***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 BACKGROUND Traditional and largely qualitative review s of evidence are now giving way to much more structured systematic overviews that use a quantitative method to calculate the overall effect of treatment . The latter approach is dependent on the quality of primary studies , which may introduce bias if they are of poor method ologic quality . OBJECTIVE To test the hypothesis that the inclusion of poor- quality trials in meta-analyses would bias the conclusions and produce incorrect estimates of treatment effect . METHODS An overview of r and omized trials of antiestrogen therapy in subfertile men with oligospermia was performed to test the hypothesis . Data sources included online search ing of MEDLINE and Science Citation Index data bases between 1966 and 1994 , scanning the bibliography of known primary studies and review articles , and contacting experts in the field . After independent , blind assessment , nine of 149 originally identified studies met the inclusion criteria and were selected . We assessed study quality independently . Outcome data from each study were pooled and statistically summarized . RESULTS There was a marginal improvement in pregnancy rate with antiestrogen treatment ( odds ratio , 1.6 ; 95 % confidence interval , 0.9 to 2.6 ) . Sensitivity analyses on the basis of method ologic quality demonstrated that poor- quality studies produced a positive effect with treatment , whereas no benefit was observed with high- quality studies . CONCLUSION The results of a meta- analysis are influenced by the quality of the primary studies included . Method ologically , poor studies tend to exaggerate the overall estimate of treatment effect and may lead to incorrect inferences 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 Amitriptyline reduces the pain caused by peripheral-nerve disease , but treatment is often limited by side effects related to the drug 's many pharmacologic actions . Selective agents might be safer and more effective . METHODS We carried out two r and omized , double-blind , crossover studies in patients with painful diabetic neuropathy , comparing  amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients , and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients . Fifty-seven patients were r and omly assigned to a study as well as to the order of treatment , permitting comparison among all three drugs and placebo as the first treatment . The patients rated the degree of pain present each day using verbal descriptors , and they also assessed the extent of pain relief globally at the end of each treatment period . RESULTS After individual dose titration , the mean daily doses of the drugs were as follows : amitriptyline , 105 mg ; desipramine , 111 mg ; and fluoxetine , 40 mg . There was moderate or greater relief of pain in 28 of the 38 patients ( 74 percent ) who received amitriptyline , 23 of the 38 patients ( 61 percent ) who received desipramine , 22 of the 46 patients ( 48 percent ) who received fluoxetine , and 19 of the 46 patients ( 41 percent ) who received placebo . The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant , but both amitriptyline and desipramine were superior to placebo .  Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients , but fluoxetine was effective only in depressed patients . CONCLUSIONS Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline , offering an alternative for patients unable to tolerate the latter . Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy . Fluoxetine , which blocks serotonin uptake , is no more effective than placebo for the relief of pain UNLABELLED Progress in the underst and ing of chronic pain with neuropathic features has been hindered by a lack of epidemiologic research in the general population . The Leeds Assessment of Neuropathic Symptoms and Signs score ( S-LANSS ) was recently vali date d for use in postal surveys , making the identification of pain of predominantly neuropathic origin possible . Six family practice s in 3 UK cities ( Aberdeen , Leeds , and London ) generated a total r and om sample of 6,000 adults . The mailed question naire included demographic items , chronic pain identification , and intensity questions , the S-LANSS , the Level of Expressed Needs question naire , and the Neuropathic Pain Scale . With a corrected response rate of 52 % , the prevalence of any chronic pain was 48 % and the prevalence of pain of predominantly neuropathic origin was 8 % . Respondents with this chronic neuropathic pain were significantly more likely to be female , slightly older , no longer married , living in council rented accommodation , unable to work , have no educational qualifications , and be smokers than all other respondents . Multiple logistic regression modeling found that pain of predominantly neuropathic origin was independently associated with older age , gender , employment ( being unable to work ) , and lower educational attainment . Respondents with this pain type also reported significantly greater pain intensity , higher scores on the NPS , higher levels of expressed need , and longer duration of pain . This is the first estimate of the prevalence and distribution of pain of predominantly neuropathic origin in the general population , using a previously vali date d and reliable data collection instrument . PERSPECTIVE Chronic pain with neuropathic features appears to be more common in the general population than previously suggested . This type of pain is more severe than other chronic pain but distributed similarly throughout sociodemographic groups & 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 UNLABELLED In 47 patients with postherpetic neuralgia ( PHN ) who had never had an adequate trial of any antidepressant , we performed a r and omized , double-blind , parallel design trial comparing desipramine , amitriptyline , and fluoxetine . Patients were titrated to a maximum of 150 mg/day for desipramine and amitriptyline and 60 mg/day for fluoxetine over a 3-week period and then treated for an additional 3 weeks before tapering off study medication . A total of 38 subjects ( 81 % ) completed the entire trial . The modified intent-to-treat analysis of percent change in daily diary pain intensity scores showed no significant differences among the 3 drugs ( ANOVA P = .120 ) . Desipramine produced the greatest reduction in pain intensity ( 47 % ) , followed by amitriptyline ( 38 % ) and fluoxetine ( 35 % ) . Clinical ly meaningful pain relief ( moderate or better ) was significantly more likely with desipramine ( 12/15 patients ) than with amitriptyline ( 9/17 ) or fluoxetine ( 5/15 ) ; chi(2)P = 0.036 ) . The 11 subjects using opioids at study entry had smaller reductions in pain than those not using concomitant opioids . The fluoxetine group had the highest noncompletion rate ( 33 % ) , with 1 subject hospitalized for hyponatremia . Although the magnitude of pain reduction and the category pain relief rating was not significantly different among the 3 drugs , the tricyclics desipramine and amitriptyline were well tolerated and provided clinical ly meaningful pain relief in 53 % to 80 % of subjects . PERSPECTIVE Few clinical trials focus on patients who are naïve to an entire class of medication . In this r and omized blinded trial , the tricyclic antidepressants desipramine and amitriptyline were compared to the serotonin-selective antidepressant fluoxetine . All 3 drugs reduced PHN pain , with desipramine providing satisfactory relief in 80 % of those treated & NA ; R and omized , double‐blind , placebo‐controlled trials on neuropathic pain treatment are accumulating , so an up date d review of the available evidence is needed . Studies were identified using MEDLINE and EMBASE search es . Numbers needed to treat ( NNT ) and numbers needed to harm ( NNH ) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions . One hundred and seventy‐four studies were included , representing a 66 % increase in published r and omized , placebo‐controlled trials in the last 5 years . Painful poly‐neuropathy ( most often due to diabetes ) was examined in 69 studies , postherpetic neuralgia in 23 , while peripheral 
    Output:
    
This review found little evidence to support the use of desipramine to treat neuropathic pain .
Effective medicines with much greater supportive evidence are available .
There may be a role for desipramine in patients who have not obtained pain relief from other treatments