Intravenous Delta-9-Tetrahydrocannabinol to Prevent Postoperative Nausea and Vomiting: A Randomized Controlled Trial.

BACKGROUND Evidence suggests that cannabinoids can prevent chemotherapy-induced nausea and vomiting. The use of tetrahydrocannabinol (THC) has also been suggested for the prevention of postoperative nausea and vomiting (PONV), but evidence is very limited and inconclusive. To evaluate the effectiveness of IV THC in the prevention of PONV, we performed this double-blind, randomized, placebo-controlled trial with patient stratification according to the risk of PONV. Our hypothesis was that THC would reduce the relative risk of PONV by 25% compared with placebo. METHODS With IRB approval and written informed consent, 40 patients at high risk for PONV received either 0.125 mg/kg IV THC or placebo at the end of surgery before emergence from anesthesia. The primary outcome parameter was PONV during the first 24 hours after emergence. Secondary outcome parameters included early and late nausea, emetic episodes and PONV, and side effects such as sedation or psychotropic alterations. RESULTS The relative risk reduction of overall PONV in the THC group was 12% (95% confidence interval, -37% to 43%), potentially less than the clinically significant 25% relative risk reduction demonstrated by other drugs used for PONV prophylaxis. Calculation of the effect of treatment group on overall PONV by logistic regression adjusted for anesthesia time gave an odds ratio of 0.97 (95% confidence interval, 0.21 to 4.43, P = 0.97). Psychotropic THC side effects were clinically relevant and mainly consisted of sedation and confusion that were not tampered by the effects of anesthesia. The study was discontinued after 40 patients because of the inefficacy of THC against PONV and the finding of clinically unacceptable side effects that would impede the use of THC in the studied setting. CONCLUSIONS Because of an unacceptable side effect profile and uncertain antiemetic effects, IV THC administered at the end of surgery before emergence from anesthesia cannot be recommended for the prevention of PONV in high-risk patients.

Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial

Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated.

Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA)

Critical limb ischemia due to peripheral arterial occlusive disease is associated with a severely increased morbidity and mortality. There is no effective pharmacological therapy available. Injection of autologous bone marrow-derived mononuclear cells (BM-MNC) is a promising therapeutic option in patients with critical limb ischemia, but double-blind, randomized trials are lacking.

Double-blinded, randomized controlled trial comparing real versus placebo acupuncture to improve tolerance of diagnostic esophagogastroduodenoscopy without sedation: a study protocol

Background Sedation prior to performance of diagnostic esophagogastroduodenoscopy (EGDE) is widespread and increases patient comfort. But 98% of all serious adverse events during EGDEs are ascribed to sedation. The S3 guideline for sedation procedures in gastrointestinal endoscopy published in 2008 in Germany increases patient safety by standardization. These new regulations increase costs because of the need for more personnel and a prolonged discharge procedure after examinations with sedation. Many patients have difficulties to meet the discharge criteria regulated by the S3 guideline, e.g. the call for a second person to escort them home, to resign from driving and working for the rest of the day, resulting in a refusal of sedation. Therefore, we would like to examine if an acupuncture during elective, diagnostic EGDEs could increase the comfort of patients refusing systemic sedation. Methods/Design A single-center, double blinded, placebo controlled superiority trial to compare the success rates of elective, diagnostic EGDEs with real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic EGDE who refuse a systemic sedation are eligible. 354 patients will be randomized. The primary endpoint is the rate of successful EGDEs with the randomized technique. Intervention: Real or placebo acupuncture before and during EGDE. Duration of study: Approximately 24 months. Discussion Organisation/Responsibility The ACUPEND - Trial will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Interdisciplinary Endoscopy Center (IEZ) of the University Hospital Heidelberg is responsible for design and conduct of the trial, including randomization and documentation of patients' data. Data management and statistical analysis will be performed by the independent Institute for Medical Biometry and Informatics (IMBI) and the Center of Clinical Trials (KSC) at the Department of General, Visceral and Transplantation Surgery, University of Heidelberg.

Randomised controlled trials of homeopathy in hyperactive children: treatment procedure leads to an unconventional study design. Experience with open-label homeopathic treatment preceding the Swiss ADHD placebo controlled, randomised, double-blind, cross-over trial

BACKGROUND: Treatment of patients with attention deficit hyperactivity disorder (ADHD) with homeopathy is difficult. The Swiss randomised, placebo controlled, cross-over trial in ADHD patients (Swiss ADHD trial) was designed with an open-label screening phase prior to the randomised controlled phase. During the screening phase, the response of each child to successive homeopathic medications was observed until the optimal medication was identified. Only children who reached a predefined level of improvement participated in the randomised, cross-over phase. Although the randomised phase revealed a significant beneficial effect of homeopathy, the cross-over caused a strong carryover effect diminishing the apparent difference between placebo and verum treatment. METHODS: This retrospective analysis explores the screening phase data with respect to the risk of failure to demonstrate a specific effect of a randomised controlled trial (RCT) with randomisation at the start of the treatment. RESULTS: During the screening phase, 84% (70/83) of the children responded to treatment and reached eligibility for the randomised trial after a median time of 5 months (range 1-18), with a median of 3 different medications (range 1-9). Thirteen children (16%) did not reach eligibility. Five months after treatment start, the difference in Conners Global Index (CGI) rating between responders and non-responders became highly significant (p = 0.0006). Improvement in CGI was much greater following the identification of the optimal medication than in the preceding suboptimal treatment period (p < 0.0001). CONCLUSIONS: Because of the necessity of identifying an optimal medication before response to treatment can be expected, randomisation at the start of treatment in an RCT of homeopathy in ADHD children has a high risk of failure to demonstrate a specific treatment effect, if the observation time is shorter than 12 months.

Preemptive carprofen for peri-operative analgesia in dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO): a prospective, randomized, blinded, placebo controlled clinical trial

Eighteen client-owned dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO) were included in this blinded clinical study and randomly assigned to one of two treatment groups. Group C (carprofen) received intravenous (IV) carprofen, 4 mg/kg, prior to anesthesia, whereas group P (placebo) received IV saline. General anesthesia was maintained with isoflurane in oxygen and a constant rate infusion (CRI) of sufentanyl IV. Intra-operatively, assessment of nociception was based on changes in physiological parameters and on the analgesics requirement, whereas in the post-operative period evaluation of pain was performed by using a Hellyer and Gaynor pain score and by comparing the doses of rescue buprenorphine required by the two treatment groups. Although no statistically significant differences in intra-operative sufentanyl doses were found between treatment groups, group C had superior cardiovascular stability, and lower post-operative pain scores and rescue buprenorphine doses than group P. Our results indicate that administration of carprofen prior to surgery was effective in improving peri-operative analgesia in dogs undergoing TPLO.

Ultrasound-guided pudendal nerve block in cats undergoing perineal urethrostomy: a prospective, randomised, investigator-blind, placebo-controlled clinical trial

The objective of this study was to evaluate the clinical usefulness, in terms of analgesic efficacy and safety, of ultrasound-guided pudendal nerve block performed with bupivacaine in cats undergoing perineal urethrostomy. Eighteen client-owned male cats scheduled for perineal urethrostomy were enrolled in the study and assigned to one of two treatment groups. The pudendal nerve block was performed under general anaesthesia as described elsewhere, with 0.3 ml/kg of either saline (group C) or 0.5% bupivacaine (group B) - the total injection volume being split equally on the two sites of injection (left and right). Intra-operatively, assessment of nociception was based on the rescue analgesics requirement, as well as on the evaluation of changes in physiological parameters in comparison with the baseline values. Post-operative pain assessment was performed using three different pain scales at recovery and then 1, 2 and 3 h after recovery. Cats in group B showed lower heart rates and required fewer analgesics during surgery than group C. Post-operatively, group B had lower pain scores and needed less rescue buprenorphine than group C. Iatrogenic block-related complications were not observed. In conclusion, the ultrasound-guided pudendal nerve block can be considered clinically useful in feline medicine as it provides reliable analgesia in cats undergoing perineal urethrostomy.

Sono-Electro-Magnetic Therapy for Treating Chronic Pelvic Pain Syndrome in Men: A Randomized, Placebo-Controlled, Double-Blind Trial.

OBJECTIVE To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro-magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks. RESULTS The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was -3.1 points (95% CI -6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks -1.6, 95% CI -2.8 to -0.4, p = 0.015). In stratified analyses, the benefit of sono-electro-magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score -8.3, 95% CI -14.5 to 2.6) than in patients with a longer symptom duration (-0.8, 95% CI -4.6 to 3.1; p for interaction = 0.023). CONCLUSIONS Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation. TRIAL REGISTRATION ClinicalTrials.gov NCT00688506.

Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction

BACKGROUND Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3-6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation. DISCUSSION It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction. TRIAL REGISTRATION TRIAL REGISTRATION NUMBER http://www.clinicaltrials.gov; Identifier: NCT02165774.

Acute effects of intravenous heroin on the hypothalamic-pituitary-adrenal axis response: a controlled trial

Heroin dependence is associated with a stressful environment and with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The present study examined the acute effects of intravenous heroin versus placebo on the HPA axis response in heroin-dependent patients. Twenty-eight heroin-dependent patients in heroin-assisted treatment and 20 age- and sex-matched healthy participants were included in a controlled trial in which patients were twice administered heroin or saline in a crossover design, and healthy controls were only administered saline. The HPA axis response was measured by adrenocorticotropic hormone (ACTH) levels and by cortisol levels in serum and saliva before and 20 and 60 minutes after substance administration. Craving, withdrawal, and anxiety levels were measured before and 60 minutes after substance application. Plasma concentrations of heroin and its main metabolites were assessed using high-performance liquid chromatography. Heroin administration reduces craving, withdrawal, and anxiety levels and leads to significant decreases in ACTH and cortisol concentrations (P < 0.01). After heroin administration, cortisol concentrations did not differ from healthy controls, and ACTH levels were significantly lower (P < 0.01). In contrast, when patients receive saline, all hormone levels were significantly higher in patients than in healthy controls (P < 0.01). Heroin-dependent patients showed a normalized HPA axis response compared to healthy controls when they receive their regular heroin dose. These findings indicate that regular opioid administration protects addicts from stress and underscore the clinical significance of heroin-assisted treatment for heroin-dependent patients.

Randomized controlled trial on single dose steroid before thyroidectomy for benign disease to improve postoperative nausea, pain, and vocal function

OBJECTIVE: To evaluate the effects of a single preoperative dose of steroid on thyroidectomy outcomes. BACKGROUND: Nausea, pain, and voice alteration frequently occur after thyroidectomy. Because steroids effectively reduce nausea and inflammation, a preoperative administration of steroids could improve these thyroidectomy outcomes. METHODS: Seventy-two patients (men = 20, women = 52) undergoing thyroidectomy for benign disease were included in this randomized, controlled, 2 armed (group D: 8 mg dexamethasone, n = 37; group C: 0.9% NaCl, n = 35), double-blinded study (clinical trial number NCT00619086). Anesthesia, surgical procedures, antiemetics, and analgesic treatments were standardized. Nausea (0-3), pain (visual analog scale), antiemetic and analgesic requirements, and digital voice recording were documented before and 4, 8, 16, 24, 36, and 48 hours after surgery. Patients were followed-up 30 days after hospital discharge. RESULTS: Baseline characteristics were similar among the 2 treatment groups. Nausea was pronounced in the first 16 hours postoperatively (scores were <0.3 and 0.8-1.0 for group D and C, respectively (P = 0.005)), and was significantly lower in group D compared with group C during the observation period (P = 0.001). Pain diminished within 48 hours after surgery (visual analog scale 20 and 35 in group D and C, respectively (P = 0.009)). Antiemetic and analgesic requirements were also significantly diminished. Changes in voice mean frequency were less prominent in the dexamethasone group compared with the placebo group (P = 0.015). No steroid-related complications occurred. CONCLUSION: A preoperative single dose of steroid significantly reduced nausea, vomiting, and pain, and improved postoperative voice function within the first 48 hours (most pronounced within 16 hours) after thyroid resection; this strategy should be routinely applied in thyroidectomies.

Intravaginal and intracervical application of seminal plasma in in vitro fertilization or intracytoplasmic sperm injection treatment cycles--a double-blind, placebo-controlled, randomized pilot study

OBJECTIVE: To evaluate whether intravaginal application of seminal plasma at the time of follicle aspiration in IVF or intracytoplasmic sperm injection treatment cycles has the potential to increase pregnancy rate. To calculate the number of patients needed to achieve significance in a multicenter trial. DESIGN: Double-blind, placebo-controlled randomized pilot study. SETTING: University department of gynecological endocrinology and reproductive medicine. PATIENT(S): One hundred sixty-eight patients undergoing IVF or intracytoplasmic sperm injection treatment. INTERVENTION(S): Cryopreserved seminal plasma from the patient's partner or sodium chloride (placebo) was injected into the cervix and the posterior fornix of the vagina just after follicle aspiration. MAIN OUTCOME MEASURE(S): Clinical-pregnancy rate. RESULT(S): One hundred sixty-eight patients agreed to participate in the study. Participation was limited to one treatment cycle. Thirty-one patients (18%) were excluded from the study, mainly as a result of canceled embryo transfers. Seventy patients received placebo, and 67 received seminal plasma. The clinical-pregnancy rate was 25.7% (18/70) in the placebo group. The clinical-pregnancy rate in the seminal plasma group reached 37.3% (25/67), corresponding to a relative increase of 45%. CONCLUSION(S): Even though significance was not reached in this pilot study, the data suggest that seminal plasma has the potential to improve pregnancy rate. It is estimated that around 450 patients need to be recruited to reach significance in a multicenter study.