Pharmacodynamic modeling of moderate sedation and rationale for dosing using midazolam, propofol and alfentanil.

PURPOSE: Regulations have broadened to allow moderate sedation administration for gastrointestinal endoscopy by non-anesthesia personnel. The line between moderate and deep sedation is ambiguous. Deep sedation offers patient comfort as well as greater safety concerns. Unintended deep sedation can occur if drug interactions are overlooked. We present a pharmacodynamic model for moderate sedation using midazolam, alfentanil and propofol. The model is suitable for training and devising rationales for appropriate dosing. METHODS: The study consists of two parts: modeling and validation. In modeling, patients scheduled for esophagogastroduodenoscopy (EGD) or colonoscopy sedation are enrolled. The modified observer's assessment of alertness/sedation (MOAA/S) score < 4 is defined as loss of response to represent moderate sedation. Two patient groups receiving bronchoscopy or endoscopic retrograde cholangiopancreatography (ERCP) are used for validation. Model performance is assessed by receiver operating characteristic (ROC) curves and area under the curve (AUC). Simulations are performed to demonstrate how the model is used to rationally determine drug regimen for moderate sedation. RESULTS: Interaction between propofol and alfentanil is stronger than the other pairwise combinations. Additional synergy is observed with three drugs. ROC AUC is 0.83 for the modeling group, and 0.96 and 0.93 for ERCP and bronchoscopy groups respectively. Model simulation suggests that 1 mg midazolam, 250 µg alfentanil and propofol maximally benefits from drug interactions and suitable for moderate sedation. CONCLUSION: We demonstrate the accurate prediction of a three-drug response surface model for moderate sedation and simulation suggests a rational dosing strategy for moderate sedation with midazolam, alfentanil and propofol.

Alfentanil Pretreatment for Electroconvulsive Therapy-Associated Hemodynamic Lability: A Prospective Randomized Crossover Trial.

OBJECTIVES: Electroconvulsive therapy (ECT) is frequently associated with significant hemodynamic changes that increase myocardial oxygen demand including significant hypertension poststimulus. This raises concern about the cumulative effect of repetitive stress from ECT. Historically, various agents have been used to blunt this response and reduce hemodynamic fluctuations in these patients with varying degrees of efficacy. We hypothesized that bolus alfentanil administration timed with the ECT stimulus may reduce near-term hypertension and heart rate (HR) increases in patients undergoing ECT. METHODS: A randomized, double-blind, placebo-controlled AB/BA crossover trial of 87 patients 18 years or older with mood disorders was carried out. Patients received a standardized anesthetic regimen including induction with methohexital and succinylcholine and were randomized to receive either 20 µg/kg ideal bodyweight of alfentanil or placebo 60 seconds before the ECT stimulus for the first treatment and then crossed over to the other group for the second treatment. The primary outcome was the within-individual difference in preinduction systolic blood pressure and the first systolic blood pressure after the ECT stimulus. RESULTS: Eighty-seven patients completed the protocol. The primary outcome of increase in systolic blood pressure pre-ECT to post-ECT was 16.9 mm Hg less in the alfentanil group than the placebo group (95% confidence interval, -26.0 to -7.8; P < 0.001). The maximum HR was 6.5 beats per minute lower (95% confidence interval, -12.1 to -0.9; P = 0.024) when patients received alfentanil compared with placebo. CONCLUSIONS: Premedication with alfentanil reduces poststimulus hypertension and increased HR in patients receiving ECT and therefore, may reduce morbidity related to this in susceptible patients.

Respiratory Effects of the Atypical Tricyclic Antidepressant Tianeptine in Human Models of Opioid-induced Respiratory Depression.

BACKGROUND: Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans. METHODS: Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion. RESULTS: Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (-11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment. CONCLUSIONS: Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil.

Sedation with alfentanil versus fentanyl in patients receiving extracorporeal membrane oxygenation: outcomes from a single-centre retrospective study.

INTRODUCTION: In November 2016, our institution switched from alfentanil to fentanyl for analgesia and sedation in adult patients receiving extracorporeal membrane oxygenation. There is no published evidence comparing the use of alfentanil with fentanyl for sedation in extracorporeal membrane oxygenation patients. We conducted a retrospective observational study to explore any significant differences in patient outcomes or in the prescribing of adjunct sedatives before and after the switch. METHODS: Patients were retrospectively identified from a prospectively recorded database of all patients who received extracorporeal membrane oxygenation at our institution between January 2016 and October 2017. Patients included those sedated with alfentanil or fentanyl. The total daily doses of intravenous opioids (alfentanil or fentanyl) were calculated for each patient, and the prescribing of adjunctive sedative or analgesic agents was recorded. Patient demographics, extracorporeal membrane oxygenation modality, clinical outcomes including mortality and length of intensive care and hospital stay were recorded. RESULTS: A total of 174 patients were identified, 69 on alfentanil and 95 on fentanyl. There was no difference found between groups for mode of extracorporeal membrane oxygenation, age, Acute Physiology and Chronic Health Evaluation 2 score (APACHE II) and Charlson score, except for body mass index (p = 0.002). No differences in patient outcomes was observed between groups, although patients in the alfentanil group received a significantly higher median total daily dose of adjuvant sedatives (quetiapine (p = 0.016) and midazolam (p = 0.009)). CONCLUSIONS: No differences in patient outcomes were found between extracorporeal membrane oxygenation patients sedated with alfentanil compared with fentanyl. There was a statistically significant reduction in some adjunctive sedatives in patients managed with a fentanyl-based regimen. Prospective studies are required to confirm these results.

Evaluation of two different radiotherapy anaesthetic protocols for dogs: a randomized clinical crossover trial.

OBJECTIVES: To describe alfentanil-propofol admixture for induction of anaesthesia for canine radiotherapy and compare it to alfentanil-atropine followed by propofol induction in terms of heart rate (HR), mean arterial pressure (MAP), recovery duration and quality. STUDY DESIGN: Prospective, masked, randomized clinical crossover trial. ANIMALS: A group of 40 client-owned dogs anaesthetized from October 2017 to June 2018. METHODS: Dogs were randomly assigned to be administered one of two protocols. For both protocols, IV preanaesthetic medication was given 30 seconds before rapid IV administration of a set volume of induction agent, with further induction agent administered as needed to permit intubation. For protocol ADMIX, the preanaesthetic medication was 0.04 mL kg-1 0.9% sodium chloride and the induction agent was 0.2 mL kg-1 propofol-alfentanil admixture. For protocol ATRO, the preanaesthetic medication was 10 µg kg-1 alfentanil with 12 µg kg-1 atropine (0.04 mL kg-1 total volume) and the induction agent was 0.2 mL kg-1 propofol. Anaesthesia was maintained with sevoflurane. Cardiorespiratory variables, agitation, hypotension, or inadequate depth of anaesthesia requiring supplemental boluses of propofol or increased vaporizer settings were recorded. Time to extubation, sternal recumbency and walking was noted. Videos were recorded for recovery quality scoring. Owner questionnaires gave feedback about recoveries at home. The other protocol was administered for the next radiotherapy session. RESULTS: The only significantly different variable between protocols was mean HR during anaesthesia, which was lower in ADMIX (p < 0.001). Hypotension was recorded in seven (17.5%) dogs in ATRO and three (7.5%) in ADMIX, with an association (p < 0.005) between ATRO and hypotension. Owners reported animals recovered 'normal' behaviour and appetite by the next morning. CONCLUSIONS AND CLINICAL RELEVANCE: Both protocols were acceptable for dogs undergoing radiotherapy, with minimal differences in anaesthetic quality, recovery duration and quality. Although MAP did not differ overall, the incidence of hypotension was higher in ATRO.

PBPK Models for CYP3A4 and P-gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin.

According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool to explore and quantitatively predict drug-drug interactions (DDIs) and may offer an alternative to dedicated clinical trials. This study provides whole-body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology (OSP) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies. In total, 112 studies were used for model development and 57 studies for DDI prediction. 93% of the predicted area under the plasma concentration-time curve (AUC) ratios and 94% of the peak plasma concentration (Cmax ) ratios are within twofold of the observed values. This study lays a cornerstone for the qualification of the OSP platform with regard to reliable PBPK predictions of enzyme-mediated and transporter-mediated DDIs during model-informed drug development. All presented models are provided open-source and transparently documented.

Comparison of a New Intranasal Naloxone Formulation to Intramuscular Naloxone: Results from Hypothesis-generating Small Clinical Studies.

Easy-to-use naloxone formulations are needed to help address the opioid overdose epidemic. The pharmacokinetics of i.v., i.m., and a new i.n. naloxone formulation (2 mg) were compared in six healthy volunteers. Relative to i.m. naloxone, geometric mean (90% confidence interval [CI]) absolute bioavailability of i.n. naloxone was modestly lower (55%; 90% CI, 43-70% vs. 41%; 90% CI, 27-62%), whereas average (±SE) mean absorption time was substantially shorter (74 ± 8.8 vs. 6.7 ± 4.9 min). The opioid-attenuating effects of i.n. naloxone were compared with i.m. naloxone (2 mg) after administration of oral alfentanil (4 mg) to a separate group of six healthy volunteers pretreated with 240 mL of water or grapefruit juice. The i.m. and i.n. naloxone attenuated miosis by similar extents after water (40 ± 15 vs. 41 ± 21 h*%) and grapefruit juice (49 ± 18 vs. 50 ± 22 h*%) pretreatment. Results merit further testing of this new naloxone formulation.

Synergistic antinociceptive effects of alfentanil and propofol in the formalin test.

The present study was conducted to determine the combined analgesic effect of alfentanil and propofol in the formalin test. Diluted formalin was injected into the dorsal surface of the right hind paw in rats. Nociceptive behavior was determined by counting the number of flinches of the injected paw for 1 h after injection; a reduction in formalin­induced flinching was interpreted as an antinociceptive effect. Isobolographic analysis was used to determine the type of antinociceptive interaction (additivity, antagonism or synergism). Extracellular signal­regulated kinase (ERK) and c­fos protein levels were also detected by western blot analysis to determine the potential mechanisms of the synergistic effect. Alfentanil, propofol or an alfentanil­propofol combination had an antinociceptive effect in the formalin test. The median effective dose (ED50), value of the individual drug was also obtained. The derived theoretical ED50 for the antinociceptive effect (4.36 mg/kg) was different from the observed experimental ED50 value (2.51 mg/kg). The interaction between alfentanil and propofol that produced the antinociceptive effect was synergistic according to isobolographic analysis. Furthermore, the combination of alfentanil and propofol treatments may produce synergistically antinociceptive effects by inhibiting the phosphorylation of ERK1/2 and decreasing the expression of c­fos in the spinal cord. These results demonstrated that combined treatment, with alfentanil and propofol, produced synergistic antinociceptive effects in the formalin test and may have therapeutic potential for the treatment of acute pain.

Dose requirements of alfentanil to eliminate autonomic responses during rapid-sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg.

STUDY OBJECTIVE: Opioids are integral part of anesthesia induction, but information on optimal dosing is limited. We aimed to determine doses of alfentanil needed to eliminate increases in 5 autonomic response variables (plasma concentrations of epinephrine, norepinephrine and vasopressin, arterial blood pressure [ABP], and heart rate) during rapid-sequence induction of anesthesia with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. DESIGN: Prospective, randomized, observer-blinded, interventional clinical study. SETTING: Large academic institution. PATIENTS: Eighty-four healthy patients, aged 18 to 55 years, received 1 of 7 assessor-blinded doses of alfentanil (0, 10, 20, 30, 40, 50, and 60 µg/kg) together with thiopental 4 mg/kg and rocuronium 0.6 mg/kg, administered in rapid succession (15 seconds). Laryngoscopy was initiated 40 seconds after rocuronium, and tracheal intubation was concluded within 15 seconds thereafter. MEASUREMENTS: An indwelling radial artery catheter was used for hemodynamic monitoring and blood sampling. Relationships between alfentanil dose and response variables were tested with linear regression, and the influence of covariates (sex, body weight, and age) was determined. Alfentanil dose needed to prevent increases in ABP >10% above baseline with 95% probability was estimated with logistic regression. MAIN RESULTS: Significant relationships were determined between alfentanil dose and response variables. Clinically interesting influence of covariates was not found. Alfentanil 55 µg/kg was needed to prevent increases in ABP postintubation >10% above baseline with 95% probability. One individual needed a bolus of vasopressor postintubation. CONCLUSIONS: Optimal control of autonomic responses during rapid-sequence induction was achieved with clinically relevant doses of alfentanil in healthy patients anesthetized with thiopental 4 mg/kg and rocuronium 0.6 mg/kg.

Synergistic analgesic effect of propofol-alfentanil combination through detecting the inhibition of cAMP signal pathway.

OBJECTIVE: The study aims to investigate the possible mechanism of the synergistic analgesic effect of propofol-alfentanil combination. METHODS: The synergistic analgesic effects of propofol-alfentanil combination in Sprague-Dawley (SD) rats were analysed through the von Frey test. Then, we examined the activity of phospholipase C (PLC) and the intracellular levels of Ca(2+) and adenosine 3', 5'cyclic monophosphate (cAMP) in primary neuronal cells of fetal SD rats. We detected the intracellular Ca(2+) concentration by fluorescence and flow cytometry. The PLC activity of the primary neuronal cells was assayed using the EnzChek(®) Direct Phospholipase C Assay Kit. The cAMP content of the cells was assayed using the cAMP Direct Immunoassay Kit (Fluorometric). KEY FINDINGS: Both propofol and alfentanil treatments depressed cAMP levels and PLC activity, but propofol-alfentanil combination decreased these parameters to a greater extent than alfentanil treatment alone. Propofol and alfentanil both inhibited Ca(2+) channel, but propofol-alfentanil combination suppressed this channel to a greater extent than alfentanil treatment alone. Fluorescent image analysis revealed that both propofol and alfentanil reduced the intracellular levels of Ca(2+) , and propofol-alfentanil combination showed weaker signals than alfentanil alone. Propofol-alfentanil combination significantly reduced intracellular Ca(2+) level, cAMP level and PLC activity. CONCLUSION: Propofol and alfentanil exert synergistic analgesic effects through the adenylyl cyclase pathway.

Previously published midazolam-alfentanil response surface model cannot predict patient response well in gastrointestinal endoscopy sedation.

BACKGROUND: A response surface model is a mathematical model used to predict multiple-drug pharmacodynamic interactions. With the use of a previously published volunteer model, we tested the accuracy of the midazolam-alfentanil response surface model during gastrointestinal endoscopy. METHODS: We enrolled 35 adult patients scheduled for combined endoscopic procedures. Patients were sedated with intravenous midazolam and alfentanil, and monitored with real-time auditory evoked potential. Sedation Observer's Assessment of Alertness/Sedation (OAA/S) scores were recorded by an independent observer every 2 minutes. Patients with OAA/S scores of ≥ 4 were designated as "awake". Pharmacokinetic profiles were calculated using the TIVA trainer. The published response surface model was modified to make estimations more reasonable. Patient response (OAA/S score ≥ 4 or <4) was then estimated using the modified version of the model. RESULTS: The average procedural times were 3.3 ± 2 minutes and 6.5 ± 2.3 minutes for esophagogastroduodenoscopy and colonoscopy, respectively. The model poorly predicted patient response during gastrointestinal endoscopic procedure sedation. Accuracy in predicting an OAA/S score of <4 was 6% for the original model and 0% for the modified model. The estimated probability of loss of response ranged from 0.04% to 2.94% at the time of arousal (OAA/S score ≥ 4) and from 0.24% to 15.55% when the patient was asleep (OAA/S score < 4). CONCLUSION: The model showed significant synergy between midazolam and alfentanil; however, it was inadequate in predicting the response of patients undergoing sedated gastrointestinal endoscopic procedures. Future model parameter adjustments are required.

µ-Opioid agonists for preventing emergence agitation under sevoflurane anesthesia in children: a meta-analysis of randomized controlled trials.

BACKGROUND: Emergence agitation (EA) is an adverse effect after sevoflurane anesthesia in pediatric patients. The effectiveness of prophylactic µ-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil in preventing EA is debatable. METHODS: A literature search was conducted to identify clinical trials that observed the effect of µ-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil on preventing EA in pediatric patients under sevoflurane anesthesia. The statistical software RevMan 5.3 was used for meta-analysis. Data from each study were combined using the relative ratio (RR), weighted mean differences, and their associated 95% confidence intervals. I(2) was used to evaluate heterogeneity. Subgroup analysis was conducted to investigate the possible influences of patient age, adenotonsillectomy, premedication, N2 O, propofol, and regional block/local anesthetics on preventing EA with prophylactic administration of µ-opioid agonists. Publication bias was checked using funnel plots and Begg's test. RESULTS: This meta-analysis showed the inclusion of 19 randomized controlled trials with 1528 patients (857 patients received µ-opioid agonists therapy and 671 patients had placebo). The pooled data indicated that prophylactic µ-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil significantly decreased the incidence of EA [RR = 0.49 (0.38, 0.64), I(2) = 42%, P = 0.04; RR = 0.57 (0.33, 0.99), I(2) = 37%, P = 0.19; RR = 0.18 (0.08, 0.39), I(2) = 0%, P = 0.98; and RR = 0.56 (0.40, 0.78), I(2) = 6%, P = 0.34, respectively]. All subgroup analyses strengthened the proof for lower incidence of EA under sevoflurane anesthesia after fentanyl administration. A possibility of publication bias was detected in the fentanyl group. CONCLUSIONS: This meta-analysis suggested that prophylactic µ-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil could significantly decrease the incidence of EA under sevoflurane anesthesia in children compared to placebo. Considering the limitations of the included studies, more clinical studies are required.

Synergistic antinociceptive interactions between fospropofol and alfentanil in mice.

BACKGROUND: Combination therapy, which provides the opportunity to achieve optimal analgesia with reduced side effects at lower drug doses, is a valid approach for the treatment of pain. The analgesic interaction between fospropofol and alfentanil has not been investigated till date. We sought to determine the nature of the interaction between fospropofol and alfentanil in mice models of the formalin test, hot-plate test and the tail-flick test. METHODS: The effects of fospropofol, alfentanil and their combinations were examined in the formalin-induced paw inflammatory hyperalgesia, the hot-plate test and the tail-flick test in mice. In the three models, dose-response curves were established and their respective ED50 (50% effective dose) values were determined separately for each agent. Fixed-ratio combinations of fospropofol and alfentanil were tested for their combined antinociceptive effects, and the type of interaction was determined by the isobolographic analysis. RESULTS: Fospropofol, alfentanil and their combination produced a dose-dependent decrease in the number of flinches during phase 1 of the formalin test. In the hot-plate test and in the tail-flick test, fospropofol, alfentanil and their combination significantly and dose dependently prolonged the latency of withdrawal. In the three models, isobolographic analysis revealed a significant synergistic interaction between fospropofol and alfentanil. The ED50 value for the drug combination was significantly lower than the theoretical additive value (p<0.05). CONCLUSIONS: The results demonstrate that fospropofol and alfentanil provide synergistic antinociceptive interactions in the formalin, hot-plate, and tail-flick tests. The observed synergistic interaction between fospropofol and alfentanil are indicative of the effectiveness of the combination treatment in pain management and should be explored further in patients undergoing minor surgical procedures.

Effects of opioids on human serotonin transporters.

The serotonin (5-hydroxtryptamine, 5-HT) system plays a role in analgesia and emesis. The aim of this study was to test whether opioids or ketamine inhibit the human 5-HT transporter and whether this increases free plasma 5-HT concentrations. HEK293 cells, stably transfected with the human 5-HT transporter cDNA, were incubated with morphine, hydromorphone, fentanyl, alfentanil, pethidine (meperidine), tramadol, ketamine, and the reference substance citalopram (specific 5-HT transporter inhibitor). The uptake of [(3)H]5-HT was measured by liquid scintillation counting. In a second series of experiments, study drugs were incubated with plasma of ten healthy blood donors and change of 5-HT plasma-concentrations were measured (ELISA). The end point was the inhibition of the 5-HT transporter by different analgesics either in HEK293 cells or in human platelets ex vivo. Tramadol, pethidine, and ketamine suppressed [(3)H]5-HT uptake dose-dependently with an IC50 of 1, 20.9, and 230 µM, respectively. These drugs also prevented 5-HT uptake in platelets with an increase in free plasma 5-HT. Free 5-HT concentrations in human plasma were increased by citalopram 1 µM, tramadol 20 µM, pethidine 30 µM, and ketamine 100 µM to 280 [248/312]%, 269 [188/349]%, and 149 [122/174]%, respectively, compared to controls without any co-incubation (means [95 % CI]; all p < 0.005). No change in both experimental settings was observed for the other opioids. Tramadol and pethidine inhibited the 5-HT transporter in HEK293 cells and platelets. This inhibition may contribute to serotonergic effects when these opioids are given in combination, e.g., with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.

Direct effects of morphine but not of fentanyl-type opioids on human 5-HT3A receptors in outside-out patch-clamp studies.

BACKGROUND: The alkaloid morphine is historically the oldest opiate, yet still today it has clinically important uses in analgesic therapies. The main analgesic effect of opioids, including synthetic opioids belonging to the family of 4-anilidopiperidines, is mediated via activation of opioid receptors spread throughout the peripheral and central nervous system. However, morphine acting as a 'dirty' drug also exhibits effects on other receptor systems, e.g., the serotonergic system and its 5-HT3 receptor. Therefore, this study focuses on the interaction of morphine and fentanyl-type opioids (alfentanil, remifentanil and sufentanil) with 5-HT3A receptors. METHODS: Excised outside-out patches from human embryonic kidney-293 cells, stably transfected with the human 5-HT3A receptor cDNA, were used to determine the opioid effects using the patch-clamp technique. RESULTS: Within clinical concentrations, the effects of morphine are concentration-dependent. Morphine reduced current amplitudes, as well as activation and decay time constants. These effects were not competitive. Contrary to these results, all fentanyl-type opioids only exerted effects far above their clinical concentration ranges. These effects were not homogenous but varying. CONCLUSIONS: Morphine is an opioid compound exhibiting special antagonistic interaction with 5-HT3A receptors. This interaction is not shared by the newer synthetic derivatives of the fentanyl-type opioids in the clinical relevant concentration range.

Synergistic antinociception of propofol-alfentanil combination in mice.

Drug combination is frequently used in pain treatment, which can produce similar analgesia with reduced dosage and side effects. In the present study, we examined the effects of co-administration of propofol, a general anesthetic, and alfentanil, an opioid analgesic drug, and the types of interactions between them in heat induced acute phasic and acetic-acid induced acute tonic pain models using the up-and-down method. In both pain models, alfentanil was administered in fixed-dose fractions of the 50% effective dose (ED50), and the types of interactions were determined by isobolographic analysis. In hot plate test, alfentanil (35.6-50.0 µg/kg, i.v.), propofol (6.5-15.5mg/kg, i.v.), and their combinations (80%, 50%, 30% and 10% of a single drug ED50) produce a significant, dose-dependent antinociception. In the tail-flick test, alfentanil (35.6-50.0 µg/kg, i.v.), propofol (5.0-14.3mg/kg, i.v.), and their combination significantly and dose dependently extend the tail-flick latency. In the acetic-acid induced writhing test, alfentanil (12.5-23.2 µg/kg, i.p.), propofol (15.0-28.5mg/kg, i.p.), and their combination significantly and dose dependently reduce the frequency of writhing. In all the above pain models, isobolographic analysis revealed a significant synergistic interaction between alfentanil and propofol, with about 4-fold reduction of doses of both drugs, in comparison with each single drug's ED50. These data suggest that the combination of alfentanil and propofol synergistically suppresses acute phasic and tonic pain in mice, indicating a potential application in pain treatment.

Pairwise comparisons with ordered categorical data.

Clinical trials frequently involve pairwise comparisons of different treatments to evaluate their relative efficacy. In this study, we examine methods for conducting pairwise tests of treatments with ordered categorical responses. A modified version of the Wilcoxon-Mann-Whitney test based on a logistic regression model assuming proportional odds is a popular choice for comparing two treatments. This paper discusses the extension of this test to pairwise comparisons involving more than two treatments. However, when the proportional odds assumption is not valid, the Wilcoxon-Mann-Whitney-type test procedure cannot control the overall type I error rate at the prespecified level of significance. We therefore propose a better strategy in which a latent normal model is employed. We presented a simulated comparative study of power and the overall type I error rate to illustrate the superiority of the latent normal model. Examples are also given for illustrative purposes.