Randomized, Double-blind, Placebo-controlled Phase III Trial of Duloxetine Monotherapy in Japanese Patients With Chronic Low Back Pain

Shinichi Konno, MD, PhD; Natsuko Oda, MS; Toshimitsu Ochiai, MS; Levent Alev, MD


Spine. 2016;41(22):1709-1717. 

In This Article

Abstract and Introduction


Study Design. A 14-week, randomized, double-blind, multicenter, placebo-controlled study of Japanese patients with chronic low back pain (CLBP) who were randomized to either duloxetine 60 mg once daily or placebo.

Objective. This study aimed to assess the efficacy and safety of duloxetine monotherapy in Japanese patients with CLBP.

Summary of Background Data. In Japan, duloxetine is approved for the treatment of depression, diabetic neuropathic pain, and pain associated with fibromyalgia; however, no clinical study of duloxetine has been conducted for CLBP.

Methods. The primary efficacy measure was the change in the Brief Pain Inventory (BPI) average pain score from baseline to Week 14. Secondary efficacy measures included BPI pain (worst pain, least pain, pain right now), Patient's Global Impression of Improvement, Clinical Global Impressions of Severity, and Roland-Morris Disability Questionnaire, among other measures, and safety and tolerability.

Results. In total, 458 patients were randomized to receive either duloxetine (n = 232) or placebo (n = 226). The BPI average pain score improved significantly in the duloxetine group compared with that in the placebo group at Week 14 [-2.43 ± 0.11 vs. −1.96 ± 0.11, respectively; between-group difference (95% confidence interval), − 0.46 [-0.77 to-0.16]; P = 0.0026]. The duloxetine group showed significant improvement in many secondary measures compared with the placebo group, including BPI pain (least pain, pain right now) (between-group difference: −1.69 ± 0.10, P = 0.0009; −2.42 ± 0.12, P P = 0.0230, respectively), Patient's Global Impression of Improvement (2.46 ± 0.07, P = 0.0026), Clinical Global Impressions of Severity (-1.46 ± 0.06, P = 0.0019), and Roland-Morris Disability Questionnaire (-3.86 ± 0.22, P = 0.0439). Adverse events occurring at a significantly higher incidence in the duloxetine group were somnolence, constipation, nausea, dizziness, and dry mouth, most of which were mild or moderate in severity and were resolved or improved.

Conclusion. Duloxetine 60 mg was effective and well tolerated in Japanese CLBP patients.

Level of Evidence: 2


Low back pain (LBP) has an estimated lifetime prevalence of 83%, and approximately 25% to 35% of Japanese patients complain of LBP.[1,2] Chronic LBP (CLBP) is usually defined as pain persisting for at least 3 months. Patients with acute LBP show rapid improvement within 1 month after onset, followed by gradual improvement until 3 months after onset; however, a high incidence of protracted treatment has been reported along with low patient satisfaction with treatment.[3,4]

Treatment strategies for LBP include drug therapy, physical and orthotic therapy, exercise, nerve block injection, and surgery. Nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, anxiolytics, muscle relaxants, antidepressants, and opioids are recommended by international[5,6] and Japanese LBP treatment guidelines.[7] In Japan, NSAIDs, acetaminophen, and some opioids have been approved for the treatment of LBP. First-line treatment with NSAIDs has been demonstrated to be effective for acute LBP, but its efficacy for CLBP has not been confirmed,[8] and possible gastrointestinal, cardiac, and renal[9] adverse drug reactions (ADRs) should be considered with long-term use. The evidence of the effectiveness of other drugs is insufficient, and concerns about ADRs remain.

Duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI), inhibits the reuptake of serotonin and norepinephrine, which are neurotransmitters of the descending pain inhibitory pathways. Although the exact mechanisms of central pain inhibition by duloxetine in humans are unknown, it is believed that duloxetine increases synaptic cleft levels of these neurotransmitters in the spinal and supraspinal pathways, activating the descending pain inhibitory systems and producing an analgesic effect.[10] Three clinical studies in patients with CLBP have been conducted overseas.[11–13] Two of these provided clinical evidence that duloxetine significantly reduces pain compared with placebo and is well-tolerated. Based on these results and those of clinical studies of osteoarthritis patients, duloxetine has been approved for "chronic musculoskeletal pain" or "chronic low back pain and chronic pain associated with osteoarthritis" in the United States and 28 other countries. Furthermore, in the field of pain management, it has been approved for diabetic neuropathic pain and fibromyalgia.

In Japan, duloxetine is approved for the treatment of major depressive disorder, diabetic neuropathic pain, and pain associated with fibromyalgia;[14–16] however, no clinical study of duloxetine has been conducted in Japanese patients with CLBP. Therefore, the current study aimed to assess the efficacy and safety of duloxetine monotherapy in Japanese patients with CLBP.