 0‐63): missing means and SDs provided on request Anxiety: FIQ (VAS 0‐10): not reported Disability: SF‐36 physical function (0‐50): missing means and SDs provided on request Sexual function: Arizona Sexual Function Scale (5‐50): SD not reported. Data not suited for quantitative analysis. Cognitive disturbances: MASQ cognitive function (NRS 38‐190) Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | *Completer analysis Conflicts of interest: Dr. Mease has received research grant support from Pfizer Inc, Cypress Bioscience, Inc., Forest Laboratories, Inc., Eli Lilly and Company, Allergan, Wyeth Pharmaceuticals, Jazz Pharmaceuticals, and Fralex Therapeutics. Dr. Clauw has received grant support from Cypress Bioscience, Inc. and serves as a consultant to Cypress Bioscience, Inc, Forest Laboratories, Inc., Pierre Fabre Médicament, Pfizer Inc, Eli Lilly and Company, Wyeth Pharmaceuticals, and Proctor and Gamble. Dr. Mease was an investigator of this study and a consultant; Dr. Clauw was a consultant for this study. As consultants, Drs. Mease and Clauw were involved in the study design, analysis of results, and preparation of the manuscript. Drs. Gendreau, Rao, and Kranzler are employees of Cypress Bioscience, Inc. Drs. Chen and Palmer are employees of Forest Laboratories, Inc. Funding: Forest Research Institute and Cypress Bioscience | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence using an interactive response system (details provided on request) |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details provided on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar‐details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | High risk | Standard deviations of outcome 'sexual dysfunction' not reported and not provided on request |
| Group similarity at baseline | Low risk | No significant differences in demographic and clinical variables at baseline |
| Sample size bias | Low risk | > 200 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 42 outpatient research centers in Japan Study period: March 2012‐December 2013 Study design: parallel Trial duration: 1‐2 weeks' screening, 14 weeks' treatment, 1 week dose tapering, 1 week follow‐up observation | |
| Participants | DLX (N = 191): 82% female; mean age 47.8 (SD 12.0) years; ethnicity not reported; 4.2% major depressive disorder; pain baseline (0‐10) 6.1 (SD 1.3) Placebo (N = 195): 84% female; mean age 49.5 (SD 11.7) years; ethnicity not reported; 3.6% major depressive disorder; pain baseline (0‐10) 6.1 (SD 1.3) Inclusion criteria: male and female outpatients aged 20‐75 years who met the ACR 1990 criteria of FM and had a BPI and average pain score ≥ 4 at visits 1 and 2 Exclusion criteria: past DLX treatment; serious or medically unstable disease, clinically significant abnormal laboratory values, or abnormal ECG findings; pain caused by non‐FM diseases; poorly controlled thyroid dysfunction; rheumatoid, inflammatory, or infectious arthritis; autoimmune disorders other than thyroid dysfunction; psychiatric disorders other than major depressive disorder within the past year; and suicidal tendencies as assessed using the C‐SSRS | |
| Interventions | DLX: 20 mg for 1 week, followed by 40 mg for 1 week and then 60 mg for 12 weeks during the treatment phase Placebo Rescue medication: participants were prohibited from using analgesics and drugs with analgesic effects, including nonsteroidal antiinflammatory drugs, anticonvulsants, pregabalin, neurotropin, anesthetics, opioids, and adrenocorticosteroids. The use of analgesics for up to 3 consecutive days and for up to a total of 10 days was permitted only for the treatment of AEs. Co‐administration of acetaminophen at doses up to 1500 mg/d was permitted | |
| Outcomes | Pain: BPI average pain score (NRS 0‐10) PGIC much or very much improved: NRS 1‐7; average scores reported; data not suited for data entry Fatigue: FIQ subscale fatigue (VAS 0‐10) Sleep problems: BPI subscale sleep interference (NRS 0‐10) HRQoL: FIQ total score (VAS 0‐80) AEs: safety was assessed on the basis of the presence or absence and incidence of AEs and adverse drug reactions (ADRs) reported during the treatment phase until the end of the follow‐up observation phase. Additionally, laboratory tests (hematology, clinical chemistry, and urinalysis), ECG, body weight, and vital signs were measured. The presence or absence of suicidal tendencies was assessed using the C‐SSRS. Frequency of nausea, somnolence and insomnia reported Depression: BDI II total score (NRS 0‐63) Anxiety: FIQ (VAS 0‐10) Disability: SF‐36 physical function (0‐100) Sexual function: not assessed Cognitive disturbances: not assessed Tenderness: not assessed | |
| Notes | Conflicts of interest: HM and TO are employees of Shionogi & Co. Ltd. LA is an employee of Eli Lilly Japan KK, MM, KO, and KN have provided consultancy services and MM and KO received compensation from Shionogi & Co Ltd. for their participation in this study. MM, KO, and KN did not receive any compensation for their input into this study. The authors confirm that there are no non‐financial competing interests to declare in relation to this article. Funding: Forest Research Institute and Cypress Bioscience | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Web‐based patient registration system (ACRONET Corp., Tokyo, Japan) with a stochastic minimization procedure |
| Allocation concealment (selection bias) | Low risk | Blinding was maintained until the end of the study by the person responsible for the study drug assignment |
| Blinding of participants and personnel (performance bias) | Low risk | The drug allocation controller confirmed the study drugs were indiscernible in terms of appearance, packaging, and labeling, and mock titration of placebo pills was also performed to maintain blinding |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described |
| Incomplete outcome data (attrition bias) | Low risk | ITT by BOCF method |
| Selective reporting (reporting bias) | Low risk | All predefined outcomes of study protocol NCT01552057 reported |
| Group similarity at baseline | Low risk | No significant group differences in demographic and clinical variables at baseline |
| Sample size bias | Unclear risk | 100‐199 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study; 27 outpatient research centers, USA Study period: 2006‐2008 Study design: parallel Trial duration: 7‐30 days' screening, 7 days' single‐blind placebo run‐in, 8 weeks: study was stopped by the sponsor for "business reasons" | |
| Participants | Desvenlafaxine (N =42): 100%female; mean age 47.8 (SD 10.5) years; ethnicity not reported; pain baseline scores not reported Placebo (N = 40): 100% female; mean age 46.9 (SD 12.7) years; ethnicity not reported; pain baseline scores not reported Pregabalin (N = 43): 100% female; mean age 46.7 (SD 11.7) years; ethnicity not reported; duration of FM and pain baseline not reported Inclusion criteria: FM diagnosed according to 1990 ACR criteria Exclusion criteria: unstable medical or psychological conditions that would compromise the participant's safety or put the subject at greater risk during study participation. Other painful conditions that may confound the diagnosis or assessment of FM; treatment with other drugs for FM within 14 days of study start or during the study | |
| Interventions | Desvenlafaxine 200 mg/d Pregabalin 450 mg/d Placebo Rescue medication: no details reported | |
| Outcomes | Pain: pain score (NRS 0‐10) across the last 7 days: no 30% and 50% and more reduction rates reported and not calculable PGIC much or very much improved: not assessed Fatigue: not assessed Sleep problems: not assessed HRQoL: not assessed AEs: no details reported. Frequency of nausea, somnolence and insomnia reported Depression: not assessed Anxiety: not assessed Disability: not assessed Sexual function: not assessed Cognitive disturbances: not assessed Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: not reported Funding: Wyeth/Pfizer | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No details reported |
| Allocation concealment (selection bias) | Unclear risk | No details reported |
| Blinding of participants and personnel (performance bias) | Unclear risk | No details reported |
| Blinding of outcome assessment (detection bias) | Unclear risk | No details reported |
| Incomplete outcome data (attrition bias) | Unclear risk | ITT‐analysis by LOCF |
| Selective reporting (reporting bias) | Low risk | Data reported as outlined in protocol |
| Group similarity at baseline | High risk | No significant differences in demographic data at baseline; pain baseline not reported |
| Sample size bias | High risk | < 50 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 38 outpatient research centers in USA and Puerto Rico Study period: June 2005‐June 2006 Study design: parallel Trial duration: 1 week screening, 26 weeks' therapy | |
| Participants | DLX 20/60 mg/d: N = 79; 97.5% female; 83.5% white; mean age 50.9 (SD 11.4) years; pain baseline (0‐10) 6.8 (SD 1.6); 27.9% current major depression DLX 60 mg/d: N = 150; 96.7% female; 84.7% white; mean age 51.8 (SD 10.6) years; pain baseline (0‐10) 6.5 (SD 1.4); 23.3% current major depression DLX 120 mg/d: N = 147; 97.3% female; 82.6% white; mean age 51.0 (SD 10.8) years; pain baseline (0‐10) 6.4 (SD 1.6); 23.1% current major depression Placebo: N = 144; 95.1% female; 82.6% white; mean age 50.3 (SD 10.9) years; pain baseline (0‐10) 6.6 (SD 1.7); 24.3% current major depression Inclusion criteria: ACR 1990 criteria; score ≥ 4 on the pain intensity item of the FIQ; age ≥ 18 years; with and without MDD Exclusion criteria: any current primary psychiatric diagnosis other than MDD; pain symptoms unrelated to FM that could interfere with interpretation of outcome measures; regional pain syndromes; multiple surgeries or failed back syndrome; a confirmed current or previous diagnosis of rheumatoid arthritis, inflammatory arthritis, or other autoimmune disease; unstable medical or psychiatric disorders; severe liver disease; current pregnancy or breast‐feeding; or a history of substance abuse within the past year. Participants who were judged by the investigator to be treatment‐refractory or whose response might be compromised by disability compensation issues in the opinion of the investigator were also excluded | |
| Interventions | DLX 20/60 mg/d or 60 mg/d or 120 mg/d Placebo Rescue and/or allowed medication: acetaminophen up to 2 g/d and aspirin up to 325 mg/d | |
| Outcomes | Pain: BPI average pain severity (NRS 0‐10) PGIC much or very much improved: reported Fatigue: MFI general fatigue (NRS 4‐20) Sleep problems: BPI sleep interference (NRS 0‐10): not reported HRQoL: FIQ score (VAS 0‐80) AEs: physical examination, ECGs, and laboratory analysis. AEs were assessed throughout the study based on spontaneous reporting by participants. Frequency of nausea, somnolence and insomnia reported Depression: BDI‐II total score (NRS 0‐63): incompletely reported Sexual function: not assessed Cognitive disturbances: MFI mental fatigue (NRS 4‐20) Global perceived improvement: PGIC (NRS 1‐7) Tenderness: mean tender point threshold (kg/cm²) Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: at doi:10.1016/j.pain. 2008.02.024. Page only accessible by fees or institutional access Funding: Eli Lilly and Company and Boehringer Ingelheim GmbH | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomization: computer‐generated random sequence using an interactive response system |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details reported on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar, details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described |
| Incomplete outcome data (attrition bias) | Unclear risk | Imputation using LOCF for efficacy data. ITT analysis |
| Selective reporting (reporting bias) | High risk | Outcomes of sleep, anxiety and depression not reported; depression scores only reported in ClinicalStudyResults.org for 20/60 mg DLX |
| Group similarity at baseline | Low risk | No significant differences in clinical and demographic variables at baseline |
| Sample size bias | Unclear risk | 50‐199 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: single‐center study, university hospital, USA Study period: November 2009‐April 2014 Study design: Parallel Trial duration: 6 weeks | |
| Participants | MLN (N = 23): 91% women, ethnicity not reported, mean age 46.9 (SD 11.5) years; pain baseline (0‐10) 5.8 (SD 1.8) Placebo (N = 23): 96% women, ethnicity not reported, mean age 47.5 (SD 12.0) years; pain baseline (0‐10) 5.1 (SD 1.8) Inclusion criteria: adults > 18 years; the ability to give informed consent; fulfilment of the 1990 ACR criteria for FM, including widespread pain Exclusion criteria: a relevant medical condition besides FM; current participation in another research protocol that could interfere with or influence the outcome measures of the present study; the inability to give informed consent; current use of analgesic drugs, anxiolytic drugs, antidepressants (all participants taking analgesic drugs or antidepressants before enrolment went through the appropriate washout phase before study entry); and previous treatment with MLN; study participants < 30 years of age and those who showed evidence for major depression | |
| Interventions | MLN 50 mg twice daily Placebo Rescue and/or allowed medication: participants were not allowed to take any analgesics during the study except acetaminophen (365 mg ≤ 4 times daily) | |
| Outcomes | Pain: daily pain intensity (VAS 0‐100). 30% and 50% and more pain reduction rates calculated by imputation method PGIC much or very much improved: not assessed Fatigue: 24‐ hours recall pain VAS 0‐10by electronic diary Sleep problems: not assessed HRQoL: not assessed AEs: no details of dropout due to AEs and frequency of SAEs reported. Frequency of nausea, somnolence and insomnia insufficiently reported (not suited for meta‐analysis) Depression: VAS 0‐100 Anxiety: VAS 0‐100 Disability: not assessed Sexual function: not assessed Cognitive disturbances: not assessed Tenderness: quantitative sensory testing was performed. Tenderness was not considered as a clinical outcome measure for the intervention. Dropout due to lack of efficacy: insufficiently reported (not suited for meta‐analysis) | |
| Notes | Conflicts of interest: none of the authors has any financial or other relationships that might lead to a conflict of interest. Funding: Pierre Fabre | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomization performed using Research Randomizer (www.randomizer.org) |
| Allocation concealment (selection bias) | Unclear risk | No details reported |
| Blinding of participants and personnel (performance bias) | Unclear risk | No details reported |
| Blinding of outcome assessment (detection bias) | Unclear risk | No details reported |
| Incomplete outcome data (attrition bias) | High risk | Completer analysis |
| Selective reporting (reporting bias) | High risk | Study protocol NCT01294059 available; no details of dropouts due to AEs and frequency of SAEs reported |
| Group similarity at baseline | Low risk | No significant differences in clinical and demographic variables at baseline |
| Sample size bias | High risk | < 50 participants per treatment arm |
| Study characteristics | ||
| Methods | Study setting: multicenter study with 12 outpatient research centers in USA Study period: not reported Study design: parallel Trial duration: 1‐4 weeks' wash out, 2 weeks' baseline and training, 12 weeks' therapy | |
| Participants | MLN once a day (N = 46): 98% women, 82% white, mean age 47.4 (SD 11.6) years; pain baseline scores not reported; 16% current depression MLN twice a day (N = 51): 98% women, 89% white, mean age 46.2 (SD 12.2) years; pain baseline scores not reported; 7% current depression Placebo (N = 28): 96% women, 79% white, mean age 48.0 (SD 8.4) years; pain baseline scores not reported; 32% current depression Inclusion criteria: 1990 ACR criteria; 18‐70 years Exclusion criteria: severe psychiatric illness excluding depression; significant risk of suicide according to the investigator’s judgement; alcohol or other drug abuse; a history of significant cardiovascular, respiratory, endocrine, genitourinary, liver or kidney disease; autoimmune disease; systemic infection; cancer or current chemotherapy; significant sleep apnoea; life expectancy < 1 year; active peptic ulcer or inflammatory bowel disease | |
| Interventions | MLN 200 mg/d, dose escalation within 3 weeks Placebo Rescue medication: hydrocodone up to 60 mg/d | |
| Outcomes | Pain: PED 24‐h recall pain score (VAS 0‐100) Global perceived improvement: not assessed Fatigue: FIQ VAS 0‐10. Data provided on request. OC analysis Sleep problems: Jenkins Sleep Survey total score (NRS). Data provided on request. OC analysis HRQoL: FIQ total score (VAS 0‐80). Data provided on request. OC analysis AEs: physical examination, ECGs, and laboratory analysis. AEs were assessed throughout the study based on spontaneous reporting by participants. Frequency of nausea, somnolence and insomnia not reported Depression: FIQ VAS 0‐10. Data provided on request. OC analysis Anxiety: FIQ VAS 0‐10. Data provided on request. OC analysis Disability: FIQ VAS 0‐10. Data provided on request. OC analysis Sexual function: not assessed Cognitive disturbances: not assessed Tenderness: not assessed Dropout due to lack of efficacy: reported | |
| Notes | Conflicts of interest: 3 authors were employed by Cypress Bioscience, 5 authors were consultants and 3 authors were shareholders for Cypress Bioscience Funding: authors were employed by Cypress Bioscience | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random sequence (details provided on request) |
| Allocation concealment (selection bias) | Low risk | Central independent unit (details provided on request) |
| Blinding of participants and personnel (performance bias) | Low risk | Double blind (number and appearance of placebo capsules similar, details reported on request) |
| Blinding of outcome assessment (detection bias) | Low risk | Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety adequately described |
| Incomplete outcome data (attrition bias) | High risk | OC analysis |
| Selective reporting (reporting bias) | Low risk | All outcomes reported or provided on request |
| Group similarity at baseline | High risk | Pain baseline scores not reported; higher proportion of participants with depression in placebo group |
| Sample size bias | High risk | < 50 participants in two treatment arms, 51 in the third arm |
ACR: American College of Rheumatology; AE: adverse event; BAI: Beck Anxiety Inventory; BDI: Beck Depression Inventory; BOCF: baseline observation carried forward (statistical method); BP: blood pressure; BPI: Brief Pain Inventory; bpm: beats per minute; C‐SSRS: Columbia‐Suicide Severity Rating Scale; CNS: central nervous system; DLX: duloxetine; DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ECG: electrocardiogram; FIQ: Fibromyalgia Impact Questionnaire; FM: fibromyalgia; GAD: generalized anxiety disorder; HDRS: Hamilton Depression Rating Scale; HRQoL: health‐related quality of life; IVRS: Interactive Voice Respone System; ITT: intention‐to‐treat analysis; LOCF: last observation carried forward (statistical method); MASQ: Multiple Ability Self‐report Questionnaire; MDD: major depressive disorder; MDHAQ: Multi‐Dimensional Health Assessment Questionnaire; MFI: Multidimensional Fatigue Inventory: MINI: Mini International Neuropsychiatric Interview; MLN: milnacipran; MMRM: mixed‐effects model repeated measures; MOS: Medical Outcomes Study; NRS: Numerical rating scale; NSAID: non‐steroidal anti‐inflammatory drug; OC: observed cases; PED: patient electronic diary; PGIC: Patient Global Impression of Change Inventory; QT: The Q‐T interval represents the time for both ventricular depolarization and repolarization to occur, and therefore roughly estimates the duration of an average ventricular action potential in the ECG; SAE: serious adverse effect; SSR: Society of Skeletal Radiology; SSRI: selective serotonin reuptake inhibitors; VAS: visual analog scale
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| RCT with cross‐over design with MLN and placebo for 6 weeks each in 19 participants: < 20 participants | |
| 21‐week RCT (parallel design) with MLN + CBT (N = 20), MLN + education (N = 19), and placebo + CBT (N = 19) | |
| 1‐year extension study, double‐blind, randomized, not control arm, of 3 doses of MLN (468 participants) | |
| 8‐week, open‐label period followed by a 52‐week, double‐blind, that were not placebo‐controlled, randomized to 1 or 2 doses of DLX (350 participants) | |
| 8‐week, open trial with venlafaxine in 15 participants | |
| Not RCT: 6‐month extension study, double‐blind, randomized,no control arm, of 2 doses of MLN (449 participants) | |
| Not RCT: case report of 1 patient with fibromyalgia, comorbid with premenstrual dysphoric disorder with a low dose of venlafaxine | |
| Not RCT: 6‐month extension phases with no control arm of 2 RCTs with DLX (492 participants) | |
| < 20 participants per treatment arm: RCT comparing 100 mg MLN with placebo for 8 weeks | |
| Data not suited for meta‐analysis: randomized, placebo‐controlled trial with 696 FM patients on 4 fixed oral doses of DVS SR (50 mg, 100 mg, 150 mg and 200 mg). Interim data analysis indicated that none of the 4 DVS SR treatment groups showed separation from placebo, and that there was a high placebo response rate. The study was discontinued because of the failure of DVS to meet the predefined efficacy criteria (pain reduction, health‐related quality of life (FIQ‐total score) and PGIC score). Details (means, SDs, absolute numbers) not reported | |
| No RCT: observational study without control group with 1700 participants | |
| < 20 participants per study arm: RCT with cross‐over design (5 weeks each period) and 1 participant comparing MLN with placebo | |
| < 20 participants per treatment arm: RCT comparing MLN with placebo in 17 participants each for 8 weeks | |
| Outcomes (change in pain threshold from baseline to week 6 of treatment, change in diffuse noxious inhibitory control, change in functional magnetic resonance imaging brain activation patterns during pressure stimulation) did not meet inclusion criteria of this review: RCT with cross‐over design with 6 weeks in each period comparing MLN and placebo in 22 participants | |
| < 10 participants per treatment arm: RCT with cross‐over design with 6 weeks for each period and 10 participants in MLN and 9 participants in placebo group | |
| Not RCT: 6‐week randomized trial without control group; number of participants not reported | |
| Not RCT: open‐label study with 57 pediatric participants over 53 weeks; no control group | |
| Not RCT: 50‐week extension study of NCT01552057 with DLX and no control arm with 149 participants | |
| Study duration < 4 weeks: 2‐week randomized, placebo‐controlled withdrawal design. Participants who had originally received MLN 100 mg/d for 12 weeks were re‐randomized to continue MLN (n = 178) or switch directly to placebo (n = 178); participants originally receiving placebo continued with placebo (n = 359): study duration < 4 weeks | |
| Not RCT: 12‐week, open trial with venlaxafine in 15 participants with no control arm | |
| Only outcome criterion of efficacy was 24‐h blood pressure and did not meet the inclusion criteria for this review: RCT comparing 200 mg MLN versus placebo in 321 participants with FM (of whom 50% were classified to be hypertensive at baseline ) for 7 weeks | |
| Study only published as abstract: RCT comparing 75 mg venlafaxine with placebo in 90 participants with FM for 6 weeks |
CBT: cognitive behavioral therapy;DLX: duloxetine; DVS SR: desvenlafaxine sustained release; FIQ: Fibromyalgia Impact Questionnaire; FM: fibromyalgia; HRQoL: health‐related quality of life; MLN: milnacipran; PGIC: Patient Global Impression of Change; RCT: randomized controlled trial
Characteristics of studies awaiting classification [ordered by study ID]
| Methods | Pilot, open, randomized clinical trial |
| Participants | Fibromyalgia in people with HIV 1+; number not reported |
| Interventions | Duloxetine, dosage and comparator drug not reported |
| Outcomes | Not reported |
| Notes | Study completed; no data available in clinicaltrials.gov or Medline |
| Methods | Not reported |
| Participants | Fibromyalgia; number not reported |
| Interventions | Duloxetine, dosage and comparator drug not reported |
| Outcomes | Not reported |
| Notes | The recruitment status of this study is unknown because the information has not been verified recently |
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Self‐reported pain relief of 50% or greater Show forest plot | 15 | 6918 | Risk Difference (IV, Random, 95% CI) | 0.09 [0.07, 0.11] |
| Analysis 1.1  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 1: Self‐reported pain relief of 50% or greater | ||||
| 1.1.1 Duloxetine | 7 | 2582 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.06, 0.14] |
| 1.1.2 Milnacipran | 8 | 4336 | Risk Difference (IV, Random, 95% CI) | 0.09 [0.06, 0.11] |
| 1.2 PGIC much or very much improved Show forest plot | 6 | 2918 | Risk Difference (M‐H, Random, 95% CI) | 0.19 [0.12, 0.26] |
| Analysis 1.2  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 2: PGIC much or very much improved | ||||
| 1.2.1 Duloxetine | 1 | 530 | Risk Difference (M‐H, Random, 95% CI) | 0.35 [0.27, 0.42] |
| 1.2.2 Milnacipran | 5 | 2388 | Risk Difference (M‐H, Random, 95% CI) | 0.15 [0.11, 0.19] |
| 1.3 Withdrawal due to adverse events Show forest plot | 15 | 7029 | Risk Difference (IV, Random, 95% CI) | 0.07 [0.04, 0.10] |
| Analysis 1.3  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 3: Withdrawal due to adverse events | ||||
| 1.3.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | ‐0.03 [‐0.09, 0.04] |
| 1.3.2 Duloxetine | 7 | 2642 | Risk Difference (IV, Random, 95% CI) | 0.05 [0.02, 0.07] |
| 1.3.3 Milnacipran | 7 | 4305 | Risk Difference (IV, Random, 95% CI) | 0.11 [0.07, 0.14] |
| 1.4 Serious adverse events Show forest plot | 13 | 6732 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.00] |
| Analysis 1.4  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 4: Serious adverse events | ||||
| 1.4.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.00 [‐0.05, 0.05] |
| 1.4.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.01] |
| 1.4.3 Milnacipran | 6 | 4218 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.01] |
| 1.5 Self‐reported fatigue Show forest plot | 12 | 6168 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.13 [‐0.18, ‐0.08] |
| Analysis 1.5  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 5: Self‐reported fatigue | ||||
| 1.5.1 Duloxetine | 5 | 1954 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.21, ‐0.03] |
| 1.5.2 Milnacpran | 7 | 4214 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.21, ‐0.07] |
| 1.6 Self‐reported sleep problems Show forest plot | 8 | 4547 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐0.15, 0.01] |
| Analysis 1.6  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 6: Self‐reported sleep problems | ||||
| 1.6.1 Duloxetine | 3 | 1382 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.31, ‐0.10] |
| 1.6.2 Milnacipran | 5 | 3165 | Std. Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.05, 0.10] |
| 1.7 Self‐reported health‐related quality of life Show forest plot | 14 | 6861 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.25, ‐0.15] |
| Analysis 1.7  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 7: Self‐reported health‐related quality of life | ||||
| 1.7.1 Duloxetine | 7 | 2604 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.30, ‐0.13] |
| 1.7.2 Milnacipran | 7 | 4257 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.19 [‐0.25, ‐0.12] |
| 1.8 Self‐reported pain relief of 30% or greater Show forest plot | 15 | 6924 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.08, 0.12] |
| Analysis 1.8  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 8: Self‐reported pain relief of 30% or greater | ||||
| 1.8.1 Duloxetine | 7 | 2588 | Risk Difference (IV, Random, 95% CI) | 0.11 [0.07, 0.15] |
| 1.8.2 Milnacipran | 8 | 4336 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.07, 0.13] |
| 1.9 Self‐reported mean pain intensity Show forest plot | 16 | 7014 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.27, ‐0.17] |
| Analysis 1.9  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 9: Self‐reported mean pain intensity | ||||
| 1.9.1 Desvenlafaxine | 1 | 82 | Std. Mean Difference (IV, Random, 95% CI) | 0.16 [‐0.27, 0.59] |
| 1.9.2 Duloxetine | 7 | 2619 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.26 [‐0.35, ‐0.18] |
| 1.9.3 Milncipran | 8 | 4313 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.26, ‐0.13] |
| 1.10 Self‐reported depression Show forest plot | 14 | 6478 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.21, ‐0.11] |
| Analysis 1.10  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 10: Self‐reported depression | ||||
| 1.10.1 Duloxetine | 7 | 2264 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.25 [‐0.34, ‐0.17] |
| 1.10.2 Milnacipran | 7 | 4214 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.17, ‐0.05] |
| 1.11 Self‐reported anxiety Show forest plot | 9 | 3533 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐0.21, 0.05] |
| Analysis 1.11  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 11: Self‐reported anxiety | ||||
| 1.11.1 Duloxetine | 4 | 1403 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐0.17, 0.04] |
| 1.11.2 Milnacipran | 5 | 2130 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.36, 0.13] |
| 1.12 Self‐reported disability Show forest plot | 13 | 6789 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.26, ‐0.16] |
| Analysis 1.12  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 12: Self‐reported disability | ||||
| 1.12.1 Duloxetine | 7 | 2602 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.29 [‐0.37, ‐0.21] |
| 1.12.2 Milnacipran | 6 | 4187 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.22, ‐0.10] |
| 1.13 Self‐reported cognitive disturbances Show forest plot | 8 | 5444 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.21, ‐0.10] |
| Analysis 1.13  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 13: Self‐reported cognitive disturbances | ||||
| 1.13.1 Duloxetine | 3 | 1360 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.27 [‐0.38, ‐0.16] |
| 1.13.2 Milnacipran | 5 | 4084 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.18, ‐0.05] |
| 1.14 Tenderness Show forest plot | 5 | 1444 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.33, ‐0.09] |
| Analysis 1.14  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 14: Tenderness | ||||
| 1.14.1 Duloxetine | 4 | 1364 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.23 [‐0.35, ‐0.12] |
| 1.14.2 Milnacipran | 1 | 80 | Std. Mean Difference (IV, Random, 95% CI) | 0.12 [‐0.31, 0.56] |
| 1.15 Withdrawal due to lack of efficacy Show forest plot | 14 | 6924 | Risk Difference (IV, Random, 95% CI) | ‐0.03 [‐0.04, ‐0.02] |
| Analysis 1.15  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 15: Withdrawal due to lack of efficacy | ||||
| 1.15.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.07 [‐0.02, 0.16] |
| 1.15.2 Duloxetine | 7 | 2642 | Risk Difference (IV, Random, 95% CI) | ‐0.04 [‐0.06, ‐0.02] |
| 1.15.3 Milnacipran | 6 | 4200 | Risk Difference (IV, Random, 95% CI) | ‐0.02 [‐0.04, ‐0.01] |
| 1.16 Nausea Show forest plot | 12 | 6606 | Risk Difference (IV, Random, 95% CI) | 0.16 [0.14, 0.19] |
| Analysis 1.16  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 16: Nausea | ||||
| 1.16.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.04 [‐0.10, 0.18] |
| 1.16.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | 0.19 [0.15, 0.22] |
| 1.16.3 Milnacipran | 5 | 4092 | Risk Difference (IV, Random, 95% CI) | 0.15 [0.12, 0.18] |
| 1.17 Somnolence Show forest plot | 7 | 2514 | Risk Difference (IV, Random, 95% CI) | 0.05 [0.02, 0.08] |
| Analysis 1.17  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 17: Somnolence | ||||
| 1.17.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | ‐0.05 [‐0.17, 0.06] |
| 1.17.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | 0.06 [0.03, 0.09] |
| 1.18 Insomnia Show forest plot | 9 | 5387 | Risk Difference (M‐H, Random, 95% CI) | 0.03 [0.01, 0.04] |
| Analysis 1.18  Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 18: Insomnia | ||||
| 1.18.1 Desvenlafaxine | 1 | 82 | Risk Difference (M‐H, Random, 95% CI) | ‐0.08 [‐0.18, 0.03] |
| 1.18.2 Duloxetine | 4 | 1684 | Risk Difference (M‐H, Random, 95% CI) | 0.04 [0.01, 0.07] |
| 1.18.3 Milnacipran | 4 | 3621 | Risk Difference (M‐H, Random, 95% CI) | 0.03 [0.01, 0.04] |
Study flow diagram
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 1: Self‐reported pain relief of 50% or greater
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 2: PGIC much or very much improved
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 3: Withdrawal due to adverse events
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 4: Serious adverse events
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 5: Self‐reported fatigue
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 6: Self‐reported sleep problems
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 7: Self‐reported health‐related quality of life
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 8: Self‐reported pain relief of 30% or greater
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 9: Self‐reported mean pain intensity
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 10: Self‐reported depression
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 11: Self‐reported anxiety
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 12: Self‐reported disability
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 13: Self‐reported cognitive disturbances
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 14: Tenderness
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 15: Withdrawal due to lack of efficacy
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 16: Nausea
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 17: Somnolence
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 18: Insomnia
| Serotonin noradrenaline reuptake inhibitors compared with placebo for fibromyalgia ‐ studies with parallel design | ||||||
| Patient or population: people with fibromyalgia Settings: study centers in North, Central and South America, Asia and Europe Intervention: serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) Comparison: placebo | ||||||
| Outcomes | Probable outcome with intervention (95% CI) | Probable outcome with placebo | Relative effect SMD or risk difference | No of participants | Quality of the evidence | Comments |
|---|---|---|---|---|---|---|
| Self‐reported pain relief of 50% or greater | 309 per 1000 (282 to 344) | 210 per 1000 | RD 0.09 (0.07 to 0.11) | 6918 (15 studies) | ⊕⊕⊝⊝ | NNTB 11 (95% CI 9 to 14) |
| Patient Global Impression to be much or very much improved (PGIC) | 519 per 1000 (459 to 573) | 293 per 1000 | RD 0.19 (0.12 to 0.26) | 2918 (6 studies) | ⊕⊕⊝⊝ | NNTB 5 (95% CI 4 to 8) |
| Self‐reported fatigue (20‐100 scale) Higher scores indicate higher fatigue problem levels | Mean fatigue | Baseline mean score 69.4 (SD 12.3)3 | SMD ‐0.13 (‐0.18 to ‐0.08) | 6168 (12 studies) | ⊕⊕⊝⊝ | NNTB 18 (95% CI 12 to 29) |
| Self‐reported sleep problems (0‐100 scale) Higher scores indicate higher sleep problem levels | Mean sleep problems | Baseline mean score 68.0 (23.8)4 | SMD ‐0.07 (‐0.15 to 0.01) | 4547 (8 studies) | ⊕⊕⊝⊝ | NNTB not calculated due to lack of statistically significant difference |
| Self‐reported health‐related quality of life (0‐100 scale) Higher scores indicate higher burden of disease (lower quality of life) | Mean health‐related quality of life problems score was 3.9 points lower (2.3 to | Baseline mean score 57.9 (SD | SMD ‐0.20 (‐0.25 to ‐0.15) | 6861 (14 studies) | ⊕⊕⊝⊝ | NNTB 11 (95% CI 8 to 14) |
| Tolerability (withdrawal due to adverse events) | 191 per 1000 (172 to 210) | 102 per 1000 | RD 0.07 (0.04 to 0.10) | 7029 (15 studies) | ⊕⊕⊝⊝ | NNTH 14 (95% CI 10 to 25) |
| Safety (serious adverse events) | 18 per 1000 (16 to 20) | 21 per 1000 | RD ‐0.00 (‐0.01 to 0.00) | 6732 (13 studies) | ⊕⊝⊝⊝ | NNTH not calculated due to lack of statistically significant difference |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; FIQ: Fibromyalgia Impact Questionnaire; MFI: Multidimensional Fatigue Inventory; MOS‐Sleep problem index: Medical Outcome Study ‐ sleep problem index; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harm; NRS: numerical rating scale; RD: risk difference; SMD: standardized mean difference; VAS: visual analog scale | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded once: indirectness: participants with major medical diseases and mental disorders except major depression excluded in > 50% of studies | ||||||
| Outcome | Number of participants (studies) | Effect size RD (95% CI) | Test for overall effect P value | Heterogeneity I² (%)
| Test of interaction: effect estimate and P value |
| Self‐reported pain relief 50% or greater |
|
|
|
| Z = 0.78; P = 0.43 |
| Only North American participants | 3935 (8) | 0.10 (0.08 to 0.13) | < 0.001 | 0 | |
| Only European participants | 960 (2) | 0.06 (0.01 to 0.12) | 0.02 | 0 |
|
| Withdrawal due to adverse events |
|
|
|
| Z = 1.14; P = 0.25 |
| Only North American participants | 3935 (8) | 0.08 (0.04 to 0.13) | < 0.0002 | 71 | |
| Only European participants | 960 (2) | 0.12 (0.08 to 0.17) | < 0.0001 | 0 |
|
| CI: confidence interval; RD: risk difference; SNRIs: serotonin and noradrenaline reuptake inhibitors | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Self‐reported pain relief of 50% or greater Show forest plot | 15 | 6918 | Risk Difference (IV, Random, 95% CI) | 0.09 [0.07, 0.11] |
| 1.1.1 Duloxetine | 7 | 2582 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.06, 0.14] |
| 1.1.2 Milnacipran | 8 | 4336 | Risk Difference (IV, Random, 95% CI) | 0.09 [0.06, 0.11] |
| 1.2 PGIC much or very much improved Show forest plot | 6 | 2918 | Risk Difference (M‐H, Random, 95% CI) | 0.19 [0.12, 0.26] |
| 1.2.1 Duloxetine | 1 | 530 | Risk Difference (M‐H, Random, 95% CI) | 0.35 [0.27, 0.42] |
| 1.2.2 Milnacipran | 5 | 2388 | Risk Difference (M‐H, Random, 95% CI) | 0.15 [0.11, 0.19] |
| 1.3 Withdrawal due to adverse events Show forest plot | 15 | 7029 | Risk Difference (IV, Random, 95% CI) | 0.07 [0.04, 0.10] |
| 1.3.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | ‐0.03 [‐0.09, 0.04] |
| 1.3.2 Duloxetine | 7 | 2642 | Risk Difference (IV, Random, 95% CI) | 0.05 [0.02, 0.07] |
| 1.3.3 Milnacipran | 7 | 4305 | Risk Difference (IV, Random, 95% CI) | 0.11 [0.07, 0.14] |
| 1.4 Serious adverse events Show forest plot | 13 | 6732 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.00] |
| 1.4.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.00 [‐0.05, 0.05] |
| 1.4.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.01] |
| 1.4.3 Milnacipran | 6 | 4218 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.01] |
| 1.5 Self‐reported fatigue Show forest plot | 12 | 6168 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.13 [‐0.18, ‐0.08] |
| 1.5.1 Duloxetine | 5 | 1954 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.21, ‐0.03] |
| 1.5.2 Milnacpran | 7 | 4214 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.21, ‐0.07] |
| 1.6 Self‐reported sleep problems Show forest plot | 8 | 4547 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐0.15, 0.01] |
| 1.6.1 Duloxetine | 3 | 1382 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.31, ‐0.10] |
| 1.6.2 Milnacipran | 5 | 3165 | Std. Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.05, 0.10] |
| 1.7 Self‐reported health‐related quality of life Show forest plot | 14 | 6861 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.25, ‐0.15] |
| 1.7.1 Duloxetine | 7 | 2604 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.30, ‐0.13] |
| 1.7.2 Milnacipran | 7 | 4257 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.19 [‐0.25, ‐0.12] |
| 1.8 Self‐reported pain relief of 30% or greater Show forest plot | 15 | 6924 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.08, 0.12] |
| 1.8.1 Duloxetine | 7 | 2588 | Risk Difference (IV, Random, 95% CI) | 0.11 [0.07, 0.15] |
| 1.8.2 Milnacipran | 8 | 4336 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.07, 0.13] |
| 1.9 Self‐reported mean pain intensity Show forest plot | 16 | 7014 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.27, ‐0.17] |
| 1.9.1 Desvenlafaxine | 1 | 82 | Std. Mean Difference (IV, Random, 95% CI) | 0.16 [‐0.27, 0.59] |
| 1.9.2 Duloxetine | 7 | 2619 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.26 [‐0.35, ‐0.18] |
| 1.9.3 Milncipran | 8 | 4313 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.26, ‐0.13] |
| 1.10 Self‐reported depression Show forest plot | 14 | 6478 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.21, ‐0.11] |
| 1.10.1 Duloxetine | 7 | 2264 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.25 [‐0.34, ‐0.17] |
| 1.10.2 Milnacipran | 7 | 4214 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.17, ‐0.05] |
| 1.11 Self‐reported anxiety Show forest plot | 9 | 3533 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐0.21, 0.05] |
| 1.11.1 Duloxetine | 4 | 1403 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐0.17, 0.04] |
| 1.11.2 Milnacipran | 5 | 2130 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.36, 0.13] |
| 1.12 Self‐reported disability Show forest plot | 13 | 6789 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.26, ‐0.16] |
| 1.12.1 Duloxetine | 7 | 2602 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.29 [‐0.37, ‐0.21] |
| 1.12.2 Milnacipran | 6 | 4187 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.22, ‐0.10] |
| 1.13 Self‐reported cognitive disturbances Show forest plot | 8 | 5444 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.21, ‐0.10] |
| 1.13.1 Duloxetine | 3 | 1360 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.27 [‐0.38, ‐0.16] |
| 1.13.2 Milnacipran | 5 | 4084 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.18, ‐0.05] |
| 1.14 Tenderness Show forest plot | 5 | 1444 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.33, ‐0.09] |
| 1.14.1 Duloxetine | 4 | 1364 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.23 [‐0.35, ‐0.12] |
| 1.14.2 Milnacipran | 1 | 80 | Std. Mean Difference (IV, Random, 95% CI) | 0.12 [‐0.31, 0.56] |
| 1.15 Withdrawal due to lack of efficacy Show forest plot | 14 | 6924 | Risk Difference (IV, Random, 95% CI) | ‐0.03 [‐0.04, ‐0.02] |
| 1.15.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.07 [‐0.02, 0.16] |
| 1.15.2 Duloxetine | 7 | 2642 | Risk Difference (IV, Random, 95% CI) | ‐0.04 [‐0.06, ‐0.02] |
| 1.15.3 Milnacipran | 6 | 4200 | Risk Difference (IV, Random, 95% CI) | ‐0.02 [‐0.04, ‐0.01] |
| 1.16 Nausea Show forest plot | 12 | 6606 | Risk Difference (IV, Random, 95% CI) | 0.16 [0.14, 0.19] |
| 1.16.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.04 [‐0.10, 0.18] |
| 1.16.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | 0.19 [0.15, 0.22] |
| 1.16.3 Milnacipran | 5 | 4092 | Risk Difference (IV, Random, 95% CI) | 0.15 [0.12, 0.18] |
| 1.17 Somnolence Show forest plot | 7 | 2514 | Risk Difference (IV, Random, 95% CI) | 0.05 [0.02, 0.08] |
| 1.17.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | ‐0.05 [‐0.17, 0.06] |
| 1.17.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | 0.06 [0.03, 0.09] |
| 1.18 Insomnia Show forest plot | 9 | 5387 | Risk Difference (M‐H, Random, 95% CI) | 0.03 [0.01, 0.04] |
| 1.18.1 Desvenlafaxine | 1 | 82 | Risk Difference (M‐H, Random, 95% CI) | ‐0.08 [‐0.18, 0.03] |
| 1.18.2 Duloxetine | 4 | 1684 | Risk Difference (M‐H, Random, 95% CI) | 0.04 [0.01, 0.07] |
| 1.18.3 Milnacipran | 4 | 3621 | Risk Difference (M‐H, Random, 95% CI) | 0.03 [0.01, 0.04] |
