***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: A r and omized , double-blind , placebo-controlled study of brain-derived neurotrophic factor ( rhBDNF ) was conducted in 30 patients with insulin-treated diabetes mellitus , with obligatory abnormalities of sural nerve conduction studies and vibration perception threshold ( VPT ) at the great toe on recruitment . Nine patients received placebo , 11 rhBDNF ( 25 microg/ kg ) and 10 rhBDNF ( 100 microg/kg ) s.c . daily for 3 months , and were assessed at days 0 , 8 , 15 , 29 , 43 , 57 and 85 with nerve conduction and quantitative sensory and autonomic tests including VPT , thermal and light touch thresholds , and cutaneous axon-reflexes . No statistically significant differences were found among the 3 treatment groups between baseline and day 85 values . To examine possible reasons for lack of effect , post hoc analysis was performed . In the subset of patients with abnormal but detectable cool detection threshold ( CDT ) at baseline , there was improvement of CDT at day 85 when compared to baseline in the treated ( p < 0.02 ) but not placebo group . Further , from days 43 to 85 , in the treated group but not the placebo group , CDT was indistinguishable from a group of matched normal subjects ( p > 0.05 ) . Skin biopsies failed to show evidence of structural change ; assessment of innervation of hair follicles , which is partly dependent on BDNF , was not possible because of the marked loss of this end-organ in diabetic neuropathic skin . The only side effects of rhBDNF were infrequent non-painful injection-site skin reactions and increased gut motility at the higher dose . We conclude that further pre clinical studies are warranted before any future clinical trials to see if rhBDNF improves CDT and constipation in diabetics Background : The Norfolk Quality of Life Question naire-Diabetic Neuropathy ( Norfolk QOL-DN ) is a vali date d comprehensive question naire design ed to capture the entire spectrum of DN related to large fiber , small fiber , and autonomic neuropathy not captured in existing instruments . We aim ed to determine if the Norfolk QOL-DN could be used to capture changes in QOL that correlate with nerve fiber-specific objective measures in a placebo-controlled trial of two agents that affect different nerve fibers . Methods : Sixty patients with DN were allocated to treatment on ruboxistaurin ( RBX ) ( n = 18 ) , topiramate ( TPX ) ( n = 18 ) , or placebo ( n = 18 ) . QOL-DN was administered and objective measures of nerve function were performed at entry and end of the study period . Results : Total QOL scores improved significantly in the active treatment groups ( RBX −9.56 ± 4.13 ; TPX −12.22 ± 2.76 ) but not in placebo ( −5.56 ± 3.49 ) . There were differences in nerve function improvement between treatments . Neurological symptom scores ( NSS ) improved with TPX from 5.5 ( 2.3 ) to 4.3 ( 0.65 ) ( p = .007 ) , sensory scores improved with TPX from 15.5 ( 1.79 ) to 8.3 ( 1.19 ) ( p < .001 ) , motor scores did not change , and sensory and motor impairment scores improved with TPX from 18.8 ( 2.15 ) to 12.1 ( 1.71 ) ( p = .003 ) . Total neuropathy scores ( TNS ) improved with TPX from 24.35 ( 2.61 ) to 16.35 ( 2.02 ) ( p = .001 ) . Neuropathy total symptom score−6 ( NTSS−6 ) changes were significant for both treatments : RBX 4.38 ( 0.75 ) to 1.49 ( 0.38 ) ( p < .001 ) and TPX 7.57 ( 1.3 ) to 4.26 ( 0.95 ) ( p = .036 ) . Changes in QOL-DN large fiber subscores correlated ( Spearman 's rank ) significantly with changes in NTSS-6 ( r = 0.55 ; p < .0001 ) , NSS ( r = 0.31 ; p < .04 ) , neuropathy impairment score ( NIS ) ( r = 0.35 ; p < .02 ) , and TNS ( r = 0.48 ; p < .0006 ) . Changes in QOL-DN small fiber subscores correlated significantly with changes in NTSS-6 total scores ( r = 0.40 ; p < .005 ) and intraepidermal nerve fiber density ( IENFD ) ( r = −0.29 ; p < .05 ) . Conclusion : Ruboxistaurin produced significant improvement in large fiber measures while TPX produced significant changes in small fiber measures . The Norfolk QOL-DN tool differentiated between these changes captured in the fiber-specific domains . Correlations were found between objective measures of neuropathy and total QOL , but those with nerve fiber domain scores were modest and reinforce the need to quantify QOL as an endpoint in neuropathy independent of other measures Summary The role of afferent sensory input in neuropathic pain was examined in 2 groups . Peripheral nerve blocks abolished spontaneous and evoked pain in all patients . Systemic lidocaine was more effective in pain due to polyneuropathy than nerve injury . Central sensitization does not act as an autonomous spontaneous pain‐generating mechanism . Peripheral sensory input is critical in maintaining pain after peripheral nerve damage . ABSTRACT Central sensitization after peripheral nerve injury may result in ectopic neuronal activity in the spinal cord dorsal horn , implying a potential autonomous pain‐generating mechanism . This study used peripheral nerve blockade and systemic lidocaine administration , with detailed somatosensory assessment , to determine the contribution of primary afferent input in maintaining peripheral neuropathic pain . Fourteen patients with neuropathic pain ( 7 with unilateral foot pain due to peripheral nerve injury and 7 with bilateral pain in the feet due to distal polyneuropathy ) underwent comprehensive characterization of somatosensory function by quantitative sensory testing . Patients were then administered an ultrasound‐guided peripheral nerve block with lidocaine and intravenous lidocaine infusion in r and omized order . The effect of these interventions on spontaneous pain intensity and on evoked cold , warm , pinprick , and brush responses was assessed at each session . All patients had sensory disturbances at baseline . The peripheral nerve block result ed in a complete abolition of ipsilateral pain within 10 min ( median ) in all patients , with lidocaine plasma concentrations being too low to account for a systemic effect of the drug . Intravenous lidocaine infusion reduced the spontaneous pain by 45.5 % ( ±31.7 % ) , and it reduced mechanical and thermal hypersensitivity in most patients who displayed such signs . However , the improvement in evoked hypersensitivity was not related to the effect of the drug on spontaneous pain intensity . This study demonstrated that regardless of the individual somatosensory phenotype and signs of central sensitization , primary afferent input is critical for maintaining neuropathic pain in peripheral nerve injury and distal polyneuropathy Background Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy . We set out to investigate small fiber conduction in Fabry patients using  pain-related evoked potentials ( PREP ) . Methods In this case – control study we prospect ively studied 76 consecutive Fabry patients for  electrical small fiber conduction in correlation with small fiber function and morphology . Data were compared with healthy controls using non-parametric statistical tests . All patients underwent neurological examination and were investigated with pain and depression question naires .  Small fiber function ( quantitative sensory testing , QST ) , morphology ( skin punch biopsy ) , and electrical conduction ( PREP )  were assessed and correlated . Patients were stratified for gender and disease severity as reflected by renal function . Results All Fabry patients ( 31 men , 45 women ) had small fiber neuropathy . Men with Fabry disease showed impaired cold ( p < 0.01 ) and warm perception ( p < 0.05 ) , while women did not differ from controls . Intraepidermal nerve fiber density ( IENFD ) was reduced at the lower leg ( p < 0.001 ) and the back ( p < 0.05 ) mainly of men with impaired renal function . When investigating A-delta fiber conduction with PREP , men but not women with Fabry disease had lower amplitudes upon stimulation at face ( p < 0.01 ) , h and s ( p < 0.05 ) , and feet ( p < 0.01 ) compared to controls . PREP amplitudes further decreased with advance in disease severity . PREP amplitudes and warm ( p < 0.05 ) and cold detection thresholds ( p < 0.01 ) at the feet correlated positively in male patients . ConclusionS mall fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity . PREP are well-suited to measure A-delta fiber conduction & NA ; The sodium channel blocker oxcarbazepine is efficacious in peripheral neuropathic pain patients , with preserved thermal sensation and some gain of sensory function , that is , the “ irritable nociceptor ” phenotype . & NA ; In neuropathic pain it has been suggested that pain phenotype based on putative pain mechanisms may predict response to treatment . This was a r and omised , double‐blind , placebo‐controlled , and phenotype‐stratified study with 2 6‐week treatment periods of oxcarbazepine ( 1800‐2400 mg ) and placebo . The primary efficacy measure was change in median pain intensity between baseline and the last week of treatment measured on an 11‐point numeric rating scale , and the primary objective was to compare the effect of oxcarbazepine in patients with and without the irritable nociceptor phenotype as defined by hypersensitivity and preserved small nerve fibre function determined by detailed quantitative sensory testing . Ninety‐seven patients with peripheral neuropathic pain due to polyneuropathy , surgical or traumatic nerve injury , or postherpetic neuralgia were r and omised . The intention‐to‐treat population comprised 83 patients : 31 with the irritable and 52 with the nonirritable nociceptor phenotype . In the total sample , oxcarbazepine relieved pain of 0.7 points ( on a numeric rating scale 0‐10 ; 95 % confidence interval [ CI ] 0.4‐1.4 ) more than placebo ( P = 0.015 ) and there was a significant interaction between treatment and phenotype of 0.7 ( 95 % CI 0.01‐1.4 , P = 0.047 ) . The number needed to treat to obtain one patient with more than 50 % pain relief was 6.9 ( 95 % CI 4.2‐22 ) in the total sample , 3.9 ( 95 % CI 2.3‐12 ) in the irritable , and 13 ( 95 % CI 5.3‐∞ ) in the nonirritable nociceptor phenotype . In conclusion , oxcarbazepine is more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype Summary Topical clonidine significantly reduces pain associated with diabetic neuropathy in subjects with functional nociceptors in the affected skin , as revealed by testing with topical capsaicin . Abstract A length‐dependent neuropathy with pain in the feet is a common complication of diabetes ( painful diabetic neuropathy ) . It was hypothesized that pain may arise from sensitized‐hyperactive cutaneous nociceptors , and that this abnormal signaling may be reduced by topical administration of the α2‐adrenergic agonist , clonidine , to the painful area . This was a r and omized , double‐blind , placebo‐controlled , parallel‐group , multicenter trial . Nociceptor function was measured by determining the painfulness of 0.1 % topical capsaicin applied to the pretibial area of each subject for 30 minutes during screening . Subjects were then r and omized to receive 0.1 % topical clonidine gel ( n = 89 ) or placebo gel ( n = 90 ) applied 3 times a day to their feet for 12 weeks . The difference in foot pain at week 12 in relation to baseline , rated on a 0–10 numerical pain rating scale ( NPRS ) , was compared between groups . Baseline NPRS was imputed for missing data for subjects who terminated the study early . The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo‐treated group ( the primary endpoint ; P = 0.07 ) . In subjects who felt any level of  pain to capsaicin , clonidine was superior to placebo ( P < 0.05 ) . In subjects with a capsaicin pain rating ⩾2 ( 0–10 , NPRS ) , the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo ( P = 0.01 ) . Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional ( and possibly sensitized ) nociceptors in the affected skin as revealed by testing with topical capsaicin . Screening for cutaneous n 
    Output:
    
The results indicate that epidermal nerve fiber loss , in isolation , is not a useful indicator of painful symptoms or their severity in DSP .
Intraepidermal nerve fiber density correlated reasonably well with neuropathy scores on tools assessing signs and symptoms ( such as the Michigan Neuropathy Screening Instrument and the Total Neuropathy Score ) , but less so with symptom measures only .
Among various psychophysical sensory measures , warmth detection and heat pain thresholds correlated best with intraepidermal nerve fiber density , particularly when assessed at the same anatomical site .