title: Efficacy of Combination of Meloxicam and Pregabalin for Pain in Knee Osteoarthritis Effectiveness and Tolerability of Tapentadol Prolonged Release Compared With Prior Opioid Therapy for the Management of Severe, Chronic Osteoarthritis Pain Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized, double-blind, placebo-controlled trial A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee.
abstract: Purpose Osteoarthritic pain is largely considered to be inflammatory pain . Sensory nerve fibers innervating the knee have been shown to be significantly damaged in rat models of knee osteoarthritis ( OA ) in which the subchondral bone junction is destroyed , and this induces neuropathic pain ( NP ) . Pregabalin was developed as a pain killer for NP ; however , there are no reports on pregabalin use in OA patients . The purpose of this study was to investigate the efficacy of pregabalin for pain in OA patients . Material s and Methods Eighty-nine knee OA patients were evaluated in this r and omized prospect i ve study . Patients were divided into meloxicam , pregabalin , and meloxicam+pregabalin groups . Pain scores were evaluated before and 4 weeks after drug application using a visual analogue scale ( VAS ) , and Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Pain scales among groups were compared using a Kruskal-Wallis test . Results Before drug application , there was no significant difference in VAS and WOMAC scores among the three groups ( p>0.05 ) . Significant pain relief was seen in the meloxicam+pregabalin group in VAS at 1 , 2 , and 4 weeks , and WOMAC score at 4 weeks , compared with the other groups ( p<0.05 ) . No significant pain relief was seen in the meloxicam only group in VAS during 4 weeks and WOMAC score at 4 weeks compared with the pregabalin only group ( p>0.05 ) . Conclusion Meloxicam+pregabalin was effective for pain in OA patients . This finding suggests that OA pain is a combination of inflammatory and NP Background Tapentadol prolonged release ( PR ; 100–250 mg twice daily ) has been efficacious and well tolerated for managing moderate-to-severe , chronic osteoarthritis hip or knee pain in phase 3 studies with washout of previous analgesic treatment . Objective The objective of this study was to evaluate the effectiveness and tolerability of tapentadol PR ( 50–250 mg twice daily ) after direct rotation from World Health Organization ( WHO ) step III opioids in patients with severe osteoarthritis knee pain who previously responded to WHO step III therapy but showed poor tolerability . Methods This open-label , phase 3b study ( NCT00982280 ) was conducted from October 2009 through June 2010 ( prematurely terminated due to slow recruitment and study drug shortages ) in clinical care setting s in Europe and Australia . The study population included patients with severe , chronic osteoarthritis knee pain who had taken WHO step III opioids daily for ≥2 weeks before screening , responded to therapy ( average pain intensity [ 11-point numerical rating scale-3 ( NRS-3 ) ] ≤5 at screening ) , and reported opioid-related adverse effects  as their reason for changing analgesics . Patients switched directly from WHO step III therapy to tapentadol . Patients received oral tapentadol PR ( 50–250 mg twice daily ) during 5-week titration and 7-week maintenance periods . Oral tapentadol immediate release ( IR ) was permitted ( ≤twice/day , ≥4 h apart ) for acute pain episodes due to index pain or withdrawal symptoms following discontinuation of previous opioids ( combined dose of tapentadol [ PR and IR ] ≤500 mg/day ) . This study was planned to evaluate conversion  to tapentadol PR , based on responder rate 1 ( percentage of patients with same/less pain [ NRS-3 ] versus Week −1 ) at Week 6 ( primary endpoint ) , adverse events ( AEs ) , and discontinuation rates . Equianalgesic ratios were calculated for tapentadol prior to WHO step III opioids ( PR and PR plus IR formulations ) . Results Of 82 patients enrolled , 63 received study medication . In the per- protocol population , responder rate 1 at Week 6 ( last observation carried forward ) was 94.3 % ( 50/53 ; P < 0.0001 vs. the null hypothesis rate [ < 60 % ] ) . Mean ( st and ard deviation ) pain intensity scores were 4.7 ( 0.66 ) at baseline , 2.5 ( 1.46 ) at Week 6 , and 1.8 ( 1.41 ) at Week 12 in the main analysis population ( change from baseline at Weeks 6 and 12 , P < 0.0001 ) . Tapentadol to transdermal buprenorphine equianalgesic ratios ( PR [ n = 48 ] , 262.9:1 ; PR plus IR [ n = 48 ] , 281.1:1 ) and tapentadol to oral oxycodone equianalgesic ratios ( PR [ n = 4 ] , 4.3:1 ; PR plus IR [ n = 6 ] , 4.6:1 ) were calculated for the main analysis population . In the safety population , prevalence of AEs reported as associated with prior opioids at Week −1 ( reasons for rotation ) and related to tapentadol treatment at Week 12 decreased over time ; the most common were nausea ( 46.0 vs. 24.1 % ) and constipation ( 31.7 vs. 7.4 % ) . Overall , 14.3 % of patients discontinued the study early ; reasons included AEs ( 9.5 % ) , lack of efficacy ( 3.2 % ) , and withdrawal of consent ( 1.6 % ) . Conclusions Significant improvements in effectiveness were observed for tapentadol PR ( 50–250 mg twice daily ) versus WHO step III opioids in patients with severe , chronic osteoarthritis knee pain who previously responded to WHO step III therapy . Equianalgesic ratios were calculated for tapentadol to transdermal buprenorphine and oral oxycodone and were in line with observations from previous phase 3 studies 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 % pain reduction . The primary efficacy measure was Brief Pain Inventory ( BPI ) 24-hour average pain . Secondary efficacy measures included Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) ; Clinical Global Impressions of Severity ( CGI-S ) . Safety and tolerability was also assessed . RESULTS Of the total ( n = 256 ) patients , 111 ( 86.7 % ) in placebo group and 93 ( 72.7 % ) in duloxetine group completed the study . Patients treated with duloxetine had significantly ( P ≤ 0.001 ) greater improvement at all time points on BPI average pain and had significantly greater improvement on BPI pain severity ratings ( P ≤ 0.05 ) , WOMAC total ( P = 0.044 ) and physical functioning scores ( P = 0.016 ) , and CGI-S ( P = 0.009 ) at the study endpoint . Frequency of treatment-emergent nausea , constipation , and hyperhidrosis were significantly higher in the duloxetine group ( P ≤ 0.05 ) . Significantly more duloxetine-treated patients discontinued the trial because of adverse events ( P = 0.002 ) . CONCLUSIONS Treatment with duloxetine 60 mg to 120 mg QD was associated with significant pain reduction and improved function in patients with pain due to osteoarthritis of the knee
target: Results There is good evidence for a role of central sensitisation in chronic OA pain in a subgroup of patients .
  Biomarkers may be helpful for confirming the presence of central sensitisation , especially when there is diagnostic uncertainty .
  Several non‐pharmacological and pharmacological treatments may be effective in OA patients with central sensitisation features .
  Multimodal therapy may be required to achieve control of symptoms .
background: Summary Aims The aim of this non‐ systematic review was to provide a practical guide for clinicians on the evidence for central sensitisation in chronic osteoarthritis ( OA ) pain and how this pain mechanism can be addressed in terms of clinical diagnosis , investigation and treatment .
  Clinical ly , a central sensitisation component in chronic OA pain can be suspected based on characteristic pain features and non‐pain features seen in other conditions involving central sensitisation .