***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: The microcirculation appears to be impaired in cold chronic complex regional pain syndrome ( CRPS ) . This double-blind , placebo-controlled , r and omized trial investigated the effect of the nitric oxide ( NO ) donor isosorbide dinitrate ( ISDN ) on the peripheral blood flow in patients with chronic CRPS . Twenty-four patients received 1 % ISDN in Vaseline or a placebo ointment applied to the dorsum of the affected h and four times daily for 10 weeks . The patients participated in a physical therapy program to improve activity . The primary outcome measure was blood distribution in the affected extremity , which was determined by measuring the skin temperature using videothermography . We also measured NO and endothelin-1 concentrations in blister fluid , pain using the visual analog scale , and activity limitations using an upper limb activity monitor and the Disabilities of Arm Shoulder and H and Question naire .  ISDN failed to produce a significant improvement in temperature asymmetry in chronic cold CRPS patients , and it did not result in the expected reduction in pain and increase in activity compared with placebo either . There may be other central or peripheral factors contributing to the disturbed vasodynamics in cold chronic CRPS that are not influenced by NO substitution . This study does not show an improvement of the regional blood distribution by ISDN  in the involved extremity of patients with cold-type CRPS Background Placebo treatment can significantly influence subjective symptoms . However , it is widely believed that response to placebo requires concealment or deception . We tested whether open-label placebo ( non-deceptive and non-concealed administration ) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome ( IBS ) . Methods Two-group , r and omized , controlled three week trial ( August 2009-April 2010 ) conducted at a single academic center , involving 80 primarily female ( 70 % ) patients , mean age 47±18 with IBS diagnosed by Rome III criteria and with a score ≥150 on the IBS Symptom Severity Scale ( IBS-SSS ) . Patients were r and omized to either open-label placebo pills presented as “ placebo pills made of an inert substance , like sugar pills , that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes ” or no-treatment controls with the same quality of interaction with providers . The primary outcome was IBS Global Improvement Scale ( IBS-GIS ) . Secondary measures were IBS Symptom Severity Scale ( IBS-SSS ) , IBS Adequate Relief ( IBS-AR ) and IBS Quality of Life ( IBS-QoL ) . Findings Open-label placebo produced significantly higher mean ( ±SD ) global improvement scores ( IBS-GIS ) at both 11-day midpoint ( 5.2±1.0 vs. 4.0±1.1 , p<.001 ) and at 21-day endpoint ( 5.0±1.5 vs. 3.9±1.3 , p = .002 ) . Significant results were also observed at both time points for reduced symptom severity ( IBS-SSS , p = .008 and p = .03 ) and adequate relief ( IBS-AR , p = .02 and p = .03 ) ; and a trend favoring open-label placebo was observed for quality of life ( IBS-QoL ) at the 21-day endpoint ( p = .08 ) . Conclusion Placebos administered without deception may be an effective treatment for IBS . Further research is warranted in IBS , and perhaps other conditions , to eluci date whether physicians can benefit patients using placebos consistent with informed consent . Trial Registration Clinical Trials.gov OBJECTIVES Complex regional pain syndrome ( CRPS ) , formerly known as reflex sympathetic dystrophy ( RSD ) , is a painful , disabling disorder for which treatment is difficult . The aim of this study was to determine the efficacy of pamidronate in a double-blind r and omized placebo-controlled trial . METHODS Patients referred to our regional multidisciplinary pain management center who fulfilled the International Association for the Study of Pain criteria for CRPS Type I were enrolled in the study over a 2-year period . Patients were administered , intravenously , either pamidronate , 60 mg as a single dose , or normal saline . Patients ' pain scores , global assessment of disease severity scores , and functional assessment ( SF-36 ) scores were documented at baseline and at 1 and 3 months . RESULTS Twenty-seven patients ( 18 female , 9 male ; average age 45 years ) were recruited , of whom 14 received pamidronate and 13 received placebo . Overall improvements in pain score , patient 's global assessment of disease severity score , and physical function ( SF-36 ) score were noted in the pamidronate group at 3 months , and improvements in role physical ( SF-36 ) score were noted at 1 and 3 months . There was variability in pamidronate response among individuals . CONCLUSIONS Pamidronate may be a useful treatment option in the management of patients with CRPS Type I. Although treatment response was variable , the majority of patients improved . Early administration in t and em with other treatment measures is recommended Background . Complex regional pain syndrome type 1 ( CRPSt1 ) of the upper limb is a painful and debilitating condition , frequent after stroke , and interferes with the rehabilitative process and outcome . However , treatments used for CRPSt1 of the upper limb are limited . Objective . This r and omized controlled study was conducted to compare the effectiveness on pain and upper limb function of mirror therapy on CRPSt1 of upper limb in patients with acute stroke . Methods . Of 208 patients with first episode of unilateral stroke admitted to the authors ’ rehabilitation center , 48 patients with CRPSt1 of the affected upper limb were enrolled in a r and omized controlled study , with a 6-month follow-up , and assigned to either a mirror therapy group or placebo control group . The primary end points were a reduction in the visual analogue scale score of pain at rest , on movement , and brush-induced tactile allodynia . The secondary end points were improvement in motor function as assessed by the Wolf Motor Function Test and Motor Activity Log . Results . The mean scores of both the primary and secondary end points significantly improved in the mirror group ( P < .001 ) . No statistically significant improvement was observed in any of the control group values ( P > .001 ) . Moreover , statistically significant differences after treatment ( P < .001 ) and at the 6-month follow-up were found between the 2 groups . Conclusions . The results indicate that mirror therapy effectively reduces pain and enhances upper limb motor function in stroke patients with upper limb CRPSt1 OBJECTIVE Complex regional pain syndrome type I ( CRPS-I ) is a severely disabling pain syndrome for which no definite treatment has been established . The aim of this multi-centre , r and omized , double-blind placebo-controlled trial was to test the efficacy of the amino-bisphosphonate neridronate in patients with CRP-I. METHODS Eighty-two patients with CRP-I at either h and or foot were r and omly assigned to i.v . infusion of 100 mg neridronate given four times over 10 days or placebo . After 50 days the former placebo patients were given open label the same regimen of neridronate . RESULTS Within the first 20 days , visual analogue scale ( VAS ) score decreased significantly more in the neridronate group . In the following 20 days , VAS remained unchanged in the placebo group and further decreased in the active group by 46.5 mm ( 95 % CI -52.5 , -40.5 ) vs 22.6 mm ( 95 % CI -28.8 , -16.3 ) for placebo group ( P < 0.0001 ) . Significant improvements vs placebo were observed also for a number of other indices of pain and quality of life . During the open-extension phase in the formerly placebo group the results of treatment were superimposable on those seen during the blind phase in the active group . A year later none of the patients was referring symptoms linked to CRPS-I. CONCLUSION In patients with acute CRPS-I , four i.v . infusions of neridronate 100 mg are associated with clinical ly relevant and persistent benefits . These results provide conclusive evidence that the use of bisphosphonates , at appropriate doses , is the treatment of choice for CRPS-I. TRIAL REGISTRATION EU Clinical Trials Register , https://www . clinical trialsregister.eu/ , 2007 - 003372 - 18 Background Complex Regional Pain Syndrome type one ( CRPS I ) or formerly Reflex Sympathetic Dystrophy ( RSD ) is a disabling syndrome , in which a painful limb is accompanied by varying symptoms . Neuropathic pain is a prominent feature of CRPS I , and is often refractory to treatment . Since gabapentin is an anticonvulsant with a proven analgesic effect in various neuropathic pain syndromes , we sought to study the efficacy of the anticonvulsant gabapentin as treatment for pain in patients with CRPS I. Methods We did a r and omized double blind placebo controlled crossover study with two three-weeks treatment periods with gabapentin and placebo separated by a two-weeks washout period . Patients started at r and om with gabapentin or placebo , which was administered in identical capsules three times daily . We included 58 patients with CRPS type 1 . Results Patients reported significant pain relief in favor of gabapentin in the first period . Therapy effect in the second period was less ; finally result ing in no significant effect combining results of both periods . The CRPS patients had sensory deficits at baseline . We found that this sensory deficit was significantly reversed in gabapentin users in comparison to placebo users . Conclusions Gabapentin had a mild effect on pain in CRPS I. It significantly reduced the sensory deficit in the affected limb . A sub population of CRPS patients may benefit from gabapentin UNLABELLED To assess the effects of intravenous administration of the free radical scavenger mannitol 10 % on complaints associated with  complex regional pain syndrome Type I ( CRPS I ) , a r and omized , placebo-controlled , double-blinded trial was performed . Forty-one CRPS I patients according to the Bruehl et al diagnostic criteria , were included in 2 outpatient pain clinics of 2 university medical centers and r and omly assigned to receive either 10 % mannitol iv in 1 L 0.9 % NaCL in 4 hours for 5 consecutive days or equal volumes of 0.9 % NaCL ( placebo ) . Patients in both groups received physical therapy according to protocol and rescue pain medication if required . Complaints on impairment and disability level and quality of life were assessed up to 9 weeks after baseline , with primary measurement points at 2 , 6 , and 9 weeks . Monitoring of pain using the visual analogue scale took place continuously during the course of the trial . Except for a significant improvement on a subscale of the Jebsen-Taylor h and function test , no significant differences were found between mannitol and placebo treatment . Changes in both groups in the course of the trial were small and clinical ly irrelevant on all measurement indices . We conclude that intravenous administration of 10 % mannitol is not more effective than placebo in reducing complaints for CRPS I patients and provides no addition to already-established interventions for CRPS I. Whether 10 % mannitol can provide beneficial effects for subgroups of CRPS I patients with a pathophysiological profile more closely fitting the presumed mode of action for this intervention remains to be established . PERSPECTIVE This article addresses the efficacy of the intravenous administration of the free radical scavenger mannitol for treatment of CRPS type 1 . This intervention is not more effective than placebo in reducing complaints for CRPS I patients and provides no addition to already-established interventions for CRPS Background This double-blind , r and omized , controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome ( CRPS ) in one lower extremity . Methods Twenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks . The patients also participated in a physical therapy program . The primary outcome measure was temperature difference between the CRPS side and the contralateral side , determined by measuring the skin temperature with videothermography . Secondary outcomes were : pain measured on a Visual Analogue Scale , muscle force measured with a MicroFet 2 dynamometer , and level of activity measured with an Activity Monitor ( AM ) and walking tests . Results At the end of the study period , the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group , but there was a significant and clinical ly relevant reduction of pain in the tadalafil group . Muscle force improved in both treatment groups and the AM revealed small , non-significant improvements in time spent st and ing , walking , and the number of short walking periods . Conclusion Tadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction , and deserves further investigation . Trial Registration The registration number in the Dutch Trial Register is IS RCT N60226869 ABSTRACT Complex Regional Pain Syndrome Type 1 ( CRPS‐1 ) responds poorly to st and ard pain treatment . We evaluated if the N‐methyl‐d‐aspartate receptor antagonist S(+)‐ketamine improves pain in CRPS‐1 patients . Sixty CRPS‐1 patients ( 48 females ) with severe pain participated in a double‐blind r and omized placebo‐controlled parallel‐group trial . Patients were given a 4.2‐day intravenous infusion of low‐dose ketamine ( n = 30 ) or placebo ( n = 30 ) using an individualized stepwise tailoring of dosage based on effect ( pain relief ) and side effects ( nausea/vomiting/psychomimetic effects ) . The primary 
    Output:
    
Placebo response was significant at the earliest time period ( 15 - 30 minutes ) .
There was no significant evidence of placebo response at any of the other time periods .
PERSPECTIVE In this meta- analysis of placebo responses in r and omized controlled trials in long-st and ing CRPS , published during 1966 to 2013 , we found no evidence for placebo analgesia , except at very early time points .