The digital thermal hyperemia pattern is associated with the onset of digital ulcerations in systemic sclerosis during 3 years of follow-up.

OBJECTIVES: One of the most important skin complications in systemic sclerosis (SSc) is digital ulceration. Local thermal hyperemia (LTH) in the skin is a biphasic response to local heating involving both neurovascular and endothelial responses. Since LTH is abnormal in SSc patients, we aimed at testing whether LTH could be a prognostic tool for the onset of digital ulcers. METHODS: We prospectively enrolled 51 patients with SSc. Nailfold capillaroscopy and LTH were recorded at baseline, and patients were followed for 3 years. RESULTS: No patient with a LTH peak/plateau ratio ≥1 (n=19) developed digital ulcerations during the 3 year follow-up (100% negative predictive value), while 6 out of 32 patients with a LTH peak/plateau ratio <1 at enrolment presented with finger pad ulcerations within 3 years (p=0.05). In contrast, when lidocaine/prilocaine was applied to the finger pad, no relationship between thermal hyperemia and digital ulcerations was observed. CONCLUSIONS: A LTH peak/plateau ratio on the finger pad greater than 1, which can easily be determined in routine clinical practice, could be used to reassure patients, whatever the subtype of SSc, about the low probability of future digital ulceration. However, the prognostic value of this parameter should be confirmed in a larger cohort.

Abnormal amplitude and kinetics of digital postocclusive reactive hyperemia in systemic sclerosis.

OBJECTIVES: Postocclusive reactive hyperemia is mediated by two major mediators: sensory nerves and endothelium-derived hyperpolarizing factors. We hypothesized that the skin microvascular response to 5 min ischemia would differ depending upon the hand location in patients with systemic sclerosis (SSc), primary Raynaud's phenomenon (PRP) and healthy controls. METHODS: Fifteen patients with SSc, 15 sex- and age-matched patients with PRP and healthy controls were enrolled. Their right hands were subjected to 5 min ischemia followed by a postocclusive hyperemia test, with local microcirculation monitoring by laser speckle contrast imaging on the dorsal face of the hand. RESULTS: Postocclusive reactive hyperemia was abnormal in terms of peak and area under the curve (AUC) on all fingers except the thumb in patients with SSc and PRP compared with controls. In contrast, the kinetics of the response was longer only in SSc patients, with mean (SD) time to peak on the index, middle and ring finger were respectively 72 (58), 73 (51) and 67 (47) s for SSc; 40 (20), 40 (20) and 36 (19) s for PRP; and 34 (30), 34 (30) and 29 (24) s for controls (P=0.009 for interaction). CONCLUSIONS: We observed decreased distal digital microvascular perfusion following 5 min of ischemia in patients presenting with PRP or SSc, while the kinetics was prolonged only in SSc. A dynamic assessment of digital skin blood flow using laser speckle contrast imaging following 5 min ischemia could be used as a tool to assess microvascular abnormalities in patients with Raynaud's phenomenon secondary to SSc.

Association of the CD226 Ser(307) variant with systemic sclerosis: evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis.

OBJECTIVE: The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. METHODS: CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. RESULTS: The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 × 10(-5) . The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 × 10(-6) , OR 1.82 (95% CI 1.38-2.40), P = 2.16 × 10(-5) , and OR 1.61 (95% CI 1.25-2.08), P = 2.73 × 10(-4) , respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. CONCLUSION: Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.

BACKGROUND: Recent evidence has highlighted a potential role of interleukin 1ß (IL-1ß) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1ß. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. OBJECTIVE: /st> To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. METHODS: NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. RESULTS: Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. CONCLUSIONS: Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

Comparison between laser speckle contrast imaging and laser Doppler imaging to assess skin blood flow in humans.

OBJECTIVE: We tested the linearity between skin blood flux recorded with laser speckle contrast imaging (LSCI) and laser Doppler imaging (LDI), comparing different ways of expressing data. A secondary objective was to test within-subject variability of baseline flux with the two techniques. METHODS: We performed local heating at 36, 39, 42, and 44°C on the forearm of healthy volunteers, and measured cutaneous blood flux with LDI and LSCI. Biological zero (BZ) was obtained by occluding the brachial artery. We expressed data as raw arbitrary perfusion units (APUs) and as a percentage increase from baseline (%BL), with and without subtracting BZ. Inter-site variability was expressed as a within subject coefficient of variation (CV). RESULTS: Twelve participants were enrolled. Inter-site variability at baseline was lower with LSCI (CV=9.2%) than with LDI (CV=20.7%). We observed an excellent correlation between both techniques when data were expressed as raw APUs or APU-BZ (R=0.90; p<0.001). The correlation remained correct for %BL (R=0.77, p<0.001), but decreased for %BL-BZ (R=0.44, p=0.003). Bland-Altman plots revealed a major proportional bias between the two techniques. CONCLUSION: This study suggests that skin blood flux measured with LSCI is linearly related to the LDI signal over a wide range of perfusion. Subtracting BZ does not affect this linearity but introduces variability in baseline flux, thus decreasing the correlation when data are expressed as a function of baseline. Finally, systematic bias makes it impossible to assimilate arbitrary perfusion units provided by the two systems.

Skin microdialysis coupled with laser speckle contrast imaging to assess microvascular reactivity.

OBJECTIVE: Laser speckle contrast imaging (LSCI) can be used to assess real-time responses of skin microcirculation to pharmacological interventions. The main objective of this study was to determine whether intradermal or subdermal microdialysis fiber insertion, coupled with skin flux recording using LSCI, can be used to assess baseline cutaneous flux and the post-occlusive reactive hyperemic response. The microdialysis sites were compared to control area without microdialysis fibers. METHODS: One dermal and two subdermal microdialysis fibers were randomly inserted in the right forearm skin of six healthy volunteers. We performed consecutively tests of post-occlusive hyperemia, infusion of 29 mM sodium nitroprusside (SNP), local thermal hyperemia at 43°C and a second 29 mM SNP infusion at the end of the experiment. RESULTS: Two hours after fiber insertion, cutaneous vascular conductances (CVC) at the subdermal fiber sites were not different from their respective control regions of interest, while at the dermal site CVC remained higher (0.48+/-0.15 versus 0.37+/-0.1 PU.mm Hg(-1), P=0.003). The peak CVC and area under the curve observed during post-occlusive reactive hyperemia were similar at all fiber sites and their respective controls. We observed a similar increase in CVC using 29 mM SNP infusion, 40 min local heating at 43°C, and their combination. Finally, physiological and pharmacological responses of the subdermal sites were reproducible in terms of amplitude, whether expressed as raw CVC or as % CVCmax. CONCLUSIONS: We showed that studying skin microvascular physiological or pharmacological responses using inserted subdermal microdialysis fibers coupled with LSCI is feasible and reproducible, and provides two-dimensional information. This technique will be useful for future mechanistic studies of skin microcirculation.

Association of a KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population.

OBJECTIVE: Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor ß receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. METHODS: Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. RESULTS: The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48-0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13-0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21-0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. CONCLUSION: Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population.

BACKGROUND: TNFAIP3 encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between TNFAIP3 variants and autoimmune diseases have been reported. OBJECTIVE: To investigate the association of TNFAIP3 polymorphisms with systemic sclerosis (SSc). METHODS: Three single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in TNFAIP3 intron 2, rs5029939, were selected. The TNFAIP3 rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel-Haenszel meta-analysis. RESULTS: The rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16×10⁻7), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91×10⁻8), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2×10⁻9), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5×10⁻6) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3×10⁻5). CONCLUSION: These results suggest that TNFAIP3 is a genetic susceptibility factor for SSc.

Reproducibility and methodological issues of skin post-occlusive and thermal hyperemia assessed by single-point laser Doppler flowmetry.

OBJECTIVE: The primary objective of this study was to evaluate 1-week reproducibility of post-occlusive reactive hyperemia (PORH) and local thermal hyperemia (LTH) assessed by single-point laser-Doppler flowmetry (LDF) on different skin sites. We also evaluated spatial reproducibility of both tests on the forearm. Finally, we assessed the influence of mental stress and room temperature variations on PORH and LTH. METHODS: We performed PORH and LTH assessing skin blood flow on the forearm and on the finger pad with LDF. We repeated the sequence 1 week later. We also performed PORH and LTH during mental stress (Stroop test) and at room temperatures of 21 degrees C and 27 degrees C. Data were expressed as cutaneous vascular conductance (CVC), as a function of baseline and as a function of 44 degrees C vasodilation (%CVC(44)). Reproducibility was expressed as within subject coefficients of variation (CV) and intra-class correlation coefficients (ICC). RESULTS: Fourteen Caucasian healthy volunteers were recruited. Median age was 25 (2.7) and 50% were female. Median body mass index was 21.2 (5). PORH was reproducible on the finger, whether expressed as raw CVC (CV=25%; ICC=0.56) or as %CVC(44) (CV=24%; ICC=0.60). However, PORH showed poor reproducibility on the forearm. In the same way, LTH was reproducible on the finger pad when expressed as CVC (CV=17%; ICC=0.81) but not on the forearm. Spatial reproducibility was poor on the forearm. Elevated room temperature (27 degrees C) affected PORH and LTH on the finger pad (p<0.05) but not on the forearm. CONCLUSION: Single-point LDF is a reproducible technique to assess PORH and LTH on the finger pad when data are expressed as raw CVC or %CVC(44). On the forearm, however, it shows great inter-day variability, probably due to spatial variability of capillary density. These results highlight the need for alternative techniques on the forearm.

Excellent reproducibility of laser speckle contrast imaging to assess skin microvascular reactivity.

OBJECTIVE: We compared the inter-day reproducibility of post-occlusive reactive hyperemia (PORH) assessed by single-point laser Doppler flowmetry (LDF) and laser speckle contrast analysis (LSCI), and the reproducibility of local thermal hyperemia (LTH) assessed by LDF, laser Doppler imaging (LDI) and LSCI. We also tested whether skin blood flow assessment by LDF and by LSCI are correlated. METHODS: Skin blood flow was evaluated during PORH and LTH using LDF, LDI (for LTH only) and LSCI on the forearms of healthy volunteers, at a 7day interval. Data are expressed as cutaneous vascular conductance (CVC), as a function of baseline and scaled to the thermal plateau. Reproducibility is expressed as within subject coefficients of variation (CV, in %) and intra-class correlation coefficients (ICC). RESULTS: Twenty-eight healthy participants were enrolled in this study. The reproducibility of the PORH peak CVC was better when assessed with LSCI compared to LDF (CV=8%; ICC=0.76 and CV=30%; ICC=0.54, respectively). Inter-day reproducibility of the LTH plateau was better when assessed with LSCI or LDI than LDF (CV=15%, ICC=0.66; CV=17%, ICC=0.51 and CV=42%, ICC=0.28 respectively). Finally, we observed significant correlation between simultaneous LDF and LSCI measurements of the PORH peak CVC (R=0.54; p=0.001). CONCLUSION: The recently developed LSCI technique showed very good inter-day reproducibility for assessing PORH and LTH. Moreover, we showed significant correlation between LSCI and single-point LDF for PORH. However, more data are needed to evaluate the linearity between the LSCI signal and skin blood flow.

Reproducibility of a local cooling test to assess microvascular function in human skin.

OBJECTIVE: In the present study we aimed to assess the reproducibility of skin microvascular reactivity while fast cooling locally with a custom-designed laser-Doppler flowmetry (LDF) probe. METHODS: Twenty-two healthy volunteers underwent local 15 degrees C cooling on the forearm during 5 (protocol 1, n=12) or 30 min (protocol 2, n=10). Skin blood flow was concomitantly assessed using LDF. Measurements were repeated after 30 min (protocol 1) or 7 days (protocols 1 and 2). Data were expressed as cutaneous vascular conductance (CVC) and percentage of baseline (%BL). Within subject coefficients of variation (CV) and intra-class correlation coefficients (ICC) were calculated. RESULTS: Immediate reproducibility of the 5-min cooling was very good, either expressed as CVC or %BL (CV were 8% and 18%; ICC were 0.85 and 0.78, respectively). However, the 30-min cooling was the most reproducible at 1 week, either as CVC or %BL (CV were 26% and 23%; ICC were 0.86 and 0.75, respectively). Local cooling was well tolerated by all volunteers. CONCLUSIONS: We propose in the present work a reproducible 30-min LDF cooling test. Such a tool could be of great interest to assess microvascular reactivity to local cooling in diseases such as Raynaud's syndrome, and to further evaluate drugs for such diseases.

Sodium nitroprusside iontophoresis on the finger pad does not consistently increase skin blood flow in healthy controls and patients with systemic sclerosis.

OBJECTIVE: Sodium nitroprusside (SNP) iontophoresis is a commonly used technique to assess non endothelium-dependent skin microvascular function in the forearm. However, the lack of data on the finger pad is a limitation when studying diseases affecting the digits (e.g. systemic sclerosis, SSc). We thus aimed to validate this technique in the finger pad compared to the forearm in SSc patients and healthy controls. METHODS: Six SSc patients and six controls were recruited. SNP and NaCl iontophoresis were performed on the finger pad and the forearm, with and without lidocaine/prilocaine. Cutaneous blood flow was simultaneously monitored using laser Doppler flowmetry. RESULTS: In all subjects, iontophoresis of SNP induced hyperemia in the forearm, which was not affected by pretreatment with lidocaine/prilocaine. In contrast, no increase in cutaneous vascular conductance was observed in the finger pad in any subject (apart from one patient with SSc). CONCLUSIONS: The iontophoresis of SNP leads to a consistent, non axon reflex-dependent, increase in cutaneous vascular conductance in the forearm, both in patients with SSc and in healthy controls. On the finger pad however, such hyperemia was not consistent. As a consequence, other tools should be considered to assess non endothelium-dependent skin microvascular function in the finger pad.

Learning condyle repositioning during orthognathic surgery with a surgical navigation system.

Condyle repositioning during bilateral sagittal splint osteotomy (BSSO) is a challenging step for the inexperienced surgeon. We aimed to demonstrate the benefit of navigation for learning the condyle repositioning. We treated 100 patients who underwent a BSSO. A trainee performed the condyle repositioning of one side in two phases. In the first one, the trainee positioned without watching the screen of the Orthopilot Navigation system (ONS). In the second one, the trainee could use the ONS to replace the condyle. Heuristic, anatomical and functional scores of each phase were recorded. Heuristic (17% vs. 75%; p<0.0001), anatomical (35% vs. 86%; p<0.0001) and functional (14% vs. 56%; p<0.0001) scores were significantly greater with the ONS. The ONS is a promising and original intraoperative learning tool for the repositioning of the condyle during BSSO.

Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis.

OBJECTIVES: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients. METHODS: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist. RESULTS: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc. CONCLUSIONS: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

Abnormal digital neurovascular response to local heating in systemic sclerosis.

OBJECTIVES: To investigate neurovascular dysfunction using the axon reflex-dependent hyperaemia (initial peak of skin local heating response) in fingers of patients with SSc or primary RP. METHODS: Ten healthy subjects were initially enrolled to compare axon reflex-dependent thermal hyperaemia between the finger and forearm cutaneous circulations. Then, 10 patients with primary RP and 16 patients with SSc participated in a similar protocol focusing on the finger circulation only. Lidocaine/prilocaine cream was applied for 1 h to produce local blockade of cutaneous sensory nerves. After lidocaine/prilocaine pre-treatment, laser Doppler probes were heated from skin temperature to 42 degrees C for 30 min, and 44 degrees C for 5 min to achieve maximal skin blood flow. Data were expressed as a percentage of maximal cutaneous vascular conductance. RESULTS: In healthy volunteers, we observed a significantly higher initial peak on the finger compared with the forearm, with both responses blunted following topical anaesthesia. In primary RP patients, we observed a decreased initial peak following lidocaine/prilocaine pre-treatment in the finger circulation [96.7% (33.4) vs 75.9% (29.5) with anaesthesia, P = 0.02]. In contrast, pre-treatment did not alter the initial peak in patients with SSc. A minute-by-minute analysis showed no delay of the initial peak. CONCLUSIONS: We show an abnormal digital neurovascular response to local heating in SSc. Thermal hyperaemia could be monitored as a clinical test for neurovascular function in SSc. Further studies are required to test whether the abnormal digital neurovascular response correlates to the degree of peripheral vascular involvement.

Effect of homeopathy on analgesic intake following knee ligament reconstruction: a phase III monocentre randomized placebo controlled study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The efficacy of homeopathy is still under debate and a recent meta-analysis recommended further randomized double-blind clinical trials to identify any clinical situation in which homeopathy might be effective. WHAT THIS STUDY ADDS: The complex of homeopathy tested in this study (Arnica montana 5 CH, Bryonia alba 5 CH, Hypericum perforatum 5 CH and Ruta graveolens 3 DH) is not superior to placebo in reducing 24 h morphine consumption after knee ligament reconstruction. AIMS: The efficacy of homeopathy is still under debate. The objective of this study was to assess the efficacy of homeopathic treatment (Arnica montana 5 CH, Bryonia alba 5 CH, Hypericum perforatum 5 CH and Ruta graveolens 3 DH) on cumulated morphine intake delivered by PCA over 24 h after knee ligament reconstruction. METHODS: This was an add-on randomized controlled study with three parallel groups: a double-blind homeopathic or placebo arm and an open-label noninterventional control arm. Eligible patients were 18-60 years old candidates for surgery of the anterior cruciate ligament. Treatment was administered the evening before surgery and continued for 3 days. The primary end-point was cumulated morphine intake delivered by PCA during the first 24 h inferior or superior/equal to 10 mg day(-1). RESULTS: One hundred and fifty-eight patients were randomized (66 in the placebo arm, 67 in the homeopathic arm and 25 in the noninterventional group). There was no difference between the treated and the placebo group for primary end-point (mean (95% CI) 48% (35.8, 56.3), and 56% (43.7, 68.3), required less than 10 mg day(-1) of morphine in each group, respectively). The homeopathy treatment had no effect on morphine intake between 24 and 72 h or on the visual analogue pain scale, or on quality of life assessed by the SF-36 questionnaire. In addition, these parameters were not different in patients enrolled in the open-label noninterventional control arm. CONCLUSIONS: The complex of homeopathy tested in this study was not superior to placebo in reducing 24 h morphine consumption after knee ligament reconstruction.