Yeephu 2013.

Study characteristics
Methods	Study setting: single centre study at the Department of Rehabilitation Medicine and Pain Clinic, Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand Study period: December 2008 to December 2011 Study design: parallel Duration therapy: the investigational drug was introduced to subjects at a lower starting dose of 7.5 mg (half tablet) and titrated up to the randomised dose over 1 or 2 weeks and then continued with stable dosage for 13 weeks
Participants	Participants: Mirtazapine 15 mg: N = 13; 100% women, 100% Thai, mean age 42.7 (SD 12.6) years; pain baseline (0 ‐ 100) 60.2 (SD 14.1): years after diagnosis 1.1 (SD 1.3) Mirtazapine 30 mg: N = 14; 100% women, 100% Thai, mean age 43.9 (SD 9.4) years; pain baseline (0 ‐ 100) 63.7 (SD 12.8): years after diagnosis 0.8 (SD 1.1) Placebo: N = 13; 100% women, 100% Thai, mean age 47.4 (SD 10.5) years; pain baseline (0‐10) 60.2 (SD 14.1): years after diagnosis 1.1 (SD 1.3) Inclusion criteria: ACR 1990 criteria; age 18 years or older; pain score of ≥ 40 on a 100 VAS during screening period; descended from Thai parents Exclusion criteria: Any severe or unstable physical or psychiatric disorder; inflammation, injury, or trauma in the previous month; substance abuse within the past year; serious suicide risk; comorbid inflammatory rheumatic diseases such as systemic lupus erythematosus or rheumatoid arthritis; were pregnant or breastfeeding; had allergic history to any constituent of investigational products; or had severe allergic reactions to multiple medications. Additional exclusion were use of medications or herbal agents with CNS activity; regular use of analgesics, with the exception of acetaminophen up to 2 g/day, and chronic use of sedatives/hypnotics. Individuals who were unable to discontinue medications that might affect the study results (i.e. all antidepressants; mood stabilisers; antipsychotics; sleep aids, such as hypnotics; tranquillizers; sedating antihistamines and benzodiazepines; all analgesics, including anticonvulsants; muscle relaxants; stimulant medications, such as dextroamphetamine and methylphenidate; any other medications used for the treatment of FM) or were unable to adhere to the follow‐up schedule of the study were excluded, as were participants who would not agree with avoidance or stable maintenance of unconventional or alternative therapies, such as Thai traditional massage. Participants with FM with concurrent depressive disorder identified at screening were not excluded. During the index visit, all participants were interviewed by the counselling psychologist about thoughts of harming themselves and/or suicidal ideation. If those risks were detected, the individual was withdrawn from the study
Interventions	Active drug: Mirtazapine 7.5 mg/d and titrated up to the randomised dose of 15 mg/d or 30 mg/d over 1 or 2 weeks and then continued with stable dosage for 13 weeks Placebo: 14 to 15 weeks Rescue medication and allowed co‐therapies: not reported
Outcomes	Primary outcomes Participant‐reported pain relief of 50% or greater: pain, time frame not reported (VAS 0 ‐ 100); number of responders not reported. Calculated by imputation method (Furukawa 2005) PGIC very much improved: assessed; only rates of 'any improvement' reported Serious AEs: "Patients were encouraged to contact the investigators at any time for consultation regarding any symptoms of concern to them." No reports of physical examination or laboratory test Withdrawal due to AEs: reported Secondary outcomes Participant‐reported pain relief of 30% or greater: pain, time frame not reported (VAS 0 ‐ 100); number of responders reported PGIC much improved: assessed; only rates of 'any improvement' reported Participant‐reported sleep problems: Jenkins Sleep Scale (NRS 0 ‐ 20). No SDs reported and not provided on request. SD calculated according to Cochrane Handbook based on P value (0.1) Participant‐reported fatigue: FIQ, subscale fatigue (VAS 0 ‐ 10); not reported and not provided on request Participant‐reported mean pain intensity: pain, time frame not reported (VAS 0 ‐ 100). SD extracted from figure Participant‐reported improvement of health‐related quality of life of 20% or greater: FIQ (VAS 0 ‐ 100). SD not reported. SD calculated according to Cochrane Handbook based on P value (0.1). Calculated by imputation method (Furukawa 2005) Participant‐reported negative mood: Hamilton Depression Rating Scale (0 ‐ 53). SD not reported. SD calculated according to Cochrane Handbook based on P value (0.1) (Higgins 2011) Withdrawal due to lack of efficacy: reported Any AEs: methods of assessment and data not reported and not provided on request Specific AEs: methods of assessment not reported and not provided on request. Weight gain and somnolence reported. No reports on technical findings
Notes	Funding sources: this study was supported by a scholarship from the Commission on Higher Education Staff Development Project for the Joint PhD Programme in Biopharmaceutical Sciences, Thailand. Mirtazapine used in this study was purchased from a retail pharmacy distributor at market prices Declaration of interest of primary investigators: authors reported none
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) All outcomes	Unclear risk	No details reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Participant‐reported outcomes; blinding of participants to intervention not adequately described. Blinding of outcome assessors of safety not adequately described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Baseline observation forward method
Selective reporting (reporting bias)	High risk	Outcome fatigue not reported as outlined in NCT00919295
Sample size	High risk	< 50 participants per treatment arm
Group similarity at baseline	Low risk	No significant differences in demographic and clinical baseline characteristics of the study groups

ACR: American College of Rheumatology; AE: adverse event; FIQ: Fibromyalgia Impact Questionnaire; FM: fibromyalgia; MAO: monoamine oxidase; N = number of participants; NRS: numeric rating scale; SD: standard deviation; VAS: visual analogue scale.