***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background The heterogeneity statistic I2 , interpreted as the percentage of variability due to heterogeneity between studies rather than sampling error , depends on precision , that is , the size of the studies included . Methods Based on a real meta- analysis , we simulate artificially ' inflating ' the sample size under the r and om effects model . For a given inflation factor M = 1 , 2 , 3 , ... and for each trial i , we create a M-inflated trial by drawing a treatment effect estimate from the r and om effects model , using si2MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi = xH8viVGI8Gi = hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY = rqGqVepae9pg0db9vqaiVgFr0xfr = xfr = xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGaem4Cam3aa0baaSqaaiabdMgaPbqaaiabikdaYaaaaaa@2FBE@/M as within-trial sampling variance . Results As precision increases , while estimates of the heterogeneity variance τ2 remain unchanged on average , estimates of I2 increase rapidly to nearly 100 % . A similar phenomenon is apparent in a sample of 157 meta-analyses . Conclusion When deciding whether or not to pool treatment estimates in a meta- analysis , the yard-stick should be the clinical relevance of any heterogeneity present . τ2 , rather than I2 , is the appropriate measure for this purpose OBJECTIVE We assessed the efficacy and safety of duloxetine ( 60 mg , once daily ) , compared with placebo , during a 13-week treatment period in Chinese patients with chronic pain due to osteoarthritis ( OA ) . DESIGN Patients were at least 40 years old ( male or female ) who met American College of Rheumatology clinical and radiographic criteria for the diagnosis of OA of the knee or hip . The primary efficacy measure in this phase 3 , r and omized , double-blind , placebo-controlled clinical trial was assessment of pain severity by the Brief Pain Inventory ( BPI ) 24-h Average Pain rating . The clinical trial was conducted at 17 study centers . Statistical approaches included mixed-effects model repeated measures and analysis of covariance . A Fisher exact test was applied to categorical variables . RESULTS Of 407 patients r and omized ( duloxetine :  N = 205 ;  placebo : N = 202 ) , 166 ( 81.0 % ) patients from the duloxetine group and 176 ( 87.1 % ) patients from the placebo group completed the 13-week treatment phase . The majority ( 76.4 % ) of patients was female ; mean age was 60.5 years . Duloxetine-treated patients reported significant pain reduction , compared with placebo treatment , on the BPI 24-h Average Pain rating ( least-squares mean ( LS Mean ) change from baseline to endpoint [ 95 % confidence interval ( CI ) ] , duloxetine : -2.23 ; placebo : -1.73 ; difference = -0.50 [ -0.80 , -0.20 ] ; P = 0.001 ) . The incidence of discontinuations due to adverse events was 9.0 % in duloxetine-treated patients and 4.5 % in placebo-treated patients ( P = 0.109 ) . CONCLUSIONS This study demonstrated the efficacy of duloxetine in Chinese patients with chronic pain due to OA . The safety profile of duloxetine observed in this study was consistent with that in previous duloxetine trials . This trial is registered with Clinical Trials.gov ( NCT01931475 ) Osteoarthritis ( OA ) is the most prevalent arthritis worldwide and is characterized by chronic pain and impaired physical function . We hypothesized that heightened pain in h and OA could be reduced with duloxetine or pregabalin . In this prospect i ve , r and omized clinical study , we recruited 65 participants , aged 40–75 years , with a Numerical Rating Scale ( NRS ) for pain of at least 5 . Participants were r and omized to one of the following three groups : duloxetine , pregabalin , and placebo . The primary endpoint was the NRS pain score , and the secondary endpoints included the Australian and Canadian H and Osteoarthritis Index ( AUSCAN ) pain , stiffness , and function scores and quantitative sensory testing by pain pressure algometry . After 13 weeks , compared to placebo , ANOVA found significant differences between the three groups ( P=0.0078 ) . In the intention-to-treat analysis , the pregabalin group showed improvement for NRS pain ( P=0.023 ) , AUSCAN pain ( P=0.008 ) , and AUSCAN function ( P=0.009 ) , but no difference between duloxetine and placebo ( P>0.05 ) was observed . In the per protocol analysis , NRS pain was reduced for pregabalin ( P<0.0001 ) and duloxetine ( P=0.029 ) compared to placebo . We conclude that central ly acting analgesics improve pain outcomes in people with h and arthritis , offering new treatment paradigms for OA pain & NA ; Hypertonic saline effectively excites muscle nociceptors . Muscle hyperalgesia was assessed in osteoarthritis ( OA ) by intramuscular infusion of 0.5 ml hypertonic saline ( 6 % ) into the tibialis anterior muscle in humans . Patients ( n=14 ) with OA in the lower extremities were compared with an equal number of age‐ and sex‐matched healthy controls . Ten of the 14 OA patients had pain in the knee joint as the most common presenting complaint . Visual analogue scale ( VAS ) pain intensity and assessment of pain areas were recorded before infusion and immediately , 2 , 5 , 10 and 20 min after infusion , and then every 10 min , until the pain vanished . The mean pain offset time in OA patients ( 11.3±7.9 min ) was larger as compared with the control subjects ( 6.04±2.1 min ) ( P=0.025 ) . OA patients had increased pain intensity VAS after the infusion in the right leg compared with controls ( P<0.05 ) . Referred and radiating pain areas at 2 min post‐infusion increased in OA patients and not in controls as compared with the local pain areas ( P<0.05 ) . It is concluded that muscle hyperalgesia and extended pain areas might be due to central sensitization caused by painful osteoarthritis Purpose To examine the efficacy and safety of duloxetine in Japanese patients with knee pain due to osteoarthritis . Patients and methods Patients were r and omized to receive duloxetine 60 mg/day or placebo for 14 weeks in a double-blind manner ( Clinical Trials.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 r and omized 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 BACKGROUND pain is the leading symptom of osteoarthritis ( OA ) and is often chronic in nature , leading to significant morbidity and decreased quality of life . Duloxetine , a selective serotonin norepinephrine reuptake inhibitor has been demonstrated to have a central ly acting analgesic effect . OBJECTIVES the aim of the present study was to investigate the efficacy of duloxetine in reducing pain in older adults with knee OA . METHODS totally , 288 patients aged 65 years and above with primary knee OA were enrolled in this study . Patients were r and omised 1:1 . Totally , 144 received 60 mg/day of duloxetine HCL and 144 received placebo for 16 weeks . Outcome measures included pain reduction and improvement in physical functioning scores . Pain was assessed using the visual analogue pain scale ( VAS ; 0 - 100 mm ) . The Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) scores were used to assess function . RESULTS two-hundred and seventy four of the 288 patients completed the study . There was a statistically significant reduction in pain and a significant improvement in WOMAC scores at 16 weeks in the duloxetine group versus the placebo group . No serious side effects were reported . CONCLUSIONS the findings of the present study provide evidence for the efficacy and tolerability of duloxetine in reducing pain and subsequently improving function in older adults with knee OA . TRIAL REGISTRATION NCT01425827 Abstract Objective : To determine the efficacy , tolerability , and safety of duloxetine when added to oral nonsteroidal anti-inflammatory drugs ( NSAIDs ) in patients with osteoarthritis ( OA ) of the knee with pain of moderate or greater severity . Research design and methods : This was a 10-week r and omized , double-blind , flexible-dose ( duloxetine 60/120 mg/day ) , placebo-controlled trial that enrolled adult out patients who had persistent moderate pain ( ≥4 on a 0–10 numerical rating scale ) due to OA of the knee , despite , per protocol , having received optimized oral NSAID therapy  ( specific drug , dose , and frequency at investigator discretion ) . Clinical trials registration : Trial registration : Clinical Trials.gov identifier : NCT01018680 . Main outcome measure : Patients entered daily pain ratings in a telephone-based diary . The primary efficacy outcome was the weekly mean of the daily average pain rating at week 8 . Safety outcomes were assessed during the entire 10-week study . Results : A total of 524 patients r and omly received duloxetine 60/120 mg/day ( N = 264 ) or placebo ( N = 260 ) . In total , 74 % of the patients completed the study . Mean age was 61 years ( SD 9.2 ) , 57 % were female , and 81 % were white .  Duloxetine-treated patients had significantly greater pain reduction at week 8 ( p < 0.001 ) than placebo-treated patients . In addition , relative to placebo at week 8 , duloxetine-treated patients had significant improvements in physical function as measured by the Western Ontario and McMaster Universities Osteoarthritis Index ( p < 0.001 ) , and Patient Global Impression of Improvement ( p < 0.001 ) . Compared to placebo , significantly more nausea , dry mouth , constipation , fatigue and decreased appetite were reported by patients taking duloxetine ( each p < 0.05 ) . Discontinuation due to adverse events occurred more commonly in the duloxetine group than the placebo group ( p = 0.03 ) . Conclusion : Duloxetine added to oral NSAID therapy provided additional significant pain reduction , improved function , and patient-rated impression of improvement . Adverse events were consistent with those seen in previous duloxetine trials . The short duration of the study may not reflect the longer term efficacy and safety of NSAID/duloxetine cotherapy OBJECTIVE To evaluate the efficacy and safety of duloxetine in the treatment of chronic pain due to osteoarthritis of the knee . METHODS This was a 13-week , r and omized , double-blind , placebo-controlled trial in patients meeting American College of Rheumatology clinical and radiographic criteria for osteoarthritis of the knee . At baseline , patients were required to have a ≥ 4 weekly mean of the 24-hour average pain ratings . Patients were r and omized to either duloxetine 60 mg once daily ( QD ) or placebo . At week 7 , the duloxetine dosage was increased , in a blinded fashion , to 120-mg QD in patients reporting < 30 % 
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The results of our analyses indicate that duloxetine has statistically significant , moderate benefits on pain , function , and quality of life in knee OA patients for up to 13 weeks .
Reported incidences of gastrointestinal adverse events were three to four times higher in participants who received duloxetine versus placebo .
Duloxetine may be an effective treatment option for individuals with knee OA , but use of the drug is associated with a significantly higher risk of adverse events .