Background This controlled, randomized study investigated the hypothesis that the combined use of pregabalin plus paroxetine for fibromyalgia management would be associated with comparable Somatic Symptoms Scale‐8 (SSS‐8) and Center for Epidemiological Studies Depression Scale (CESDS) scores, but higher tolerability than the combined use of pregabalin plus either amitriptyline or venlafaxine.

Methods After institutional ethics committee approval, 75 female subjects diagnosed with fibromyalgia and in receipt of pregabalin (75 mg/day) were randomly allocated to concurrently receive amitriptyline (25 mg/day; n = 24), venlafaxine (75 mg/day; n = 25), or paroxetine (25 mg/day; n = 26). All patients were assessed bimonthly for 6 consecutive months for changes in SSS‐8 and CESDS scores, life satisfaction, mood, sleep quality, fatigue, medication tolerability, and adverse events.

Results Compared with pregabalin plus amitriptyline or venlafaxine, the combined use of pregabalin plus paroxetine in fibromyalgia patients resulted in significantly lower SSS‐8 and CESDS scores from 18 (P < 0.05) and 10 weeks (P < 0.001) after the initiation of study medications, respectively; higher medication tolerability (P < 0.001); improved life satisfaction, mood, and sleep quality at most observation times (P < 0.05); and fewer instances of dry mouth and elevated blood pressure (P < 0.02). Medication termination due to poor tolerability was observed most frequently in the venlafaxine group (P < 0.05), while drowsiness, dizziness, blurred vision, abnormal taste, hunger, hallucination, urination problems, and sexual dysfunction were observed most frequently in the amitriptyline group (P < 0.02).