Efficacy of duloxetine on painful physical symptoms in major depressive disorder for patients with clinically significant painful physical symptoms at baseline: a meta-analysis of 11 double-blind, placebo-controlled clinical trials.

Although the diagnosis of major depressive disorder (MDD) is based on a number of core symptoms, painful physical symptoms are increasingly recognized as frequently associated symptoms that have clinical relevance for the patient's outcome.1 In a naturalistic study of 573 outpatients with MDD, pain was reported by more than two-thirds of depressed patients at baseline, with the severity of pain rated as mild in 25% of patients, moderate in 30%, and severe in 14%.2 In the Re-Engineering Systems for Primary Care Treatment of Depression (RESPECT) study, 405 patients with depression were followed in primary care settings while receiving either treatment as usual or enhanced intervention.3 At baseline, painful physical symptoms of sufficient severity to impact daily activities, at least moderately, were present in 42% of the patients. Although there was some improvement in pain, the degree of severity was at least moderate for 32% of the patients at 6 months, and the severity of pain negatively impacted both response and remission rates with treatment.3 Similarly, Leuchter and colleagues4 found that, among patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, 80% of patients reported having painful physical symptoms, and these symptoms were associated with lower remission rates and with longer time to remission. However, in the STAR*D trial, painful physical symptoms were no longer predictive of depression outcomes after adjustment for race, medical comorbidity, and severity of depression.4 Other studies have demonstrated a negative impact of painful physical symptoms on outcome measures such as increase in treatment costs,5 decrease in productivity,6 and poor quality of life.7 Thus, painful physical symptoms associated with depression present an important target for therapeutic intervention. The neurobiological pathways underlying depression and pain suggest commonalities in the activity of serotonin and norepinephrine transmission.8 Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) that has demonstrated both antidepressant and analgesic efficacy within different conditions including MDD, fibromyalgia, diabetic peripheral neuropathic pain, osteoarthritis, and chronic low back pain.9 With regard to studies of MDD, duloxetine showed an analgesic effect on painful physical symptoms that was partially independent of the improvement in MDD.10,11 In a pooled analysis of 2 identical studies, duloxetine 60 mg once daily significantly improved painful physical symptoms compared with placebo treatment.11 Other pooled analyses of duloxetine trials also indicated efficacy on painful physical symptoms associated with MDD, suggesting analgesic activity.12,13 Duloxetine's efficacy was demonstrated on painful physical symptoms in elderly patients with MDD14 and in patients with MDD with at least moderate pain.15 However, there have also been other analyses that have questioned whether duloxetine does effectively reduce painful physical symptoms associated with depression. One meta-analysis of duloxetine trials, based on 5 studies, did not support the analgesic efficacy for painful physical symptoms in MDD.16 Another meta-analysis, based on 8 studies, compared duloxetine, paroxetine, or both with placebo in patients with MDD.17 Results of that meta-analysis of pain outcomes from those trials suggested that both duloxetine and paroxetine significantly improved painful physical symptoms compared with placebo, but there was not a significant difference between paroxetine and duloxetine. Clinical Points ▪ Many patients with depression also experience painful physical symptoms. ▪ In patients with painful physical symptoms, duloxetine 60 mg once daily had a clinically significant impact on those symptoms and in reducing the severity of depressive symptoms. Given the heterogeneity of the above analyses with regard to studies and outcomes, and the differences in analytic methods used to evaluate the efficacy of painful physical symptoms associated with MDD, the current meta-analysis was undertaken to examine the efficacy of duloxetine for both painful physical symptoms and depressive illness based on the Eli Lilly and Company global database of duloxetine clinical trials, with 11 double-blind, placebo-controlled studies selected for the analyses. Because the majority of these studies were not designed to specifically address painful physical symptoms, patients with MDD in these studies were generally not required to have these symptoms at baseline, which would necessarily limit conclusions about efficacy for painful physical symptoms in the absence of the symptoms. Therefore, the present meta-analysis also specifically examined the efficacy of duloxetine for painful physical symptoms in patients with MDD who had clinically significant painful physical symptoms at baseline.