348 Absence of Withdrawal Symptoms and Rebound Insomnia Upon Discontinuation of Daridorexant in Patients with Insomnia

Introduction Abrupt discontinuation of sleep medications in patients with insomnia often causes withdrawal symptoms and rebound insomnia. In a Phase 3 program evaluating efficacy and safety of daridorexant on sleep and daytime functioning in patients with insomnia during 3 months of treatment, the risks of withdrawal symptoms and rebound insomnia were evaluated at treatment cessation. Methods In two randomized, double-blind, 3-month trials, adult (18–64 years) and elderly (≥65) patients with insomnia were assigned (1:1:1) to receive oral daridorexant 25mg, 50mg or placebo (Trial-1, NCT03545191) or 10mg, 25mg or placebo (Trial-2, NCT03575104) every evening. Each trial included a 7-day, single-blind, placebo run-out period following double-blind treatment to evaluate withdrawal symptoms and rebound insomnia. Withdrawal effects were assessed by the change in Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) total score, from last assessment on double-blind treatment to end of placebo run-out, and occurrence of relevant adverse events (AEs). Rebound insomnia was assessed objectively by change in wake-after-sleep-onset (WASO) and latency-to-persistent sleep (LPS), from baseline to first night of placebo run-out, and by subjective total-sleep-time (sTST), from baseline to end of run-out (mean of 7-days). Analyses included all patients who received ≥1 dose of placebo run-out treatment (Trial-1: N=852; Trial-2: N=851). Results No increase in mean BSWQ score from last assessment on double-blind treatment to end of placebo run-out was reported (Trial-1: 25mg, -0.6±2.3; 50mg, -0.6±2.3; placebo, -0.7±2.3; Trial-2: 10mg, -0.5±2.6; 25mg, -0.4±1.9; placebo, -0.4±1.4). No patients had a BWSQ score >20 at end of run-out. No AEs suggestive of withdrawal symptoms were reported. Mean WASO and LPS values (min) decreased from baseline to placebo run-out (WASO Trial-1: 25mg, -8.6±55.5; 50mg, -2.5±52.4; placebo, -20.4±45.8; Trial-2: 10mg, -11.6±58.3; 25mg, -5.1±57.9; placebo, -26.2±53.5; LPS Trial-1: 25mg, -17.2±56.7; 50mg, -15.0±55.8; placebo, -27.8±47.2; Trial-2: 10mg, -17.3±67.2; 25mg, -10.3±67.3; placebo, -18.3±63.8) while sTST values (min) increased (Trial-1: 25mg, 43.3±53.8; 50mg, 42.9±59.6; placebo, 42.3±52.7; Trial-2: 10mg, 43.3±52.9; 25mg, 46.8±55.4; placebo, 42.3±53.8) indicating absence of rebound effects. Conclusion Treatment with daridorexant for up to 3-months was not associated with any evidence of drug withdrawal or rebound insomnia upon abrupt discontinuation, indicating no safety concerns for patients should treatment be stopped. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

ROLE OF COMBINED KETOCONAZOLE AND TAMSULOSIN IN SUCCESSFUL TRIAL OF VOIDING WITHOUT CATHETER (TWOC) IN PATIENTS WITH ACUTE URINARY RETENTION DUE TO BENIGN PROSTATIC OBSTRUCTION

Objective: To compare the frequency of patients with successful Trial of voiding without catheter (TWOC) after acute urinary retention secondary to benign prostatic hyperplasia in patients taking ketoconazole and tamsulosin vs tamsulosin alone. Study Design: A randomized controlled trial. Place and Duration: The current study was conducted at Urology Ward, Liaquat National Hospital, Pakistan for a period of six months. Methodology: A total of 162 patients presenting with acute urinary retention were divided into two groups. Group A received tamsulosin 0.4mg OD and ketoconazole 200mg while Group B received tamsulosin and placebo. Trial of voiding without a catheter was induced after one week of medication. SPSS version 20 was used for data compilation and analysis. Results: In Group-A, 85.2% of patients were able to void as compared to group B, where only 74.1% of patients were able to void (p<0.05). Successful trial of voiding without catheter was observed in 79.0% and 60.5% in patients of Group-A and Group-B respectively. The association of successful TWOC with the two study groups was found significant (p=0.010). Conclusion: TWOC in men catheterized for AUR due to BPH was significantly more successful if treated in a combination of ketoconazole and tamsulosin as compared to tamsulosin only.

Effects of Two-Week Betaine Supplementation on Apoptosis, Oxidative Stress, and Aerobic Capacity after Exhaustive Endurance Exercise

This study evaluated the effects of 2 weeks of betaine supplementation on apoptosis, oxidative stress, and aerobic capacity after exhaustive endurance exercise (EEE). A double-blind, crossover, and counterbalanced design was adopted, with 10 healthy male participants asked to consume betaine (1.25 g of betaine mixed with 300 mL of sports beverage, twice per day for 2 weeks) or placebo (300 mL of sports beverage). All participants performed a graded exercise test on a treadmill to determine the maximal oxygen consumption (VO2max) before supplementation and then performed the EEE test at an intensity of 80% VO2max after 2 weeks of supplementation. The time to exhaustion, peak oxygen consumption, maximal heart rate, and average heart rate were recorded during the EEE test. Venous blood samples were drawn before, immediately after, and 3 h after the EEE test to assess apoptosis and the mitochondrial transmembrane potential (MTP) decline of lymphocytes as well as the concentrations of thiobarbituric acid reactive substance and protein carbonyl. The results indicated that lymphocyte apoptosis was significantly higher immediately after and 3 h after EEE than before exercise in participants in the placebo trial. However, lymphocyte apoptosis exhibited no significant differences among the three time points in participants in the betaine trial. Moreover, apoptosis in the betaine trial was significantly lower immediately after and 3 h after exercise compared with the placebo trial. No differences were noted for other variables. Thus, 2 weeks of betaine supplementation can effectively attenuate lymphocyte apoptosis, which is elevated by EEE. However, betaine supplementation exhibited no effects on MTP decline, oxidative stress, or aerobic capacity.

The effect of curcumin ointment on knee pain in older adults with osteoarthritis: a randomized placebo trial

Background Some studies have shown the effect of oral administration of curcumin on knee pain. However, limited studies are available on the effect of topical curcumin. This study aimed to investigate the effect of curcumin ointment on knee pain in older adults with osteoarthritis. Methods This double-blind randomized placebo trial was conducted on 72 older adults with knee pain associated with osteoarthritis. The subjects were randomly assigned into an intervention and a placebo group to apply either curcumin 5% ointment or Vaseline ointment twice daily for 6 weeks. Using a Visual Analog Scale, the severity of knee pain was measured at the beginning of the study, at the end of the fourth and sixth week. Data were analyzed using descriptive and inferential methods. Results The mean baseline knee pain intensity was not significantly different between the two groups (P = 0.15). The mean pain intensity was significantly lower in the intervention group than in the placebo group at the third measurement (P = 0.02). The repeated-measures analysis showed that over time, the curcumin significantly decreased the mean pain intensity in the intervention group (P = 0.001). The mixed model showed an absolute difference of 1.133 (i.e. 11.33 mm) score which signifies a medium effect size and that the patient in the intervention group achieved the minimal clinically important difference. Conclusion Topical administration of curcumin 5% ointment can significantly reduce knee pain in older adults with knee osteoarthritis. Curcumin ointment can be used as an alternative treatment in older adults with knee pain associated with osteoarthritis. Trial registration Retrospectively registered in the Iranian Registry of Clinical Trials (IRCT) (IRCT20100403003618N6, 2019-03-08), https://en.irct.ir/trial/37155

The Effect of Intraoperative Ketamine and Magnesium Sulfate on Acute Pain and Opioid Consumption After Spine Surgery

Ketamine and magnesium in brain act as an N-methyl-D-aspartate receptor antagonist that has been shown to be useful in the reduction of acute postoperative pain and analgesic consumption in a variety of surgical interventions. We hypothesized that combination of low dose ketamine and magnesium would reduce early postoperative opiate consumption and analgesic requirement after 6 weeks. This was a randomized, prospective, controlled-placebo trial involving elective and eligible patients undergoing lumbar spine surgery. Seventy patients in the treatment group were administered 0.5 mg/kg intravenous ketamine and 1 gram of magnesium as an intravenous bolus slowly during 3 minute before incision and 0.25 mg/kg/hr ketamine and 0,5 g/hr magnesium intravenous infusion during surgery. Seventy patients in the placebo group received saline of equivalent volume. Patients were observed for48 h postoperatively and followed up at 6 weeks. The primary outcome was 48h morphine consumption. The severity of pain was lower in the intervention group than in the placebo group during 48 hr post-operatively, morphine consumption in this group also decreased significantly during this period. Intraoperative ketamine-magnesium reduces opiate consumption in the 48-h postoperative period. This combination may also reduce pain intensity throughout the postoperative period in this patient population.