364 Use of Blinded Hypnotic Tapering for Hypnotic Discontinuation: Final Report

Introduction Many patients have difficulties achieving hypnotic discontinuation due to anxiety that arises when they knowingly reduce their hypnotic dose or withhold it entirely. This study tested a blinded tapering approach to reduce patients’ anxiety and help them discontinue their hypnotics. Methods The study sample included 78 (M age = 55.2 ± 12.8 yrs.; 65.4% women) users of benzodiazepine and benzodiazepine receptor agonists. Following baseline assessments, enrollees first completed 4 sessions of cognitive behavioral insomnia therapy (CBTI). Subsequently they were randomized to one of three 20-week, double-blinded tapering protocols wherein their medication dosage either remained unchanged (CTRL) or was reduced by 25% or 10% every two weeks. At the end of the 20-week period the study blind was eliminated and those who completed one of the two blinded tapering protocols entered a 3-month follow-up period, whereas CTRL participants were offered an open label taper before completing the follow-up. Results Among those who completed one of the blinded tapering protocols, 92.9% totally discontinued their medication use by the end of the 20-week tapering phase, whereas 77.3% in the CTRL group discontinued hypnotic use by the end of their open label tapering. At follow-up 72.1% of those who completed blinded tapering remained medication free whereas only 52% of those who underwent open-label tapering remained medication free. Comparisons at follow-up showed those who received the open-label taper continued to use hypnotics on average 2.06 nights/week compared to .051 times per week for the blinded taper group (p = .042). The average weekly diazepam equivalent dose of medication used by the open label tapering group was 11.29 mg whereas the weekly dose for the blinded tapering group was 3.22 (p = .069). Conclusion CBTI combined with blinded hypnotic tapering is a promising treatment approach for helping hypnotic users overcome their medication dependence. Support (if any) National Institute of Drug Abuse, Grant # R34 DA042329-01

0509 Use of Blinded Hypnotic Tapering for Hypnotic Discontinuation

Introduction Many patients have difficulties achieving hypnotic discontinuation due to anxiety that arises when they knowingly reduce their hypnotic dose or withhold it entirely. This study tested a blinded tapering approach to reduce patients’ anxiety and help them discontinue their hypnotics. Methods The study sample included 78 (M age = 55.2 ± 12.8 yrs.; 65.4% women) users of benzodiazepine and benzodiazepine receptor agonists. Following baseline assessments, enrollees first completed 4 sessions of cognitive behavioral insomnia therapy (CBTI). Subsequently they were randomized to one of three 20-week, double-blinded tapering protocols wherein their medication dosage either remained unchanged (CTRL) or was reduced by 25% or 10% every two weeks. At the end of the 20-week period the study blind was eliminated and those who completed one of the two blinded tapering protocols entered a 3-month follow-up period, whereas CTRL participants were offered an open label taper before completing the follow-up. Results Among those who completed one of the blinded tapering protocols, 92.9% totally discontinued their medication use by the end of the 20-week tapering phase, whereas 77.3% in the CTRL group discontinued hypnotic use by the end of their open label tapering. At follow-up 72.1% of those who completed blinded tapering remained medication free whereas only 52% of those who underwent open-label tapering remained medication free. Comparisons at follow-up showed those who received the open-label taper continued to use hypnotics on average 2-3 nights/week compared to about 1 time every other week for the blinded taper group (p = .05). The average weekly diazepam equivalent dose of medication used by the open label tapering group was about 5 times higher than the average weekly dose used by the blind tapering group (p = .025). Conclusion CBTI combined with blinded hypnotic tapering is a promising treatment approach for helping hypnotic users overcome their medication dependence. Support National Institute of Drug Abuse, Grant # R34 DA042329-01

JM-1232(-) and propofol, a new combination of anesthetics with short-acting and non-cumulative preferable properties

Background Drug interactions are significant in anesthesiology because drug combinations can potentially possess novel properties. The pharmacological advantages of a new combination of the benzodiazepine receptor agonist JM-1232(-) and propofol were investigated in mice.Methods Male adult mice were administered JM-1232(-) or propofol or combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis, and the time until recovery of the reflex was measured as hypnosis time. After determining the ED50, doses double and triple the ED50 of propofol were injected with JM-1232(-) to compare hypnosis time. The injections were repeated four times, and the hypnosis times were compared. Flumazenil was administered separately immediately after the last dose was injected.Results The ED50 values ([95% confidence interval]) for hypnosis were 3.76 [3.36–4.10] for JM-1232(-) and 9.88 [8.03–11.58] mg kg-1 for propofol. Co-administration of 0.05 and 0.1 mg kg-1 JM-1232(-) reduced the ED50 values of propofol to 1.76 [1.21–2.51] and 1.00 [0.46–1.86] mg kg-1, respectively. The drug combination for hypnosis produced a supra-additive interaction. Hypnosis time was significantly shorter in the groups given the mixtures compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with the hypnotic alone. Flumazenil completely restored the recovery time after anesthesia.Conclusions The combination of JM-1232(-) and propofol showed a supra-additive interaction, and the reduced hypnotic dose contributed to a faster recovery even after multiple injections.

Sub-hypnotic dose of propofol as antiemetic prophylaxis attenuates intrathecal morphine-induced postoperative nausea and vomiting, and pruritus in parturient undergoing cesarean section — a randomized control trial

Background Postoperative Nausea and Vomiting (PONV) is a dreadful and uncomfortable experience that significantly detracts patients’ quality of life after surgery. This study aimed to examine the antiemetic effect of a single sub-hypnotic dose of propofol as prophylaxis for PONV. Method In this prospective, double-blind, randomized control trial, 345 parturients presented for elective cesarean section at the Obstetric unit of Tamale Teaching Hospital were recruited. Each recruited parturient was randomly assigned to one of three groups; Propofol group (n = 115) represented those who received propofol 0.5 mg/kg, Metoclopramide group (n = 115) represented those who received metoclopramide 10 mg and, Control group (n = 115) represented those who received 0.9% saline. Spinal anesthesia with 0.5% hyperbaric bupivacaine 7.5–10 mg, and intrathecal morphine 0.2 mg was employed for the anesthesia. Results The data indicate that 108 (93.9%) parturients from the control group, 10 (8.7%) from the propofol group and 8 (7.0%) from the metoclopramide group experienced some incidence of PONV. There was no significant difference in the incidence of PONV (nausea, vomiting, and none) between the propofol and the metoclopramide groups (P = 0.99; 0.31; and 0.35 respectively). Parturients who received antiemetic agents were 105 (97.2%), 1 (10.0%) and 3 (37.5%) from the control, propofol and metoclopramide groups respectively. The data indicated that 98 (85.2%) parturients from the control, 3 (2.6%) from propofol group, and 100 (87.0%) from the metoclopramide group experienced some levels of pruritus. There was a significant difference in the incidence of pruritus (mild, moderate, and no pruritus) between the metoclopramide and propofol groups (P < 0.01; P < 0.01; and P < 0.01 respectively). Conclusion A sub-hypnotic dose of propofol is effective as metoclopramide in the prevention of PONV in parturient undergoing cesarean section under spinal anesthesia with intrathecal morphine. Sub-hypnotic dose of propofol significantly reduces the incidence of postoperative pruritus following intrathecal morphine use. Trial registration Current control trial, registered at ISRCTN trial registry: ISRCTN15475205. Date registered: 03/04/2019. Retrospectively registered.

Co-administration of JM-1232(-) reduces the dose of propofol required for hypnosis with minimal prolongation of recovery time even after repeated injections

Background: Drug interaction is an important and effective phenomenon in the area of anesthesiology because of drugs combinations potentially possessing novel properties. The characteristics of anesthesia with co-administration of JM-1232(-), benzodiazepine receptor agonist, and propofol, the most popular anesthetics, was studied using mice. Methods: Male adult mice were each administered JM-1232(-), propofol and various combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis and the time until recovery of the reflex was measured as hypnosis time. After determining the ED50, double and triple the ED50 dose of propofol with JM-1232(-) were injected to compare hypnosis time. The injections were repeated 4 times and each hypnosis time was compared. Separately, flumazenil was administered immediately after the last dose was injected. Results: The ED50s ([95% confidence interval]) for hypnosis were 3.76 [3.36 - 4.10] for JM-1232(-) and 9.88 [8.03 - 11.58] mg kg-1 for propofol. Co-administration of 0.05- and 0.1-mg kg-1 of JM-1232(-) reduced the ED50 of propofol to 1.76 [1.21 - 2.51] and 1.00 [0.46 - 1.86] mg kg-1. The interaction of the drug combinations for hypnosis was supra-additive. Hypnosis time was significantly shorter in the groups given the mixtures as compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with sole hypnotics. Flumazenil antagonized the supra-additive effects of the mixtures. Conclusions: The combination of JM-1232(-) and propofol shows supra-additive interaction and the reduced hypnotic dose translates to faster recovery even after multiple injections. Keywords: JM-1232(-), Propofol, Supra-additive interaction, Flumazenil.

Hypnotic Drugs in Hospital. Evaluation of Their use: From Prescription to Administration

In 2015, a French agency, Haute Autorité de santé (HAS), published recommendations for the use of hypnotic drugs. We evaluated the compliance with good practice in prescription and administration studying 3 hypnotics (lormetazepam, zolpidem, zopiclone) referenced in our establishment (psychiatry, rehabilitation, recuperative and long-term care) and melatonin (immediate release hospital preparation). Prescriptions were analyzed on a given day (dosage, length of treatment, prescription modalities). Night nursing practices were collected. Amongst 423 hospitalized patients, 105 had a hypnotic monotherapy, 3 an association melatonin/zopiclone and 6 a melatonin monotherapy. The most prescribed molecule was zopiclone (79%). Prevalence of hypnotic prescription was 25.5%. 17.6% of these prescriptions were for less than 28 days, 82.5% were at maximum dosage, 46.3% were in systematic mode and 53.7% in conditional mode. Amongst the 22 patients over 65 years old, only 8 received half hypnotic dose. Concerning the 9 prescriptions of melatonin, dosage varied from 3 to 9 mg, 1 was in conditional and only 1 specified terms of use. All 15 nurses met, adapt administration to the patient's bedtime. Five nurses have already woken up patients to give them hypnotics. The prevalence of patients with hypnotics is higher than the general French population (6.4%). HAS recommendations are not all followed: duration of prescription greater then 28 days, few dosage adaptations. Nurses generally respect hypnotic administration rules. Melatonin is not often prescribed and has no prescription or administration recommendations. Our results confirm the need to spread hypnotic and melatonin recommendations in health facilities. Hospital pharmacists can relay such recommendations.Disclosure of interestThe authors have not supplied their declaration of competing interest.