***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 & NA ; A prospect i ve double‐blind r and omized trial was conducted on 184 cancer patients with moderate to severe chronic pain to evaluate the analgesic efficacy and tolerability of diclofenac alone ( 50 mg q.i.d . ) or in combination with a weak opioid ( codeine 40 mg q.i.d . ) , or with an anti‐depressant ( imipramine , 10 or 25 mg t.i.d . ) . All demographic and clinical characteristics including cancer type , presence of bone metastases , baseline pain severity , neuropathic and nociceptive pain , and depressive state , were well balanced between the three treatment groups . The main analysis of the study was on the VAS scores at visit 2 ( day 4 ) . The mean VAS values for both associations imipramine plus diclofenac and codeine plus diclofenac were similar to the association placebo plus diclofenac . Patients on imipramine plus diclofenac and on placebo plus diclofenac were withdrawn mainly for inadequate efficacy , while patients on codeine plus diclofenac discontinued equally for inadequate efficacy or adverse events . In conclusion , in a short‐term evaluation the addition of a tricyclic anti‐depressant or a weak opioid to diclofenac did not provide further analgesia with respect to diclofenac administration alone Fifty-nine patients referred for painful diabetic neuropathy of the lower extremities were evaluated for depression and response to antidepressant drug therapy in a double-blind controlled study . All patients were found to have substantial degrees of depression during psychiatric interview and by Kupfer-Detre test scores ( 8.1 + /- 0.6 , as compared with control values of 4.0 to 4.3 + /- 0.2 ) . Treatment with imipramine hydrochloride or amitriptyline hydrochloride result ed in complete remission of lower extremity pains in all patients in 10 + /- 2 weeks , with concomitant relief of depression and return of depression test scores to 3.8 . These results suggest that the syndrome of painful diabetic neuropathy of the lower extremities represents a depressive equivalent in a large proportion of cases and that treatment with imipramine or amitriptyline is a successful mode of therapy for such persons Background : Tricyclic antidepressants ( TCA ) are often used in the treatment of painful polyneuropathy .  Venlafaxine is a serotonin and weak noradrenaline reuptake inhibitor antidepressant with a different profile of other pharmacologic actions from those of TCA . Objective : To test if venlafaxine would relieve painful polyneuropathy and compare its possible efficacy with that of the TCA imipramine . Methods : The study design was r and omized , double blind , and placebo controlled , with a three-way crossover . Forty patients were assigned to one of the treatment sequences , and 29 completed all three study periods . The daily doses were venlafaxine 225 mg and imipramine 150 mg . During the three treatment periods , each of 4 weeks ’ duration , patients rated pain paroxysms , constant pain , and touch- and pressure-evoked pain by use of 0- to 10-point numeric rating scales . Results : The sum of the individual pain scores during treatment week 4 was lower on venlafaxine ( 80 % of baseline score ; p = 0.006 ) and imipramine ( 77 % ; p = 0.001 ) than on placebo ( 100 % ) and did not show any statistical difference between venlafaxine and imipramine ( p = 0.44 ) . The individual pain scores for pain paroxysms , constant pain , and pressure-evoked pain showed a similar pattern , whereas touch-evoked pain was uncommon and was not altered by any of the drugs . Numbers needed to treat to obtain one patient with moderate or better pain relief were 5.2 for venlafaxine and 2.7 for imipramine . Conclusion : Venlafaxine relieves pain in polyneuropathy and may be as effective as imipramine 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 Twelve patients with severe , painful diabetic neuropathy in the lower extremities were treated with imipramine and placebo in a fixed-dose , double-blind , crossover study of five plus five weeks . Seven patients experienced notable improvement while receiving imipramine and none while receiving placebo . The rating of specific symptoms at the end of each treatment period showed a beneficial effect of imipramine on pain , paresthesia , dysesthesia , numbness , and nocturnal aggravation . The plasma levels of imipramine and its metabolite desipramine were significantly higher in patients who benefited from imipramine treatment 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 Tricyclic antidepressants ( TCA ) are the best-documented treatment of neuropathic pain .  TCAs have a pronounced interindividual pharmacokinetic variability and a narrow therapeutic index . The aim of this study was to characterize the plasma concentration – effect relationship of imipramine in neuropathic pain and to determine the usefulness of therapeutic drug monitoring ( TDM ) of TCA treatment in a population with noncancer chronic pain . To do this , 83 patients with chronic noncancer neuropathic pain were included . Information on previous use of TCA was collected , and patients were tested for the presence of hyperalgesia . Pain intensity and pain relief were recorded , and the Short Form McGill Pain Question naire and Major Depression Inventory were completed before and during a TDM-based imipramine treatment . Imipramine dose was increased in steps of 25 mg/d every second week , and blood sample s were taken at every dose . Endpoints were best possible pain relief , unacceptable side effects , or insufficient pain relief despite plasma drug level > 500 nmol/L. Dose range used was 10–300 mg/d . The study showed that imipramine 75 mg/d caused a 36-fold interindividual variation in steady-state plasma drug concentrations . In 46 responders ( global pain relief > 25 % ) the plasma drug concentration at which an individual maximal analgesic effect was obtained ranged from 50 to 1400 nmol/L , but for the majority it was below 400 nmol/L. The concentration – effect relationship was similar for patients with central versus peripheral neuropathic pain and independent of the presence of hyperalgesia . Previous treatment failure with non-TDM TCA treatment was not a predictor of poor response to TDM-based treatment . In conclusion , there is a pronounced interindividual variability in concentration – effect relationship for imipramine treatment in neuropathic pain , but the majority of patients obtain a maximal analgesic effect at drug levels below 400 nmol/L. The concentration – effect relationship is similar for patients with central and peripheral neuropathic pain . Further studies are needed to document if 
    Output:
    
No pooling of data was possible , but third tier evidence in individual studies indicated some improvement in pain relief with imipramine compared with placebo , although this is was very low quality evidence , derived mainly from group mean data and completer analyses , in small , short duration studies where major bias is possible .
Participants taking imipramine  generally experienced more adverse events , notably dry mouth , and a higher rate of withdrawal due to adverse events , than did participants taking placebo .
AUTHORS ' CONCLUSIONS This review found little evidence to support the use of imipramine to treat neuropathic pain .