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BACKGROUND: The aims of this study were to evaluate the efficacy, safety, and pharmacokinetics (PK) of continuous intravenous administration of remifentanil in mechanically ventilated patients in the intensive care unit (ICU). METHODS: This was a multicenter, randomized, double-blinded, fentanyl-controlled, non-inferiority phase 3 study. Patients aged ≥ 20 years requiring 6 h to 10 days mechanical ventilation in an ICU and requiring pain relief were randomly assigned in a 1:1 ratio to receive either remifentanil (n = 98) or fentanyl (n = 98). Dose was titrated from an infusion rate of 1 mL/h (remifentanil: 0.025 µg/kg/min, fentanyl: 0.1 µg/kg/h) until the target level of analgesia (behavioral pain scale [BPS] ≤ 5 or numerical rating score [NRS] ≤ 3) was achieved by escalating the dose in 1 mL/h increasing. Administration was then adjusted to maintain the target level of analgesia until weaning from the ventilator. The primary endpoint was the proportion of patients who did not require rescue fentanyl. Safety was assessed according to standard procedures. PK of remifentanil in the arterial blood was assessed in 24 patients. RESULTS: The proportion of patients achieving the primary endpoint in the remifentanil and fentanyl groups was 100% (92/92) and 97.8% (88/90), respectively. The difference between the groups was 2.2% (95% confidence interval, - 0.8-5.3) and non-inferiority of remifentanil to fentanyl was verified (p < 0.0001). The incidences of any adverse events in the remifentanil and fentanyl groups was 34 of 92 patients (37.0%) and 34 of 90 patients (37.8%), respectively. Adverse drug reactions was 12 in 92 patients (13.0%) and 15 in 90 patients (16.7%), respectively. In the PK analysis, blood remifentanil concentration decreased within 10 min to almost 50% of the end of administration, suggesting rapid offset of action following discontinuation of remifentanil. CONCLUSIONS: Remifentanil can be used safely for pain management in mechanically ventilated Japanese patients in the ICU. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCT2080224954. Registered 20 November 2019, https://jrct.niph.go.jp/latest-detail/jRCT2080224954 .
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Importance: Patients with pruritus receiving hemodialysis frequently experience oppressive physical and psychiatric symptoms that directly affect their quality of life and increase mortality. However, treatment options are limited. Objective: To determine the clinically recommended dose of difelikefalin, a κ-opioid receptor agonist, based on the efficacy, dose response, safety, and pharmacokinetics. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, 4-arm phase 2 trial was conducted from February 1, 2019, to October 22, 2019, at 94 sites in Japan. Patients with moderate to severe pruritus receiving hemodialysis were enrolled. Interventions: Difelikefalin (0.25, 0.5, and 1.0 µg/kg) and placebo were intravenously administered 3 times a week at the end of each hemodialysis session for 8 weeks. Main Outcome and Measures: The primary end point was the change from baseline in the weekly mean Worst Itching Intensity Numerical Rating Scale (NRS) score at week 8. Secondary outcomes measured changes in itch-related quality-of-life score using the Skindex-16 and 5-D itch scale. Safety was assessed according to adverse events, laboratory tests, vital signs, body weight, and 12-lead electrocardiogram. Results: A total of 247 Japanese patients (186 male [75%]; mean [SD] age, 64.5 [11.7] years) were randomized to placebo (n = 63), 0.25 µg/kg of difelikefalin (n = 61), 0.5 µg/kg of difelikefalin (n = 61), or 1.0 µg/kg of difelikefalin (n = 62). The changes from baseline in the adjusted mean (SE) of the 24-hour Worst Itching Intensity NRS score at week 8 were -2.86 (0.29) in the placebo group, -2.97 (0.29) in the 0.25 µg/kg of difelikefalin group, -3.65 (0.30) in the 0.5 µg/kg of difelikefalin group, and -3.64 (0.30) in the 1.0 µg/kg of difelikefalin group. Significant differences were found in the 0.5 µg/kg of difelikefalin group (adjusted mean difference, -0.80; 95% CI, -1.55 to -0.04; P = .04) and the 1.0 µg/kg of difelikefalin group (adjusted mean difference, -0.78; 95% CI, -1.54 to -0.03; P = .04) compared with placebo. The Skindex-16 overall score and 5-D itch scale total score indicated an improvement with treatment with 0.5 and 1.0 µg/kg of difelikefalin (adjusted weekly mean [SE] Skindex-16 overall score at week 8, -27.79 [2.05]; 95% CI, -31.83 to -23.74 for 0.5 µg/kg of difelikefalin and -22.69 [2.04]; 95% CI, -26.71 to -18.68 for 1.0 µg/kg of difelikefalin; adjusted weekly mean [SE] 5-D itch scale total score at week 8, -6.5 [0.4]; 95% CI, -7.2 to -5.8 for 0.5 µg/kg of difelikefalin and -6.8 [0.3]; 95% CI, -7.5 to -6.2 for 1.0 µg/kg of difelikefalin). The incidence of adverse events was 67% (42 of 63 patients) in the placebo group, 72% (44 of 61 patients) in the 0.25 µg/kg of difelikefalin group, 77% (47 of 61 patients) in the 0.5 µg/kg of difelikefalin group, and 85% (53 of 62 patients) in the 1.0 µg/kg of difelikefalin group. No dependency was reported. Conclusions and Relevance: The findings of this phase 2 randomized clinical trial of difelikefalin suggest that 0.5 µg/kg of difelikefalin should be the clinically recommended dose as a new option for treating moderate to severe pruritus in patients undergoing hemodialysis because of its efficacy, acceptable tolerability, and manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT03802617.
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Prurito , Calidad de Vida , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Piperidinas , Prurito/tratamiento farmacológico , Prurito/etiología , Diálisis Renal/efectos adversosRESUMEN
BACKGROUND: Only a few studies have been reported on the use of dexmedetomidine for sedating surgical patients requiring epidural or spinal anesthesia. We conducted a randomized, double-blind, placebo-controlled, parallel-group study at 12 hospitals in Japan. METHODS: Adult patients were randomly allocated to receive an intravenous administration of placebo or dexmedetomidine at 0.067, 0.25, 0.5 or 1.0 µg/kg over 10 min after epidural or spinal anesthesia. All dexmedetomidine groups received dexmedetomidine 0.2-0.7 µg/kg/h to maintain an Observer's Assessment of Alertness/Sedation Scale (OAA/S) score of ≤ 4; however, propofol was administered to rescue patients who exceeded this score. Surgery was then started 15 min after study drug infusion in patients with OAA/S score of ≤ 4. The primary endpoint was the percentage of patients not requiring rescue propofol to achieve and maintain an OAA/S score of ≤ 4. RESULTS: Of the 120 enrolled and randomized patients, 119 were treated the study: 22 received placebo and 97 received dexmedetomidine (23-25 patients per dose). Significantly more patients did not require propofol in the dexmedetomidine 0.5 and 1.0 µg/kg groups (68.0% and 80.0%, respectively) compared to the placebo group (22.7%) (P = 0.003 and P < 0.001, respectively). Common adverse events (AEs) were protocol-defined respiratory depression, bradycardia and hypotension. There was no significant difference in the incidence of AEs between the dexmedetomidine and the placebo groups. CONCLUSION: We concluded that loading doses of 0.5 and 1.0 µg/kg dexmedetomidine, followed by an infusion at a rate of 0.2-0.7 µg/kg/h, provide effective and well-tolerated sedation for surgical patients during epidural or spinal anesthesia.Clinical trials.gov identifier: NCT01438957.
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BACKGROUND: Few studies (in other countries than the US) have reported on the efficacy and safety of dexmedetomidine for sedation of patients undergoing surgical or medical procedures under local anesthesia without intubation outside the intensive care unit. We performed a randomized, double-blind study in Japan. METHODS: Adult patients were randomly allocated to receive placebo, dexmedetomidine 0.5 µg/kg (DEX 0.5 group), or dexmedetomidine 1.0 µg/kg (DEX 1.0 group) over 10 min. Then, both dexmedetomidine groups received dexmedetomidine 0.2-0.7 µg/kg/h for maintaining an Observer's Assessment of Alertness/Sedation Scale (OAA/S) score of ≤ 4; however, propofol was administered to rescue patients whose score exceeded this value. The primary endpoint was the percentage of patients who did not require rescue propofol to achieve and maintain an OAA/S score of ≤ 4. RESULTS: In total, 162 patients were included in the placebo (n = 53), DEX 0.5 (n = 53), and DEX 1.0 (n = 56) groups. Propofol was not required in significantly more patients in the dexmedetomidine 0.5 and 1.0 µg/kg groups (52.8% and 57.1%, respectively) compared with the placebo group (1.9%) (P < 0.001 for both). Common adverse events were protocol-defined hypotension, respiratory depression and bradycardia. The incidence of bradycardia was significantly higher in the DEX 0.5 (26.4%) and DEX 1.0 (30.4%) groups than in the placebo group (9.4%) (P = 0.041 and P = 0.008, respectively). CONCLUSION: We concluded that a loading dose of 0.5 or 1.0 µg/kg dexmedetomidine followed by infusion at a rate of 0.2-0.7 µg/kg/h provided effective and well-tolerated sedation in patients undergoing surgical or medical procedures under local anesthesia without intubation.Clinical trials.gov identifier: NCT01438931.