Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial.

ABSTRACT: We compared a combination of the nonsedating antioxidant, alpha-lipoic acid (ALA), with the sedating anticonvulsant, pregabalin, vs each monotherapy to treat neuropathic pain due to peripheral neuropathies. In this randomized, double-blind, 3-period crossover trial, participants received oral ALA, pregabalin, and their combination-each for 6 weeks. The primary outcome was mean daily pain intensity at maximal tolerated doses (MTD); secondary outcomes included quality of life (SF-36), sleep (Medical Outcomes Study-Sleep Scale), adverse effects, drug doses, and other measures. Of 55 participants randomized (20-diabetic neuropathy, 19-small fiber neuropathy, and 16-other neuropathies), 46 completed 2 periods, and 44 completed 3. At MTD, the primary outcome of mean pain intensity (0-10) was 5.32 (standard error, SE = 0.18), 3.96 (0.25), 3.25 (0.25), and 3.16 (0.25) at baseline, ALA, pregabalin, and combination, respectively ( P < 0.01 for ALA vs combination and pregabalin). Treatment differences were similar in subgroups with diabetic neuropathy and with other neuropathies. SF-36 total scores (higher number indicates better quality of life) were 66.6 (1.88), 70.1 (1.88), and 69.4 (1.87) with ALA, pregabalin, and combination ( P < 0.05 for ALA vs combination and pregabalin). At MTD, there were no statistically significant treatment differences in adverse effects or drug doses. This trial demonstrates superiority of pregabalin vs ALA but provides no evidence to suggest added benefit of combining ALA with pregabalin to treat neuropathic pain.

Combination analgesic development for enhanced clinical efficacy (the CADENCE trial): a double-blind, controlled trial of an alpha-lipoic acid-pregabalin combination for fibromyalgia pain.

ABSTRACT: Drug therapy for fibromyalgia is limited by incomplete efficacy and dose-limiting adverse effects (AEs). Combining agents with complementary analgesic mechanisms-and differing AE profiles-could provide added benefits. We assessed an alpha-lipoic acid (ALA)-pregabalin combination with a randomized, double-blind, 3-period crossover design. Participants received maximally tolerated doses of ALA, pregabalin, and ALA-pregabalin combination for 6 weeks. The primary outcome was daily pain (0-10); secondary outcomes included Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. The primary outcome of daily pain (0-10) during ALA (4.9), pregabalin (4.6), and combination (4.5) was not significantly different ( P = 0.54). There were no significant differences between combination and each monotherapy for any secondary outcomes, although combination and pregabalin were both superior to ALA for measures of mood and sleep. Alpha-lipoic acid and pregabalin maximal tolerated doses were similar during combination and monotherapy, and AEs were not frequent with combination therapy. These results do not support any additive benefit of combining ALA with pregabalin for fibromyalgia. The observation of similarly reached maximal tolerated drug doses of these 2 agents (which have differing side-effect profiles) during combination and monotherapy-without increased side effects-provides support for future development of potentially more beneficial combinations with complementary mechanisms and nonoverlapping side effects.

Double-blind, randomized, placebo-controlled crossover trial of alpha-lipoic acid for the treatment of fibromyalgia pain: the IMPALA trial.

ABSTRACT: Fibromyalgia is a common and challenging chronic pain disorder with few, if any, highly effective and well-tolerated treatments. Alpha-lipoic acid (ALA) is a nonsedating antioxidant with evidence of efficacy in the treatment of symptomatic diabetic neuropathy that has not been evaluated in the setting of fibromyalgia treatment. Thus, we conducted a single-centre, proof-of-concept, randomized, placebo-controlled, crossover trial of ALA for the treatment of fibromyalgia. Twenty-seven participants were recruited, and 24 participants completed both treatment periods of the trial. The median maximal tolerated dose of ALA in this trial was 1663 mg/day. Treatment-emergent adverse events with ALA were infrequent and not statistically different from placebo. For the primary outcome of pain intensity, and for several other validated secondary outcomes, there were no statistically significant differences between placebo and ALA. A post hoc exploratory subgroup analysis showed a significant interaction between gender and treatment with a significant favourable placebo-ALA difference in pain for men, but not for women. Overall, the results of this trial do not provide any evidence to suggest promise for ALA as an effective treatment for fibromyalgia, which is predominantly prevalent in women. This negative clinical trial represents an important step in a collective strategy to identify new, better tolerated and more effective treatments for fibromyalgia.

Effects of androgen-deprivation therapy on hypercoagulability in prostate cancer patients: A prospective, longitudinal study.

INTRODUCTION: Androgen-deprivation therapy (ADT) is the mainstay of systemic therapy for advanced prostate cancer (PCa), but has significant adverse effects, including increasing concern for cardiovascular (CV) and thromboembolic (TE) complications. This study carefully investigates any relationship between ADT use and hypercoagulability as a possible mechanism of these adverse effects. METHODS: We performed a prospective, longitudinal study in a cohort of patients with advanced PCa initiating ADT (n=18). Controls included men with biochemical failure after local therapy on watchful waiting (n=10), as well as healthy controls (n=8). Global hemostasis was evaluated using the sensitive global hemostasis assay, thromboelastography (TEG). Patients were evaluated at baseline and every three months for a minimum of 12 months. RESULTS: The results of the TEG studies demonstrated 14/18 (78%) of advanced PCa patients had evidence of a hypercoagulable state before initiating therapy. Significant baseline hypercoagulability was documented in this cohort compared to the two control groups. ADT did not appear to exacerbate hypercoagulability over time as a whole: only 10/18 (56%) patients had TEG findings consistent with hypercoagulability at the end of study. However, 3/18 (17%) PCa patients initiating ADT had significantly new hypercoagulable TEG changes on treatment compared to baseline. CONCLUSIONS: This prospective pilot study demonstrates a complex interaction between ADT and hypercoagulable state in men with advanced PCa. TEG abnormalities were mostly associated with volume of cancer as compared to ADT use; however, it is possible that ADT may lead to hypercoagulability in a subset of men, suggesting that sensitive monitoring of coagulation of men on ADT could help identify those at risk of developing CV/TE complications. Study limitations include the relatively small cohort of men followed after initiating ADT and these results require confirmation in a larger trial to rule out subtle effects on hypercoagulability.

Intraureteral lidocaine for ureteral stent symptoms post-ureteroscopy: A randomized, phase 2, placebo-controlled trial.

INTRODUCTION: Ureteral stent and ureteral manipulation-related pain is a significant complication for patients undergoing ureteroscopy. Herein, we report a phase 2, randomized trial to assess efficacy of direct instillation of intraureteral lidocaine in reducing postoperative pain and ureteral stent symptoms. METHODS: We performed a randomized, double-blinded trial of patients undergoing elective ureteroscopy for ureteral calculi. Patients were randomized to direct instillation of 2% lidocaine plus bicarbonate, or to normal saline as control. The primary outcome of interest was early postoperative pain scores. Patients completed10-point visual analog pain scale at one-hour, two-hour, four-hour, 24-hours, four- and seven-day time points. Other outcome measurements collected included a medication diary and voiding questionnaire. RESULTS: A total of 41 patients were randomized in the study. Mean flank pain scores at one hour were 2.2 (±2.9) vs.1.9 (±2.4) in the intervention and placebo group, respectively (p=0.84). There was no significant difference at any time point between the intervention and placebo groups in patient-reported pain scores. Patients reported lower dysuria scores at all time points in the lidocaine group, however, none reached statistical significance. There was no difference in complication rates or adverse effects between groups. CONCLUSIONS: In this randomized, phase 2 study, direct instillation of lidocaine into the ureter did not appear to significantly improve pain or voiding symptoms following stented ureteroscopy.

Ambulatory percutaneous nephrolithotomy: what is the rate of readmission?

BACKGROUND AND PURPOSE: Tubeless percutaneous nephrolithotomy (PCNL) has gained popularity in an attempt to decrease morbidity and accelerate discharge. Recently, ambulatory tubeless PCNL has been reported. There are no data, however, regarding readmission rates of patients who had ambulatory PCNL. Therefore, the aim of this study was to assess rates of emergency department (ED) visits and readmissions postambulatory PCNL. PATIENTS AND METHODS: A retrospective chart review of all ambulatory PCNL cases at two institutions between March 2007 and December 2013 was performed. Preoperative, intraoperative, and postoperative data were collected including the amount of narcotics used, length of hospital stay, postoperative complications, returns to the ED, and readmissions. RESULTS: Fifty patients underwent ambulatory PCNL, including two bilateral cases, making up a total of 52 renal units. All patients were discharged home on the same day with a mean hospital stay of 208.32±73.43 minutes. The mean narcotic requirement was 41.13±46.76 mg of oral morphine equivalents. Six patients (12%) returned to the ED, all within 7 days. Four of these 6 patients were discharged; three with stent colic and one with wound cellulitis. Only two (4%) patients were readmitted-one with multiresistant Escherichia coli and one with uncomplicated stent colic. Overall stone-free rate was 90.4%. There were no major complications, while low grade (I-II) Clavien complications developed in 9 (18%) patients. CONCLUSION: Ambulatory PCNL is safe in highly selected patients with a stone-free rate of 90% and readmission rate of 4%. Prospective studies comparing standard PCNL with ambulatory PCNL are warranted.

Thromboelastography identifies hypercoagulablilty and predicts thromboembolic complications in patients with prostate cancer.

Cancer patients are at higher risk for thromboembolism compared to the normal population. This may be related to tumour burden and/or enhanced by systemic therapy. While there is ample evidence regarding venous thromboembolism, systematic studies investigating arterial thrombotic events are scarce. Conventional coagulation tests have limited capacity in evaluating the coagulability or the need for anticoagulant prophylaxis. In this pilot study, we investigated whether assessment of global haemostasis using thromboelastography (TEG) and quantification of plasma pro-coagulant microparticles can help determine the risk of adverse thrombotic events in patients with prostate cancer (PCa). Thirty two patients were recruited a priori into three groups: 11 men on 'watchful waiting' following recurrent disease after definitive treatment (Group A); 10 patients with metastatic disease on Androgen deprivation therapy (ADT) (Group B); and 11 with castration resistant cancer (Group C) and followed up over a period of 12months. These patients were compared to a control group composed of 8 men with negative prostate biopsy. Whole blood TEG and plasma tissue factor-carrying microparticles (TF-MPs) in addition to basic coagulation testing, plasma fibrinogen and d-dimer were performed. 22/32 (68.8%) of the patients demonstrated hypercoagulable TEG traces. Hypercoagulability was marked in group B compared to the control. Plasma MPs were significantly elevated in patients compared to the controls with significant increase in group B. All other coagulation tests were normal. Seven of the 22 hypercoagulable patients (31.8%) developed one or more thromboembolic events over 12months follow up period. The data in this pilot study show that PCa patients are hypercoagulable, particularly those with advanced disease on ADT and that this hypercoagulability can be identified by TEG. While this needs to be verified in a larger study, the data indicate TEG may aid in thrombosis risk stratification and determining the subsequent need for anticoagulant prophylaxis in PCa patients.