The Clinical Relevance of Pain Severity Changes: Is There Any Difference Between Asian and Caucasian Patients With Osteoarthritis Pain?

The objective of the present analysis was to determine whether changes in Brief Pain Inventory (BPI) average pain scores by patient global impression of improvement (PGI-I) category and the cut-off for clinically important difference (CID) were different between Asian and Caucasian patients with chronic pain due to osteoarthritis. This analysis used data from 3 (Caucasian) and 2 (Asian) randomized, placebo-controlled, 10- to 14-week duloxetine studies for the treatment of patients ≥40 years of age with osteoarthritis pain. The receiver operating characteristic (ROC) analysis was used to characterize the association between changes in BPI average pain scores and PGI-I levels at study endpoint. The CID was characterized by PGI-I, and the cut-off point for CID in BPI average pain scores was determined by the intersection of a 45-degree tangent line with each ROC curve. Data from 668 Asian and 868 Caucasian patients were available for analysis. Baseline BPI average pain ratings including worst and least pain were comparable between Asians and Caucasians. Ratings for percentage change from baseline to endpoint for BPI average pain scores in Asian patients and Caucasian patients were similar across the 7 PGI-I categories, regardless of age, gender, study, and treatment. The ROC analysis results of cut-off points in BPI average pain scores demonstrated the raw change cut-off was -3.0, and percentage change cut-off was -40% for both Asian and Caucasian patients. Overall, the present analysis concludes changes in BPI average pain scores by PGI-I category and the cut-off for CID were similar for Asian and Caucasian patients with chronic pain due to osteoarthritis.

An Open-Label, 52-Week, Phase III Trial of Duloxetine in Japanese Patients with Chronic Low Back Pain.

OBJECTIVE: To evaluate the safety and efficacy of duloxetine treatment for 52 weeks. DESIGN: Multicenter, open-label, phase III clinical study. SETTING: Forty-one medical institutions in Japan. SUBJECTS: Japanese patients with chronic low back pain (CLBP). METHODS: Duloxetine 60 mg once-daily was administered for 52 weeks. Safety was evaluated based on adverse events (AEs), vital signs, laboratory test values, electrocardiogram, Columbia-Suicide Severity Rating Scale, and occurrence of falls. The efficacy outcome measures were the Brief Pain Inventory (BPI; average pain, worst pain, least pain, and pain right now), BPI Interference, Patient's Global Impression of Improvement (PGI-I), Clinical Global Impressions of Severity (CGI-S), Roland-Morris Disability Questionnaire-24 (RDQ-24), 36-Item Short-Form Health Survey (SF-36), and European Quality of Life-5 Dimensions Questionnaire (EQ-5D). RESULTS: In total, 151 patients (83 who completed a 14-week placebo-controlled superiority trial and 68 newly registered patients) were enrolled. The incidence rates of AEs and adverse drug reactions (ADRs) were 86.1% and 50.3%, respectively. ADRs with an incidence of ≥5% were somnolence, constipation, nausea, and dry mouth. Treatment discontinuation for AEs occurred in 16 patients. A significant reduction in the BPI average pain score (mean ± SD) was observed at all assessment time points from week 2 (-1.02 ± 1.37) to week 50 (-2.26 ± 1.63), compared with baseline. BPI pain severity (worst pain, least pain, and pain right now), BPI Interference, PGI-I, CGI-S, RDQ-24, SF-36, and EQ-5D showed significant improvement. CONCLUSION: Japanese patients with CLBP had significant pain reduction over 52 weeks without new safety concerns.

Duloxetine in patients with diabetic peripheral neuropathic pain in Japan: a randomized, doubleblind, noninferiority comparative study with pregabalin.

PURPOSE: Duloxetine and pregabalin are recommended as first-line treatments for diabetic peripheral neuropathic pain (DPNP). However, studies have not reported a direct comparison between duloxetine and pregabalin. We conducted a postmarketing, randomized, double-blind study to assess the noninferiority of duloxetine compared with pregabalin after 12 weeks of treatment in adult patients with DPNP in Japan (NCT02417935). PATIENTS AND METHODS: Patients (N = 303) with distal symmetrical DPNP were randomized to and were administered duloxetine (40-60 mg/day) or pregabalin (300-600 mg/day). The primary endpoint was the change from baseline in weekly mean of the 24-hour average pain score (numeric rating scale [NRS]). Noninferiority of duloxetine compared with pregabalin was assessed with the primary endpoint at week 12. Secondary measures, including night pain and worst pain, Brief Pain Inventory-Severity and Interference rating short form (BPI-SF), Clinical Global Impression of Improvement (CGI-I), Patient Global Impression of Improvement (PGI-I), and Neuropathic Pain Symptom Inventory (NPSI), health outcome measures (EuroQol 5-Dimension index and VAS), and safety were also assessed. RESULTS: For the 24-hour NRS average pain score, the difference between the duloxetine and pregabalin groups was 0.072 (95% CI: - 0.295, 0.439), and the upper bound of the 95% CI (0.439) did not exceed the predefined noninferiority margin (0.51), at the end of the study period. For secondary outcome measures (night pain, worst pain, BPI-SF, CGI-I, PGI-I, NPSI) and health outcome measures, both the duloxetine and pregabalin treatment groups showed an improvement from baseline with no significant between-group difference. Duloxetine and pregabalin were well tolerated and the safety profiles were consistent with previously reported results. CONCLUSION: This study demonstrated the noninferior efficacy of duloxetine compared with pregabalin in the treatment of adult patients with DPNP. The safety analyses showed an acceptable tolerability based on safety profiles of duloxetine and pregabalin.

A randomized, double-blind, placebo-controlled Phase III trial of duloxetine in Japanese patients with knee pain due to osteoarthritis.

PURPOSE: To examine the efficacy and safety of duloxetine in Japanese patients with knee pain due to osteoarthritis. PATIENTS AND METHODS: Patients were randomized to receive duloxetine 60 mg/day or placebo for 14 weeks in a double-blind manner (ClinicalTrials.gov Identifier: NCT02248480). The primary efficacy endpoint was mean change in Brief Pain Inventory pain severity (BPI-Severity) average pain. Secondary endpoints included improvement in other BPI-Severity scales, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, health-related quality of life (HRQoL) scales, range of motion of the knee joint, safety and tolerability, and structural changes on X-ray images. RESULTS: Of the 354 randomized patients, 161 in the duloxetine group and 162 in the placebo group completed the study. BPI-Severity average pain improved significantly with duloxetine vs. placebo (-2.57 vs. -1.80; adjusted mean difference: -0.77; 95% CI: -1.11 to -0.43; P<0.0001). Secondary efficacy endpoints and most HRQoL scales showed greater improvements in the duloxetine group than the placebo group. Adverse events observed in ≥5% of patients that were more frequent in the duloxetine than placebo group were somnolence, constipation, dry mouth, nausea, malaise, and decreased appetite. There were no marked changes in range of motion of the knee joint (efficacy), X-ray images, or Kellgren-Lawrence grade (safety) in either group. CONCLUSION: Duloxetine reduced pain and improved function in patients with knee osteoarthritis, without causing X-ray abnormalities or altered knee joint mobility. Reduced pain was associated with improved HRQoL. Adverse events were consistent with duloxetine's known safety profile.

Associations among depression severity, painful physical symptoms, and social and occupational functioning impairment in patients with major depressive disorder: a 3-month, prospective, observational study.

PURPOSE: To investigate associations among depression severity, painful physical symptoms (PPS), and social and occupational functioning impairment in patients with major depressive disorder (MDD) who had achieved complete remission (CR) or partial remission (PR) after acute treatment. PATIENTS AND METHODS: This was a 12-week, multicenter, prospective, observational study. Patients with MDD treated with an antidepressant medication for the previous 12 weeks (±3 weeks) who had achieved CR (defined as a 17-item Hamilton Rating Scale for Depression [HAM-D17] score ≤7) or PR (HAM-D17 score ≥8 and ≤18) were enrolled. Depression severity, PPS, and impairment in social and occupational functioning were assessed using the HAM-D17, the Brief Pain Inventory (Short Form) (BPI-SF), and the Social and Occupational Functioning Assessment Scale (SOFAS), respectively, at enrollment (Week 12) and after 12 weeks (Week 24). RESULTS: Overall, 323 Japanese patients with MDD were enrolled (CR n=158, PR n=165) and 288 patients completed the study (CR n=139, PR n=149). HAM-D17 and SOFAS scores were strongly and negatively correlated at enrollment (Week 12; P<0.0001) and Week 24 (P<0.0001). A weak negative correlation between the BPI-SF and SOFAS was observed at Week 24 (P=0.0011), but not at enrollment (P=0.164). Remission status at enrollment (CR or PR) was associated with achieving normal social and occupational functioning (SOFAS score ≥80) at Week 24 in patients who had not achieved normal social and occupational functioning (SOFAS score <80) at enrollment (CR vs PR, OR=0.05 [95% CIs 0.01-0.18], P<0.0001). A greater proportion of patients with CR and no PPS at enrollment achieved SOFAS scores ≥80 at Week 24 than those with CR and PPS. CONCLUSION: Our results suggest that treating both depressive symptoms and PPS is important for achieving a normal level of functioning on a long-term basis in patients with MDD.

Duloxetine 60 mg for chronic low back pain: post hoc responder analysis of double-blind, placebo-controlled trials.

INTRODUCTION: Duloxetine has demonstrated efficacy in chronic low back pain (CLBP). We examined the predictors of response to duloxetine for CLBP. PATIENTS AND METHODS: This was a post hoc analysis of pooled data from 4 double-blind, ran-domized, placebo-controlled trials of duloxetine (60 mg/day for 12-14 weeks) in adult patients with CLBP. Primary outcome was proportion of patients with ≥30% reduction in Brief Pain Inventory (BPI) average pain ("pain reduction") at 12-14 weeks. The proportion of patients with ≥30% and ≥50% (secondary outcome) pain reduction in duloxetine and placebo groups was compared. Variables for responder analyses were early improvement (≥15% pain reduction at Week 2), sex, age, baseline BPI average pain score, duration of CLBP, and number of painful body sites according to the Michigan Body Map (≥2 vs 1 [isolated CLBP]; 1 trial); relative risk (RR) and 95% confidence interval (CI) were calculated. RESULTS: Compared with placebo (n = 653), a greater proportion of duloxetine-treated patients (n = 642) achieved ≥30% (59.7% vs 47.8%; P < 0.001) and ≥50% pain reduction (48.6% vs 35.1%; P < 0.001). Among duloxetine-treated patients, early improvement was associated with greater likelihood of ≥30% (RR [95% CI], 2.91 [2.30-3.67]) or ≥50% (3.24 [2.44-4.31]) pain reduction. Women were slightly more likely than men to achieve ≥30% (RR [95% CI], 1.14 [1.00-1.30]) or ≥50% (1.17 [0.99-1.38]) pain reduction. Response rates were similar between age, CLBP duration, and baseline BPI average pain score subgroups. Patients with ≥2 painful sites were more likely to respond to duloxetine 60 mg relative to placebo than patients with isolated CLBP (RR, duloxetine vs placebo [95% CI]: ≥30% reduction, ≥2 painful sites 1.40 [1.18-1.66], isolated CLBP 1.07 [0.78-1.48]; ≥50% reduction, ≥2 painful sites 1.51 [1.20-1.89], isolated CLBP 1.23 [0.81-1.88]). CONCLUSION: Early pain reduction was indicative of overall response. Patients with multiple painful sites had more benefit from duloxetine than patients with isolated CLBP.

Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies.

BACKGROUND: Comorbid depression and depressive symptoms are common in patients with chronic low back pain (CLBP). Duloxetine is clinically effective in major depressive disorder and several chronic pain states, including CLBP. The objective of this post hoc meta-analysis was to assess direct and indirect analgesic efficacy of duloxetine for patients with CLBP in previous clinical trials. METHODS: Post hoc path analyses were conducted of 3 randomized, double-blind, clinical studies of patients receiving duloxetine or placebo for CLBP. The primary outcome measure for pain was the Brief Pain Inventory, average pain score. A secondary outcome measure, the Beck Depression Inventory-II, was used for depressive symptoms. The changes in score from baseline to endpoint were determined for each index. Path analyses were employed to calculate the proportion of analgesia that may be attributed to a direct effect of duloxetine on pain. RESULTS: A total of 851 patients (400 duloxetine and 451 placebo) were included in this analysis. Duloxetine significantly improved pain scores compared with placebo (p<0.001). It also significantly improved depressive scores compared with placebo (p=0.015). Path analyses showed that 91.1% of the analgesic effect of duloxetine could be attributed to a direct analgesic effect, and 8.9% to its antidepressant effect. Similar results were obtained when data were evaluated at weeks 4 and 7, and when patients were randomized to subgroups based on baseline pain scores, baseline depressive symptoms scores, and gender. CONCLUSION: Duloxetine significantly improved pain in patients with CLBP. Path analyses results suggest that duloxetine produced analgesia mainly through mechanisms directly impacting pain modulation rather than lifting depressive symptoms. This effect was consistent across all subgroups tested.

An open-label, long-term, phase III extension trial of duloxetine in Japanese patients with fibromyalgia.

OBJECTIVES: We aimed to evaluate the long-term safety and efficacy of duloxetine 60 mg in Japanese patients with fibromyalgia enrolled from a preceding randomized, placebo-controlled, phase III duloxetine trial. METHODS: This was a long-term, open-label extension study. Patients received oral duloxetine once daily at a dose of 20 mg for 1 week, followed by 40 mg for 1 week, and then 60 mg for 48 weeks. The primary outcome was the frequency of adverse events (AEs) and adverse drug reactions (ADRs) of duloxetine. Efficacy and health outcomes were assessed. RESULTS: In total, 149 patients were enrolled from the preceding study. The median length of treatment was 364.0 days. The incidence of AEs and ADRs was 92.6 and 63.8%, respectively. ADRs occurring at an incidence of ≥5% were somnolence, constipation, nausea, weight increase, thirst, and malaise. The proportion of patients with mild, moderate, and severe AEs was 80.5, 10.1, and 2.0%. There were no serious treatment-related AEs in this study. The Brief Pain Inventory average pain score improved at all time-points compared with baseline (mean change ± standard deviation at Week 50 was -1.31 ± 1.70). CONCLUSIONS: Duloxetine was safe and effective in the long-term treatment of Japanese patients with fibromyalgia.

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

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 ±â€Š0.11 vs. -1.96 ±â€Š0.11, 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 ±â€Š0.10, P = 0.0009; -2.42 ±â€Š0.12, P P = 0.0230, respectively), Patient's Global Impression of Improvement (2.46 ±â€Š0.07, P = 0.0026), Clinical Global Impressions of Severity (-1.46 ±â€Š0.06, P = 0.0019), and Roland-Morris Disability Questionnaire (-3.86 ±â€Š0.22, 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.

Residual symptoms in patients with partial versus complete remission of a major depressive disorder episode: patterns of painful physical symptoms in depression.

OBJECTIVE: The patterns of residual painful physical symptoms (PPS) and emotional symptoms among patients with partial remission (PR) or complete remission (CR) of a major depressive disorder (MDD) episode were compared. METHODS: This is a multicenter, cross-sectional, observational study. Patients who had originally been diagnosed with MDD, were treated with an antidepressant for 12 weeks for that episode, and achieved either PR or CR at study entry were enrolled in the study. Using the 17-item Hamilton Rating Scale for Depression (HAM-D17), PR was defined as a score of ≥8 and ≤18 and CR as a score of ≤7. Residual symptoms were assessed using the Brief Pain Inventory-Short Form (BPI-SF) and the HAM-D17. RESULTS: A total of 323 patients (CR =158, PR =165) were included in the study. Patients in the PR group had a higher mean (standard deviation) score in the HAM-D17 than those in the CR group (11.8 [3.1] and 4.4 [2.0], respectively). BPI-SF results showed that "at least moderate PPS" (score ≥3 on BPI-SF question 5) was significantly more prevalent among patients with PR than those with CR (37.0% vs 16.5%, respectively; odds ratio =3.04; P<0.001). Presence of pain (any severity) was also more prevalent among patients with PR than those with CR (54.5% vs 35.4%, respectively). The HAM-D17 results for individual items indicated that impaired work and activities, depressed mood, psychological and somatic anxiety, and general somatic symptoms were observed in at least 75% of patients with PR. CONCLUSION: PR was associated with a higher prevalence of at least moderate PPS. Other residual symptoms commonly observed in patients with PR included typical core emotional symptoms (eg, loss of interest, depressed mood, and psychological anxiety). These results underline the importance of PPS, because PPS is clinically relevant for the patients but difficult to assess with the commonly used depression evaluation scale.

The relationship between pain severity and patient-reported outcomes among patients with chronic low back pain in Japan.

OBJECTIVE: The aim of this study was to quantify the impact of pain severity on patient-reported outcomes among individuals diagnosed with chronic low back pain in Japan. METHODS: Data were provided by the 2012 Japan National Health and Wellness Survey (N=29,997), a web-based survey of individuals in Japan aged ≥18 years. This analysis included respondents diagnosed with low back pain of ≥3-month duration. Measures included the revised Medical Outcomes Study 36-Item Short-Form Survey Instrument, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 scale, the Work Productivity and Activity Impairment: General Health questionnaire, and self-reported all-cause health care visits (6 months). Generalized linear models were used to assess the relationship between outcomes and severity of pain in the past week as reported on a numeric rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine), controlling for length of diagnosis, sociodemographics, and general health characteristics. RESULTS: A total of 290 respondents were included in the analysis; mean age was 56 years, 41% were females, and 56% were employed. Pain severity was 3/10 for the first quartile, 5/10 for the median, and 7/10 for the third quartile of this sample. Increasing severity was associated with lower scores for mental and physical component summaries and Short-Form 6D health utility, higher depression (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7) scores, greater absenteeism and presenteeism, greater activity impairment, and more health care provider visits (all P<0.0001). CONCLUSION: The impact of chronic low back pain on health-related quality of life, depression and anxiety symptoms, impairment to work and daily activities, and health care use increases with the severity of pain. Interventions reducing the severity of pain may improve numerous health outcomes even if the pain cannot be eliminated.

Efficacy and safety of 40 mg or 60 mg duloxetine in Japanese adults with diabetic neuropathic pain: Results from a randomized, 52-week, open-label study.

INTRODUCTION: To examine the long-term efficacy and safety of duloxetine in the treatment of Japanese patients with diabetic neuropathic pain, we carried out a 52-week, randomized, open-label extension of a 12-week, double-blind, placebo-controlled study. MATERIALS AND METHODS: Japanese adults with diabetic neuropathic pain who completed the double-blind study were eligible for this long-term study, carried out at 71 sites in Japan (March 2008 to March 2010). Participants (n = 258) were re-randomized (1:1) to 40 mg/day or 60 mg/day duloxetine. Pain (Brief Pain Inventory severity and interference), quality of life (Patient's Global Impression of Improvement), and safety (primary outcome; adverse events, vital signs, metabolic measures) were measured. RESULTS: Significant (P < 0.0001) and sustained improvements (change ± standard deviation; n = 257) were observed in Brief Pain Inventory severity (average pain score -2.1 ± 1.7). Improvements were also seen in Brief Pain Inventory interference (mean of subscores -0.96 ± 1.52) and Patient's Global Impression of Improvement (-0.9 ± 1.1) scores; these scores decreased significantly (P < 0.0001) during the long-term study. Frequently reported adverse events included somnolence (13.6%), constipation (13.2%) and nausea (10.5%). Increases were observed in plasma glucose, glycosylated hemoglobin and total cholesterol levels, and in bodyweight and heart rate; however, none of these were clinically meaningful. Overall, there were no clinically significant safety concerns. CONCLUSIONS: This is the first publication of a long-term study carried out in Asia with an entirely Japanese patient population to suggest that long-term duloxetine therapy for diabetic neuropathic pain is effective and has an acceptable safety profile.

Correlation between pain response and improvements in patient-reported outcomes and health-related quality of life in duloxetine-treated patients with diabetic peripheral neuropathic pain.

OBJECTIVE: We assessed whether quality of life (QoL) improvement in duloxetine-treated patients with diabetic peripheral neuropathic pain (DPNP) correlates with the extent of pain relief. METHODS: Pooled data from three multicountry, double-blind, 12-week, placebo-controlled trials of duloxetine-treated (duloxetine 60 mg once daily; total number =335) patients with DPNP were analyzed. Based on improvement in 24-hour average pain scores, patients were stratified into four groups. Improvement in QoL, which was measured as the change from baseline in two patient-reported health outcome measures (Short Form [SF]-36 and five-dimension version of the EuroQol Questionnaire [EQ-5D]), was evaluated and compared among the four groups. Pearson's correlation coefficient was calculated to assess the correlation between improvement in pain scores and improvement in QoL. RESULTS: The group with more pain improvement generally showed greater mean change from baseline in all of the SF-36 scale scores and on the EQ-5D index. Pearson's correlation coefficients ranged from 0.114 to 0.401 for the SF-36 scale scores (P<0.05), and it was 0.271 for the EQ-5D (P<0.001). CONCLUSION: Improvement in pain scores was positively correlated with improvement in QoL and patient-reported outcomes in duloxetine-treated patients.

A randomized, double-blind, placebo-controlled phase III trial of duloxetine in Japanese fibromyalgia patients.

INTRODUCTION: Fibromyalgia is characterized by widespread pain and is often accompanied by accessory symptoms. There are limited treatment options for this condition in Japan. Therefore, we conducted a phase III study to assess the efficacy and safety of duloxetine in Japanese patients with fibromyalgia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group trial was conducted in Japan. Outpatients who met the American College of Rheumatology 1990 criteria for fibromyalgia and whose Brief Pain Inventory (BPI) average pain score was ≥4 were randomized to duloxetine 60 mg or placebo once daily for 14 weeks. The primary efficacy measure was the change in the BPI average pain score from baseline. Secondary efficacy, quality of life (QoL), and safety outcomes were also evaluated. Mixed-effects model repeated-measures (MMRM) analysis and last observation carried forward (LOCF) analysis of covariance were used to evaluate the primary efficacy measure. RESULTS: Overall, 393 patients were randomized to receive either duloxetine (n = 196) or placebo (n = 197). The MMRM analysis revealed no significant difference between duloxetine and placebo regarding the change in BPI average pain scores at week 14. Based on LOCF analysis, a statistically significant improvement in the change in BPI average pain scores at week 14 was observed for patients treated with duloxetine compared with placebo. Duloxetine treatment was associated with improved outcomes in nearly all secondary and post hoc analyses. The treatment was generally well tolerated. Somnolence, nausea, and constipation were the most common treatment-emergent adverse events in the duloxetine group. The discontinuation rates due to treatment-emergent adverse events were similar in both groups. CONCLUSIONS: Although the MMRM analysis did not demonstrate superiority of duloxetine over placebo, duloxetine treatment was associated with improved outcomes in secondary and post hoc analyses of the mean change in the BPI average pain score and most of the secondary outcomes, including analgesia and QoL. Duloxetine treatment was safe and well tolerated. These results suggest that duloxetine treatment could be associated with improvements in pain relief and QoL in Japanese patients with fibromyalgia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01552057 . Registered 9 March 2012.

The role of descending inhibitory pathways on chronic pain modulation and clinical implications.

The treatment and management of chronic pain is a major challenge for clinicians. Chronic pain is often underdiagnosed and undertreated, and there is a lack of awareness of the pathophysiologic mechanisms that contribute to chronic pain. Chronic pain involves peripheral and central sensitization, as well as the alteration of the pain modulatory pathways. Imbalance between the descending facilitatory systems and the descending inhibitory systems is believed to be involved in chronic pain in pathological conditions. A pharmacological treatment that could restore the balance between these 2 pathways by diminishing the descending facilitatory pain pathways and enhancing the descending inhibitory pain pathways would be a valuable therapeutic option for patients with chronic pain. Due to the lack of evidence for pharmacological options that act on descending facilitation pathways, in this review we summarize the role of the descending inhibitory pain pathways in pain perception. This review will focus primarily on monoaminergic descending inhibitory pain pathways and their contribution to the mechanism of chronic pain and several pharmacological treatment options that enhance these pathways to reduce chronic pain. We describe anatomical structures and neurotransmitters of the descending inhibitory pain pathways that are activated in response to nociceptive pain and altered in response to sustained and persistent pain which leads to chronic pain in various pathological conditions.