title: GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). Daily repetitive transcranial magnetic stimulation of primary motor cortex for neuropathic pain: A randomized, multicenter, double-blind, crossover, sham-controlled trial Addressing Dichotomous Data for Participants Excluded from Trial Analysis: A Guide for Systematic Reviewers Optimal Strategies for Reporting Pain in Clinical Trials and Systematic Reviews: Recommendations from an OMERACT 12 Workshop Lamotrigine for central poststroke pain Central post-stroke pain — a controlled trial of amitriptyline and carbamazepine Central poststroke pain in young ischemic stroke survivors in the Helsinki Young Stroke Registry Incidence of central post-stroke pain A double-blind trial of naloxone in central post-stroke pain [GRADE guidelines: 5. Rating the quality of evidence: publication bias]. Safety and efficacy of pregabalin in patients with central post-stroke pain
abstract: In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias & NA ; The double‐blinded r and omized controlled trial showed that daily repetitive transcranial magnetic stimulation of primary motor cortex provided short‐term positive effect on neuropathic pain without serious adverse events . & NA ; There is little evidence for multisession repetitive transcranial magnetic stimulation ( rTMS ) on pain relief in patients with neuropathic pain ( NP ) , although single‐session rTMS was suggested to provide transient pain relief in NP patients . We aim ed to assess the efficacy and safety of 10 daily rTMS in NP patients . We conducted a r and omized , double‐blind , sham‐controlled , crossover study at 7 centers . Seventy NP patients were r and omly assigned to 2 groups . A series of 10 daily 5‐Hz rTMS ( 500 pulses/session ) of primary motor cortex ( M1 ) or sham stimulation was applied to each patient with a follow‐up of 17 days . The primary outcome was short‐term pain relief assessed using a visual analogue scale ( VAS ) . The secondary outcomes were short‐term change in the short form of the McGill pain question naire ( SF‐MPQ ) , cumulative changes in the following scores ( VAS , SF‐MPQ , the Patient Global Impression of Change scale [ PGIC ] , and the Beck Depression Inventory [ BDI ] ) , and the incidence of adverse events . Analysis was by intention to treat . This trial is registered with the University hospital Medical Information Network Clinical Trials Registry . Sixty‐four NP patients were included in the intention‐to‐treat analysis . The real rTMS , compared with the sham , showed significant short‐term improvements in VAS and SF‐MPQ scores without a carry‐over effect . PGIC scores were significantly better in real rTMS compared with sham during the period with daily rTMS . There were no significant cumulative improvements in VAS , SF‐MPQ , and BDI . No serious adverse events were observed . Our findings demonstrate that daily high‐frequency rTMS of M1 is tolerable and transiently provides modest pain relief in NP patients Introduction Systematic review er authors intending to include all r and omized participants in their meta-analyses need to make assumptions about the outcomes of participants with missing data . Objective The objective of this paper is to provide systematic review er authors with a relatively simple guidance for addressing dichotomous data for participants excluded from analyses of r and omized trials . Methods This guide is based on a review of the Cochrane h and book and published method ological research . The guide deals with participants excluded from the analysis who were considered ‘ non-adherent to the protocol ’ but for whom data are available , and participants with missing data . Results Systematic review er authors should include data from ‘ non-adherent ’ participants excluded from the primary study authors ' analysis but for whom data are available . For missing , unavailable participant data , authors may conduct a complete case analysis ( excluding those with missing data ) as the primary analysis . Alternatively , they may conduct a primary analysis that makes plausible assumptions about the outcomes of participants with missing data . When the primary analysis suggests important benefit , sensitivity meta-analyses using relatively extreme assumptions that may vary in plausibility can inform the extent to which risk of bias impacts the confidence in the results of the primary analysis . The more plausible assumptions draw on the outcome event rates within the trial or in all trials included in the meta- analysis . The proposed guide does not take into account the uncertainty associated with assumed events . Conclusions This guide proposes methods for h and ling participants excluded from analyses of r and omized trials . These methods can help in establishing the extent to which risk of bias impacts meta- analysis results Objective . Pain is a patient-important outcome , but current reporting in r and omized controlled trials and systematic review s is often suboptimal , impeding clinical interpretation and decision making . Methods . A working group at the 2014 Outcome Measures in Rheumatology ( OMERACT 12 ) was convened to provide guidance for reporting treatment effects regarding pain for individual studies and systematic review s. Results For individual trials , authors should report , in addition to mean change , the proportion of patients achieving 1 or more thresholds of improvement from baseline pain ( e.g. , ≥ 20 % , ≥ 30 % , ≥ 50 % ) , achievement of a desirable pain state ( e.g. , no worse than mild pain ) , and /or a combination of change and state . Effects on pain should be accompanied by other patient-important outcomes to facilitate interpretation . When pooling data for meta analysis , authors should consider converting all continuous measures for pain to a 100 mm visual analog scale ( VAS ) for pain and use the established , minimally important difference ( MID ) of 10 mm , and the conventionally used , appreciably important differences of 20 mm , 30 mm , and 50 mm , to facilitate interpretation . Effects ≤ 0.5 units suggest a small or very small effect . To further increase interpretability , the pooled estimate on the VAS should also be transformed to a binary outcome and expressed as a relative risk and risk difference . This transformation can be achieved by calculating the probability of experiencing a treatment effect greater than the MID and the thresholds for appreciably important differences in pain reduction in the control and intervention groups . Conclusion . Presentation of relative effects regarding pain will facilitate interpretation of treatment effects Objective : Central poststroke pain ( CPSP ) is usually difficult to treat . Amitriptyline , the only oral preparation shown to be effective in a r and omized controlled trial , is often associated with a range of side effects related to the many mechanisms of actions of tricyclic antidepressants . We investigated the effect of lamotrigine , a drug that reduces neuronal hyperexcitability , on poststroke pain . Methods : Thirty consecutive patients with CPSP ( median age 59 years , range 37 to 77 ; median pain duration 2.0 years , range 0.3 to 12 ) from two centers participated in a r and omized , double-blind , placebo-controlled cross-over study . The study consisted of two 8-week treatment periods separated by 2 weeks of wash-out . The primary endpoint was the median value of the mean daily pain score during the last week of treatment while treated with 200 mg/d lamotrigine . Secondary endpoints were median pain scores while on lamotrigine 25 mg/d , 50 mg/d , and 100 mg/d ; a global pain score ; assessment of evoked pain ; areas of spontaneous pain ; and allodynia/dysesthesia . Results : Lamotrigine 200 mg/d reduced the median pain score to 5 , compared to 7 during placebo ( p = 0.01 ) in the intent-to-treat population of 27 patients . No significant effect was obtained at lower doses . Twelve patients ( 44 % ) responded to the treatment . There was a uniform tendency to reduction of all secondary outcome measures , but lamotrigine only had significant effects on some of the secondary outcome measures . Lamotrigine was well tolerated with few and transient side effects . Two mild rashes occurred during lamotrigine treatment , one causing withdrawal from study . Conclusions : Oral lamotrigine 200 mg daily is a well tolerated and moderately effective treatment for central poststroke pain . Lamotrigine may be an alternative to tricyclic antidepressants in the treatment of CPSP & NA ; A double‐blind , 3‐phase , cross‐over , placebo‐controlled trial of the pain‐relieving effect of amitriptyline and carbamazepine was carried out in 15 patients with central post‐stroke pain ( CPSP ) but without signs of depression . Treatment was given , in r and omized order , for periods of 4 weeks , separated by 1 week wash‐out . The final doses were 75 and 800 mg/day , respectively , for amitriptyline and carbamazepine . The treatment effects were assessed by daily ratings of pain intensity on a 10‐step verbal scale and at the end of each treatment period by a global rating of the analgesic effect on a 5‐step verbal scale . For the assessment of depression the Comprehensive Psychopathological Rating Scale ( CPRS ) was used . Amitriptyline produced a statistically significant reduction of pain when compared to placebo . According to the global rating , 10 of the 15 patients were responders to this drug . The effect could already be noticed during the second treatment week and it appeared to be correlated to the plasma concentration , since the median total ami‐ and nortriptyline concentrations were 497 and 247 nmol/1 , respectively , for responders and non‐responders . The early onset , together with the fact that the patients were not depressed , nor did they obtain reduced scores on ratings of depressive symptoms and signs , provides strong support for the conclusion that the pain relief was not caused by an antidepressive effect . Five of the 14 patients treated with carbamazepine  reported some pain relief , but the effect did not reach statistical significance when compared to placebo . No correlation was found between effect and plasma concentration . In general , the patients tolerated the planned final dose of amitriptyline well . No final dose reduction was necessary . Carbamazepine caused more side effects and the final dose had to be reduced in 4 patients . However , only 1 patient had to be taken off medication , on day 25 , due to drug interaction Objective : We describe the frequency , duration , clinical characteristics , and radiologic correlates of central poststroke pain  ( CPSP ) in young ischemic stroke survivors in a prospect i ve study setting . Methods : A question naire of pain and sensory abnormalities and EQ-5D quality -of-life question naire were sent to all 824 surviving and eligible patients of the Helsinki Young Stroke Registry . Patients ( n = 58 ) with suspected CPSP were invited to a clinical visit and filled in the PainDETECT , Brief Pain Inventory , and Beck Depression Inventory question naires . Results : Of the included 824 patients , 49 had CPSP ( 5.9 % ) , 246 patients ( 29.9 % ) had sensory abnormality without CPSP , and 529 patients ( 64.2 % ) had neither sensory abnormality nor CPSP . The median follow-up time from stroke was 8.5 years ( interquartile range 5.0–12.1 ) . Patients with CPSP had low quality of life compared to those with sensory abnormality without CPSP ( p = 0.007 ) as well as to those with no sensory abnormality and no CPSP ( p < 0.001 ) . Forty ( 82 % ) of the patients with CPSP had concomitant other pain . CPSP was associated with moderate ( p < 0.001 ) and severe ( p < 0.001 ) stroke symptoms , but there was no difference in age at stroke onset or subtype of stroke according to the TOAST classification between the groups . Stroke localization was not correlated with CPSP . Conclusions : Late persistent CPSP was found in 5.9 % of young stroke survivors and was associated with concomitant other pain , impaired quality of life , and moderate or severe stroke symptoms & NA ; Central post‐stroke pain ( CPSP ) is a neuropathic pain syndrome characterized by constant or intermittent pain in a body part occurring after stroke and associated with sensory abnormalities in the painful body part . This study describes CPSP prospect ively during the first year after stroke and characterizes the cerebrovascular lesions and neurological signs associated with the CPSP syndrome . Two hundred and sixty‐seven consecutively admitted patients younger than 81 years were examined in the first week , at 1 , 6 and 12 months after stroke . Sensibility to touch ( cotton wool ) , temperature ( 20 ° C and 40 ° C ) , and pinprick was studied using the contralateral face and extremity as control . A CT scan was done 8 ( median ) days ( range : 1–34 days ) after stroke . Two hundred and seven ( 78 % ) patients surviving at least 6 months who were able to communicate reliably formed the basis of the study . Abnormal sensory signs were found at least once in 87 ( 42 % ) patients . CPSP was found in 16 ( 8 % ) patients of whom all but 1 patient also had evoked dysesthesia or allodynia . Further 1 patient had persistent evoked dysesthesia but denied pain . CPSP was not related to sex or age . In patients with single acute cerebral lesions there were no relation between size or location of the lesions and the presence of CPSP . The pain was light in 6 ( 3 % ) patients and moderate to severe in 10 ( 5 % ) patients . The pain quality was usually lacerating or aching . Fifteen ( 94 % ) patients had decreased temperature , touch and pain sensibility and 9 ( 56 % ) reported allodynia to cold stimulation and another 9 ( 56 % ) patients reported this to touch . Pain onset was within 1 month after stroke in 10 ( 63 % ) patients , between 1 and 6 months in 3 ( 19 % ) patients and more than 6 months after stroke in 3 ( 19 % ) patients & NA ; Intravenous naloxone has been cl aim ed to produce pain relief in opioid‐resistant central post‐stroke pain ( CPSP , ‘ thalamic syndrome ’ ) . In a double‐blind trial , carried out in 20 patients with established CPSP , naloxone ( up to 8 mg in 20 ml vehicle ) was tested against normal saline ; each patient was r and omly given naloxone or saline and the other substance 2 or 3 weeks later . VAS and verbal pain scores were obtained immediately before and after naloxone or saline injection , and subjective ratings followed for 2 weeks . Three patients obtained transient pain relief with naloxone , 4 with saline , and another 4 with both . Statistical tests failed to show any influence of giving naloxone first or second . In all cases except one , pain relief had disappeared by the evening of the day on which the test was performed ; one case , following naloxone , continued to experience pain relief until the following morning . We therefore conclude that intravenous naloxone is of no value in alleviating the pain of CPSP In the GRADE approach , r and omized trials are classified as high quality evidence and observational studies as low quality evidence but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted & NA ; Pregabalin has demonstrated efficacy in several forms of neuropathic pain , but its long‐term efficacy in central post‐stroke pain ( CPSP ) is unproven . We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP . A 13‐week , r and omized , double‐blind , multicenter , placebo‐controlled , parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ⩾18 years with CPSP . The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit . Secondary endpoints included other pain parameters and patient‐reported sleep and health‐related quality ‐of‐life measures . A total of 219 patients were treated ( pregabalin  n = 110  ; placebo n = 109 ) . A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group ( LS mean difference = –0.2 ; 95 % CI = –0.7 , 0.4 ; P = 0.578 ) . Treatment with pregabalin result ed in significant improvements , compared with placebo , on secondary endpoints including MOS‐sleep , HADS‐A anxiety , and clinician global impression of change ( CGIC ) P < 0.05 . Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 ( 8.2 % ) of pregabalin patients versus 4 ( 3.7 % ) of placebo patients . Although pain reductions at endpoint did not differ significantly between pregabalin and placebo , improvements in sleep , anxiety , and CGIC suggest some utility of pregabalin in the management of CPSP . Pain reductions at endpoint did not differ significantly between pregabalin and placebo , but improvements in comorbid conditions suggest some utility of pregabalin in central post‐stroke pain management
target: Results suggested that all therapies had little to no effect on pain and other patient-important outcomes .
  Our findings are inconsistent with major clinical practice guidelines ; the available evidence suggests no beneficial effects of any therapies that research ers have evaluated in r and omized controlled trials
background: BACKGROUND AND PURPOSE Central poststroke pain is a chronic neuropathic disorder that follows a stroke .
  Current research on its management is limited , and no review has evaluated all therapies for central poststroke pain .