Estimation of the minimum effective dose of tramadol for postoperative analgesia in infants using the continual reassessment method

Tramadol is a potent analgesic.However,the analgesia efficacy of tramadol,particularly its minimum effective dose(MED),is not clear.The aim of this study is to find MED of tramadol for postoperative analgesia in infants.The continual reassessment method(CRM)was performed to find MED.Infants undergoing surgeries were included in the 3 phases of this series.In each phase,24 participants were allocated a different tramadol dose.Pain intensity was measured by face,legs,activity,cry,consolability(FLACC)measurement at 3-hour intervals.Tramadol was considered ineffective if the FLACC score was higher than 4 in 10 at anytime.In phase 1,seven dose levels were used within the range 0.1-0.4 mg·kg^(-1)·h^(-1).Phase 1 was insufficient to identify the MED,and we increased the dose to 0.4-0.8 mg·kg^(-1)·h^(-1) in phase 2.Phase 2 was insufficient to identify the MED.In phase 3,local anesthetic wound infiltration was introduced,and the tramadol dose levels tested were the same as in phase 1.The successful analgesia probability of tramadol 0.4 mg·kg^(-1)·h^(-1) was 82.1%(95%CI,0.742-0.925)in phase 1.In phase 2,it was 84.7%(95%CI,0.789-0.991)with the dose 0.8 mg·kg^(-1)·h^(-1).Phase 1 and phase 2 were insufficient to identify the MED.In phase 3,the successful analgesia probability for dose 0.35 mg·kg^(-1)·h^(-1) was 96.7%(95%CI,0.853-0.997).We have demonstrated that tramadol provides insufficient analgesia for surgeries considered to cause moderate-to-severe postoperative pain in infants if used as the sole analgesic,and that local anesthetic wound infiltration enhances the efficacy of tramadol.

Stepwise Method Based on Confidence Bound and Information Incorporation for Identifying the Maximum Tolerable Dose

The primary goal of a phase I clinical trial is to find the maximum tolerable dose of a treatment. In this paper, we propose a new stepwise method based on confidence bound and information incorporation to determine the maximum tolerable dose among given dose levels. On the one hand, in order to avoid severe even fatal toxicity to occur and reduce the experimental subjects, the new method is executed from the lowest dose level, and then goes on in a stepwise fashion. On the other hand, in order to improve the accuracy of the recommendation, the final recommendation of the maximum tolerable dose is accomplished through the information incorporation of an additional experimental cohort at the same dose level. Furthermore, empirical simulation results show that the new method has some real advantages in comparison with the modified continual reassessment method.

Determination of the ED95 of intranasal sufentanil combined with intranasal dexmedetomidine for moderate sedation during endoscopic ultrasonography

BACKGROUND Sedation during endoscopic ultrasonography(EUS)poses many challenges and moderate-to-deep sedation are often required.The conventional method to preform moderate-to-deep sedation is generally intravenous benzodiazepine alone or in combination with opioids.However,this combination has some limitations.Intranasal medication delivery may be an alternative to this sedation regimen.AIM To determine,by continual reassessment method(CRM),the minimal effective dose of intranasal sufentanil(SUF)when combined with intranasal dexmedetomidine(DEX)for moderate sedation of EUS in at least 95%of patients(ED95).METHODS Thirty patients aged 18-65 and scheduled for EUS were recruited in this study.Subjects received intranasal DEX and SUF for sedation.The dose of DEX(1μg/kg)was fixed,while the dose of SUF was assigned sequentially to the subjects using CRM to determine ED95.The sedation status was assessed by modified observer’s assessment of alertness/sedation(MOAA/S)score.The adverse events and the satisfaction scores of patients and endoscopists were recorded.RESULTS The ED95 was intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,with an estimated probability of successful moderate sedation for EUS of 94.9%(95%confidence interval:88.1%-98.9%).When combined with intranasal 1μg/kg DEX,probabilities of successful moderate sedation at each dose level of intranasal SUF were as follows:0μg/kg SUF,52.8%;0.1μg/kg SUF,75.4%;0.2μg/kg SUF,89.9%;0.3μg/kg SUF,94.9%;0.4μg/kg SUF,98.0%;0.5μg/kg SUF,99.0%.CONCLUSION The ED95 needed for moderate sedation for EUS is intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,based on CRM.

A system for determining maximum tolerated dose in clinical trial

Toxicity study,especially in determining the maximum tolerated dose(MTD)in phase I clinical trial,is an important step in developing new life-saving drugs.In practice,toxicity levels may be categorised as binary grades,multiple grades,or in a more generalised case,continuous grades.In this study,we propose an overall MTD framework that includes all the aforementioned cases for a single toxicity outcome(response).The mechanism of determining MTD involves a function that is predetermined by user.Analytic properties of such a system are investigated and simu-lation studies are performed for various scenarios.The concept of the continual reassessment method(CRM)is also implied in the framework and Bayesian analysis,including Markov chain Monte Carlo(MCMC)methods are used in estimating the model parameters.