***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: Abstract  Variability  in patients ' response to interventions in pain and other clinical setting s is large . Many explanations such as trial methods , environment or culture have been proposed , but this paper sets out to show that the main cause of the variability may be r and om chance , and that if trials are small their estimate of magnitude of effect may be incorrect , simply because of the r and om play of chance . This is highly relevant to the questions of ‘ How large do trials have to be for statistical accuracy ? ’ and ‘ How large do trials have to be for their results to be clinical ly valid ? ’ The true underlying control event rate ( CER ) and experimental event rate ( EER ) were determined from single‐dose acute pain analgesic trials in over 5000 patients . Trial group size required to obtain statistically significant and clinical ly relevant ( 0.95 probability of number‐needed‐to‐treat within ±0.5 of its true value ) results were computed using these values . Ten thous and trials using these CER and EER values were simulated using varying group sizes to investigate the variation due to r and om chance alone . Most common analgesics have EERs in the range 0.4–0.6 and CER of about 0.19 . With such efficacy , to have a 90 % chance of obtaining a statistically significant result in the correct direction requires group sizes in the range 30–60 . For clinical relevance nearly 500 patients are required in each group . Only with an extremely effective drug ( EER>0.8 ) will we be reasonably sure of obtaining a clinical ly relevant NNT with commonly used group sizes of around 40 patients per treatment arm . The simulated trials showed substantial variation in CER and EER , with the probability of obtaining the correct values improving as group size increased . We contend that much of the variability in control and experimental event rates is due to r and om chance alone . Single small trials are unlikely to be correct . If we want to be sure of getting correct ( clinical ly relevant ) results in clinical trials we must study more patients . Credible estimates of clinical efficacy are only likely to come from large trials or from pooling multiple trials of conventional ( small ) size OBJECTIVES Combination of drugs with different mechanisms of action helps in achieving synergistic analgesic effect in neuropathic pain . Keeping this point in view , the effect and safety aspects of sodium valproate and GTN were assessed alone as well as in combination in this study . DESIGN Prospect i ve double-blind r and omized placebo-controlled study . MATERIAL AND METHOD Eighty-seven type 2 diabetics with painful neuropathy were enrolled . Four were excluded : three with HbA1c>11 while one withdrew consent . The remaining 83 were given either sodium valproate and GTN spray ( group A ) or placebo drug and GTN spray ( group B ) or sodium valproate and placebo spray ( group C ) or placebo drug and placebo spray ( group D ) . Quantitative assessment of pain was done by McGill pain question naire , visual analogue score ( VAS ) and present pain intensity ( PPI ) at the beginning of the study and after 3 months along with motor and sensory nerve conduction velocities measurements . RESULTS All the three treatment groups experienced significant improvement in pain score in their drug phase of trial ( p<0.001/<0.05 ) along with some of the electrophysiological parameters . The assessment of the magnitude of therapeutic effect of sodium valproate , GTN and their combination gave numbers needed to treat ( NNT ) of 7 , 5 and 4 , respectively . CONCLUSION Sodium valproate and GTN are well tolerated and provide significant improvement in pain scores as well as in electrophysiological parameters Chronic central pain is a frequent complication after spinal cord injury .  Anticonvulsant drugs , among them valproate , have been recommended for treatment . In this paper we conducted a double-blind , cross-over study comparing valproate and placebo for severe chronic central pain . During the study , serum concentration of valproate , pain and side effects were registered and the dose was adjusted according to these . No significant analgesic effects of valproate could be demonstrated although serum concentration and dose reached a high level . Few studies of pain following spinal cord injury exist and we recommend that further studies be performed Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials . This EFNS Task Force aim ed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain . Studies were identified using first the Cochrane Data base then Medline . Trials were classified according to the aetiological condition . All class I and II controlled trials ( according to EFNS classification of evidence ) were assessed , but lower‐class studies were considered in conditions that had no top level studies . Only treatments feasible in an outpatient setting were evaluated . Effects on pain symptoms/signs , quality of life and comorbidities were particularly search ed for . Most of the r and omized controlled trials included patients with postherpetic neuralgia ( PHN ) and painful polyneuropathies ( PPN ) mainly caused by diabetes . These trials provide level A evidence for the efficacy of tricyclic antidepressants , gabapentin , pregabalin and opioids , with a large number of class I trials , followed by topical lidocaine ( in PHN ) and the newer antidepressants venlafaxine and duloxetine ( in PPN ) . A small number of controlled trials were performed in central pain , trigeminal neuralgia , other peripheral neuropathic pain states and multiple‐aetiology neuropathic pains . The main peripheral pain conditions respond similarly well to tricyclic antidepressants , gabapentin , and pregabalin , but some conditions , such as HIV‐associated polyneuropathy , are more refractory . There are too few studies on central pain , combination therapy , and head‐to‐head comparison . For future trials , we recommend to assess quality of life and pain symptoms or signs with st and ardized tools Neuropathic pain ( NeP ) , generated by disorders of the peripheral and central nervous system , can be particularly severe and disabling . Prevalence estimates indicate that 2 % to 3 % of the population in the developed world suffer from NeP , which suggests that up to one million Canadians have this disabling condition . Evidence -based guidelines for the pharmacological management of NeP are therefore urgently needed . R and omized , controlled trials , systematic review s and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting . Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one method ologically sound , r and omized , controlled trial showing significant benefit relative to placebo or another relevant control group . Recommendations for treatment are based on degree of evidence of analgesic efficacy , safety , ease of use and cost-effectiveness .  Analgesic agents recommended for first-line treatments are certain antidepressants ( tricyclics ) and anticonvulsants ( gabapentin and pregabalin ) . Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine . Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain . Recommended fourth-line treatments include cannabinoids , methadone and anticonvulsants with lesser evidence of efficacy , such as lamotrigine , topiramate and valproic acid . Treatment must be individualized for each patient based on efficacy , side-effect profile and drug accessibility , including cost . Further studies are required to examine head-to-head comparisons among analgesics , combinations of analgesics , long-term outcomes , and treatment of pediatric and central BACKGROUND Post-herpetic neuralgia is difficult to treat . Divalproex sodium ( valproic acid and sodium valproate in molar ratio 1:1 ) has been used successfully in the management of various painful neuropathies . AIM To study the effectiveness and safety of divalproex sodium in the management of post-herpetic neuralgia . DESIGN R and omized double-blind placebo-controlled trial . METHODS We enrolled 48 consecutively attending out- patients with post-herpetic neuralgia , out of whom three were excluded ( two had insufficient pain , one withdrew consent ) . Quantification of pain was by Short Form-McGill pain question naire ( SF-MPQ ) , visual analogue scale ( VAS ) , present pain intensity score ( PPI ) and 11 point Likert scale ( 11 PLS ) at the beginning of the study , after 2 weeks , 4 weeks and at the end of the study ( 8 weeks ) . We also assessed patients ' global impression of change by question naire at the end of the study . RESULTS After 8 weeks treatment with 1000 mg/day divalproex sodium , there was significant reduction in pain : SF-MPQ , 20.47 + /- 2.29 to 11.90 + /- 6.52 ( p < 0.0001 ) ; PPI 4.0 + /- 0.52 to 1.95 + /- 1.29 ( p < 0.0001 ) ; VAS 70.17 + /- 9.21 to 31.27 + /- 29.74 ( p < 0.0001 ) and 11 PLS 6.97 + /- 0.73 to 3.63 + /- 2.34 ( p < 0.0001 ) in comparison to placebo ( means + /- SEM ) . The ' global impression of change ' question naire showed much or moderate improvement in pain in 58.2 % of patients receiving divalproex vs. 14.8 % of those receiving placebo . The drug was well tolerated by all patients , except one who developed severe vertigo after 10 days of treatment . DISCUSSION Divalproex sodium provides significant pain relief in patients of post-herpetic neuralgia , with very little incidence of adverse reactions . These data provide a basis for longer trials in a larger group of patients & NA ; Chronic pain is associated with a range of other problems , including disturbed sleep , depression , anxiety , fatigue , reduced quality of life , and an inability to work or socialise . We investigated whether good symptom control of pain ( using definitions of moderate and substantial benefit ) is associated with improvement in other symptoms . Individual patient data from four r and omised trials in fibromyalgia ( 2575 patients ) lasting 8–14 weeks were used to calculate  percentage  pain reduction  for each completing patient ( 1858 ) , divided into one of five groups according to pain reduction , irrespective of treatment : substantial benefit – ≥50 % pain reduction ; moderate – 30 % to < 50 % ; minimal – 15 % to < 30 % ; marginal – 0 % to < 15 % ; worse – < 0 % ( increased pain intensity ) . We then calculated change from baseline to end of trial for measures of fatigue , function , sleep , depression , anxiety , ability to work , general health status , and quality ‐adjusted life year ( QALY ) gain over a 12‐month period . Substantial and moderate pain intensity reductions were associated with statistically significant reduction from baseline by end of trial in all measures , with values by trial end at or approaching normative values . Substantial pain intensity reduction result ed in 0.11 QALYs gained , and moderate pain intensity reduction in 0.07 QALYs gained over a 12‐month period . Substantial and moderate pain intensity reduction predicts broad beneficial outcomes and improved quality of life that do not occur without pain relief . Pain intensity reduction is a simple and effective predictor of which patients should continue treatment , and which should discontinue and try an alternative therapy BACKGROUND Various drugs are effective in the management of painful diabetic neuropathy , but none is completely satisfactory . We previously found sodium valproate to be effective and safe in a short-term study . AIM To test the effectiveness and safety of sodium valproate in the management of painful diabetic neuropathy over 3 months . DESIGN R and omized double-blind placebo-controlled study . METHODS Consecutive attending patients with type 2 diabetes mellitus with painful neuropathy were asked to participate in the trial : 48 agreed . Five were excluded : three with HbA(1c ) > 11 , one with too low a pain level and one who withdrew consent . The remaining 43 were given either drug ( group A ) or placebo ( group B ) . Each patient was assessed clinical ly . Quantitative assessment of pain was done by McGill Pain Question naire , Visual Analogue Score and Present Pain Intensity , at the beginning of the study , after 1 month and after 3 months . Motor and sensory nerve conduction velocities were measured initially and after 3 months . Liver function tests and other adverse drug-related effects were assessed periodically . RESULTS Of the 43 patients , four dropped out : one in group A and three in group B. There was significant improvement in pain score in group A , compared to group B , at 3 months ( p < 0.001 ) . Changes in electrophysiological data were not significant . The drug was well-tolerated by all patients , except one , who had raised serum AST and ALT levels after 1 month of treatment , and whose treatment was discontinued . DISCUSSION Sodium valproate is well-tolerated , and provides significant subjective improvement in painful diabetic neuropathy The aim of this r and omized , double-blind , placebo-controlled cross-over study was to test whether valproic acid relieves  painful polyneuropathy . Thirty-one patients completed two treatment phases of 4 weeks ’ duration with valproic acid ( 1,500 mg daily ) and placebo . There was no significant difference between valproic acid and placebo in the rating of total pain ( median , 5 in the valproic acid period vs 6 in the placebo period ; p = 0.24 ) or in individual pain ratings The efficacy and toxicity of sodium valproate for  cancer-related neuropathic pain  was evaluated in a phase II study at this cancer center . Twenty-five patients entered 
    Output:
    
There is insufficient evidence to support the use of valproic acid or sodium valproate as a first-line treatment for neuropathic pain .
There is more robust evidence of greater efficacy for a small number of other drugs