Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine the range and responsiveness to change of clinical outcome measures and study predictors of clinical response in patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials. METHODS: Data were combined from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials. Trials used common outcome measures: modified Rodnan skin thickness score (MRSS), Health Assessment Questionnaire disability index (HAQ DI), patient's global assessment of disease activity, pulmonary function tests (forced vital capacity, diffusing capacity for carbon monoxide), hand span, and oral aperture. RESULTS: The combined database included 629 patients (82% women, mean ± SD age 46.5 ± 11.8 years, mean ± SD disease duration 19.4 ± 15.9 months). Outcomes tended to improve during trials for patients with more severe disease at study entry and to worsen for patients with less severe disease at entry. Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = -0.27, P < 0.001), and substantial bidirectional variation in change in MRSS and HAQ DI score was seen across the spectrum of disease duration. Sixty-three percent of patients with "early" disease (disease duration <18 months) had a decline in MRSS, and 37% had an increase in MRSS. Eighty-one percent of patients with "late" disease (disease duration ≥ 18 months) had a decline in MRSS, and 19% had an increase in MRSS. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome. CONCLUSION: Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve in those with more severe disease at study entry and to worsen in those with less severe disease at entry. Overall, the MRSS improves during trials, while HAQ DI scores and lung function are mostly static. None of these variables, including disease duration, reliably identifies groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma.

Multiple dose pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers.

BACKGROUND: Oral transmucosal fentanyl citrate (OTFC) is a solid form of fentanyl that delivers the drug through the oral mucosa. The clinical utility of multiple doses of OTFC in the treatment of "breakthrough" cancer pain is under evaluation. The aim of this study was to test the hypothesis that the pharmacokinetics of OTFC do not change with multiple dosing. METHODS: Twelve healthy adult volunteers received intravenous fentanyl (15 microg/kg) or OTFC (three consecutive doses of 800 microg) on separate study sessions. Arterial blood samples were collected for determination of fentanyl plasma concentration by radioimmunoassay. The descriptive pharmacokinetic parameters (maximum concentration, minimum concentration, and time to maximum concentration) were identified from the raw data and subjected to a nonparametric analysis of variance. Population pharmacokinetic models for all subjects and separate models for each subject were developed to estimate the pharmacokinetic parameters of fentanyl after multiple OTFC doses. RESULTS: The shapes of the profiles of plasma concentration versus time for each dose of OTFC were grossly similar. No change was noted for maximum concentration or time to maximum concentration over the three doses, while minimum concentration did show a significantly increasing trend. Terminal half-lives for intravenous fentanyl and OTFC were similar. A two-compartment population pharmacokinetic model adequately represented the central tendency of the data from all subjects. Individual subject data were best described by either two- or three-compartment pharmacokinetic models. These models demonstrated rapid and substantial absorption of OTFC that did not change systematically with time and multiple dosing. CONCLUSIONS: The pharmacokinetics of OTFC were similar among subjects and did not change with multiple dosing. Multiple OTFC dosing regimens within the dosage schedule examined in this study can thus be formulated without concern about nonlinear accumulation.

Buccal absorption of etomidate from a solid formulation in dogs.

UNLABELLED: Etomidate is typically administered i.v. for the induction of general anesthesia. We believe that oral transmucosal absorption may extend etomidate's use to premedication and conscious sedation. Our objective was to study the oral mucosal absorption kinetics and bioavailability of etomidate in a solid dose form in dogs. A solid dose form containing 50 mg of etomidate in sorbitol for buccal administration was prepared. Each dog was administered both i.v. etomidate and buccal etomidate on separate days. Serum etomidate concentrations after i.v. administration were fit to a two-compartment pharmacokinetic model. The rates at which etomidate enters the systemic circulation via buccal mucosal absorption were calculated from serum concentrations from mucosal and i.v. administrations using model-dependent constrained numerical deconvolution. The apparent permeability coefficient and bioavailability were also determined. The mean (+/- SD) maximal serum etomidate concentration after buccal mucosal absorption from the 50-mg dose unit was 239 +/- 79 ng/mL. The time to reach maximal serum concentration was 12.5 +/- 1.8 min. Peak absorption rate of etomidate into the systemic circulation was 832 +/- 417 microg/min. For all dogs, 90% or more of the absorption via buccal mucosa took place during the period in which the drug was in contact with the mucosa (15 min). The apparent transbuccal mucosal permeability coefficient was 9.1 +/- 4.2 x 10(-4) cm/s, higher than values of any other compounds examined. Bioavailability calculated using the area under the serum etomidate concentration versus time curve method and the deconvolution method was 13.6% +/- 10.7% and 16.6% +/- 7.6%, respectively. In conclusion, etomidate is highly permeable through the canine buccal mucosa. IMPLICATIONS: Etomidate is highly permeable through the canine buccal mucosa. Both the onset and the termination of buccal mucosal absorption of etomidate are rapid, which suggests that titratable delivery of etomidate may be possible by buccal administration.

Dose proportionality and pharmacokinetics of oral transmucosal fentanyl citrate.

BACKGROUND: The pharmacokinetics of a single dose (15 microg/kg) of oral transmucosal fentanyl citrate (OTFC) have been characterized. A range of doses may eventually be used in clinical practice. The goal of this study was to determine if the pharmacokinetics of OTFC are dose proportional for doses ranging from 200 to 1,600 microg. METHODS: Twelve healthy male volunteers were studied on four different occasions, receiving 200, 400, 800, and 1,600 microg OTFC in a double-blind, randomized protocol. Venous blood samples were collected at selected times during and after dosing for a 24-h period and assayed for fentanyl using a radioimmunoassay. Maximum concentration, time to maximum concentration, area under the curve, and elimination half-life were determined for each dose administered. In addition, respiratory rate, need for verbal prompting to breathe, and supplemental oxygen requirements were noted. RESULTS: Mean fentanyl concentration time curves were similarly shaped with increasing doses. Both peak concentrations and area under the curve increased linearly with an increase in dose, whereas time to reach peak serum concentrations did not vary significantly between doses. Except for the 200-microg dose, the apparent elimination half-life remained relatively constant (358-386 min). The incidence of low respiratory rate, supplemental oxygen requirement, and number of breathing prompts significantly increased with increasing doses. CONCLUSIONS: Oral transmucosal fentanyl citrate exhibits dose-proportional pharmacokinetics over the dose range of 200-1,600 microg.

Oral transmucosal etomidate in volunteers.

BACKGROUND: The oral transmucosal route of delivery is now used for many drugs, including fentanyl and midazolam. Etomidate's pharmacokinetic profile and physiochemical properties suggest it may be suitable for transmucosal delivery. Transmucosal delivery might extend etomidate's use to sedation and anxiolysis. This is the first study in humans to examine the oral transmucosal administration of a novel etomidate dosage form. METHODS: Ten healthy adult volunteers consumed 12.5-mg, 25-mg, 50-mg, and 100-mg doses of oral transmucosal etomidate (OTET) on four different study days. Serum etomidate concentrations, sedation, respiratory and cardiovascular variables, taste, and side effects were determined. RESULTS: Five minutes after OTET administration, etomidate was detected in the venous blood. Mean peak concentrations occurred 20-30 min later and ranged from 61-174 ng/ml, related to the dose administered. Drowsiness and light sleep occurred in a dose-related manner 10-20 min after administration and lasted for 30-60 min. No episodes of SpO2 <90%, hypotension, or emesis occurred at any dose throughout the study. Nausea was rare. Two volunteers exhibited a brief episode of involuntary tremor after the 100-mg dose. The bitter taste of OTET was judged increasingly unpleasant with escalating doses. CONCLUSIONS: Oral transmucosal etomidate produces dose-related increases in sedation and clinically significant serum concentrations with minimal side effects. The time course of these effects suggests that OTET might be useful when brief mild to moderate sedation with rapid recovery is desirable. Further development of this novel dosage form is warranted.

A review of oral transmucosal fentanyl citrate: potent, rapid and noninvasive opioid analgesia.

The physiochemical characteristics of the potent synthetic opioid agonist fentanyl make it ideal for noninvasive transmucosal delivery. Studies of oral transmucosal fentanyl citrate (OTFC), a candied matrix formulation administered orally as a palatable lozenge on a stick, have investigated and determined this analgesic's pharmacokinetics and pharmacodynamics in a number of clinical settings, including premedication before surgery, acute analgesia for painful medical procedures, and, most recently, for the control of breakthrough cancer pain. The onset to meaningful pain relief in patients with acute pain from surgery or breakthrough pain from cancer is between 5 and 10 minutes after initiating OTFC use, equivalent to intravenous morphine. Analgesic dose equivalency studies suggest that OTFC is, on average, about 10 times more potent than morphine, although, in randomized, controlled, and blinded studies, many patients who were using relatively high doses of opioid anlagesics on an around the- clock schedule for control of cancer pain reported that even a low dose of OTFC (i.e., 200 microg) provided adequate relief from breakthrough pain. Side effects from OTFC are similar in character and frequency to other opioids, including sedation, nausea, and pruritus. These effects appear to wane rapidly with repeated use of this medication. To date there have been no reported serious adverse events in any of the population groups studied or treated with OTFC.

A comparison of remifentanil and morphine sulfate for acute postoperative analgesia after total intravenous anesthesia with remifentanil and propofol.

BACKGROUND: The transition from remifentanil intraoperative anesthesia to postoperative analgesia must be planned carefully due to the short duration of action (3-10 min) of remifentanil hydrochloride, a potent, esterase-metabolized mu-opioid agonist. This study compared the efficacy and safety of transition regimens using remifentanil or morphine sulfate for immediate postoperative pain relief in patients who had surgery under general anesthesia with remifentanil/propofol. METHODS: One hundred fifty patients who had received open-label remifentanil and propofol for intraoperative anesthesia participated in this multicenter, double-blind, double-dummy study and were randomly assigned to either the remifentanil (R) group or the morphine sulfate (M) group. Twenty minutes before the anticipated end of surgery, the propofol infusion was decreased by 50%, and patients received either a placebo bolus (R group) or a bolus of 0.15 mg/kg morphine (M group). At the end of surgery, the propofol and remifentanil maintenance infusions were discontinued and the analgesic infusion was started: either 0.1 microg x kg(-1) x min(-1) remifentanil (R group) or placebo analgesic infusion (M group). During the 25 min after tracheal extubation, remifentanil titrations in increments of 0.025 microg x kg(-1) x min(-1) and placebo boluses (R group), or 2 mg intravenous morphine boluses and placebo rate increases (M group) were administered as necessary at 5-min intervals to control pain. Patients received the 0.075 mg/kg intravenous morphine bolus (R group) or placebo (M group) at 25 and 30 min after extubation, and the analgesic infusion was discontinued at 35 min. From 35 to 65 minutes after extubation, both groups received 2-6 mg open-label morphine analgesia every 5 min as needed. RESULTS: Successful analgesia, defined as no or mild pain with adequate respiration (respiratory rate [RR] > or =8 breaths/min and pulse oximetry > or = 90%), was achieved in more patients in the R group than in the M group (58% vs. 33%, respectively) at 25 min after extubation (P < 0.05). The median remifentanil rate for successful analgesia was 0.125 microg x kg(-1) x min(-1) (range, 0.05-0.23 microg x kg(-1) x min(-1)), and the median number of 2-mg morphine boluses used was 2 (range, 0-5 boluses). At 35 min after extubation, > or = 74% of patients in both groups experienced moderate to severe pain. Median recovery times from the end of surgery were similar between groups. Transient respiratory depression, apnea, or both were the most frequent adverse events (14% for the R group vs. 6% for the M group; P > 0.05). CONCLUSIONS: Remifentanil provided safe and effective postoperative analgesia when administered at a final rate of 0.05-0.23 microg x kg(-1) x min(-1) in the immediate postextubation period. Remifentanil provided more effective postoperative analgesia than did intraoperative treatment with morphine (0.15 mg/kg) followed by morphine boluses (< or = five 2-mg boluses). The effects of remifentanil dissipated rapidly after ending the infusion, and alternate analgesia was required. Further studies are underway to define transition regimens that will improve postoperative analgesia in patients receiving anesthesia with remifentanil.

A multicenter evaluation of remifentanil for early postoperative analgesia.

We evaluated the use of an infusion of remifentanil to provide postoperative analgesia during recovery from total intravenous anesthesia (TIVA) with remifentanil and propofol. One hundred fifty-seven patients from seven medical centers underwent abdominal, spine, joint replacement, or thoracic surgery. Remifentanil was titrated in an effort to limit pain to 0 or 1 on a 0-3 scale. At the end of the 30-min titration period, 78% of infusion rates were in the range of 0.05 to < or = 0.15 microgram.kg-1.min-1, 5% were < 0.05 microgram.kg-1.min-1, and 17% were > 0.15 microgram.kg-1.min-1. Pain scores were 0 or 1 in 64% of patients. Nausea occurred in 35% and emesis in 8% of patients; the peak incidence of nausea followed discontinuation of the remifentanil infusion at the time of administering morphine. Respiratory adverse events (oxygen saturation by pulse oximetry [Spo2] < 90% or respiratory rate < 12) affected 29% of patients. Apnea occurred in 11 patients (7.0%). There was a large variation in the incidence of respiratory depression between the centers, ranging from 0 to 75%. The explanation for the large variability in respiratory outcome was not evident.

A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery.

Remifentanil is a mu-opioid receptor agonist with a context sensitive half-time of 3 min and an elimination half-life < or = 10 min. This study sought to evaluate the efficacy of remifentanil and propofol total intravenous anesthesia (TIVA) in 161 patients undergoing inpatient surgery. Remifentanil 1 microgram/kg was given intravenously (i.v.) followed by one of two randomized infusion rates: small dose (0.5 micrograms.kg-1.min-1) or large dose (1 microgram.kg-1.min-1). Propofol (0.5-1.0 mg/kg i.v. bolus and 75 micrograms.kg-1.min-1 infusion) and vecuronium were also given. Remifentanil infusions were decreased by 50% after tracheal intubation. End points included responses (hypertension, tachycardia, and somatic responses) to tracheal intubation and surgery. More patients in the small-dose than in the large-dose group responded to tracheal intubation with hypertension and/or tachycardia (25% vs 6%; P = 0.003) but there were no other differences between groups in intraoperative responses. Recovery from anesthesia was within 3-7 min in both groups. The most frequent adverse events were hypotension (systolic blood pressure [BP] < 80 mm Hg or mean BP < 60 mm Hg) during anesthesia induction (10% small-dose versus 15% large-dose group; P = not significant [NS]) and hypotension (27% small-dose versus 30% large-dose group; P = NS), and bradycardia (7% small-dose versus 19% large-dose group; P = NS) during maintenance. In conclusion, when combined with propofol 75 micrograms.kg-1.min-1, remifentanil 1 microgram/kg i.v. as a bolus followed by an infusion of 1.0 microgram.kg-1.min-1 effectively controls responses to tracheal intubation. After tracheal intubation, remifentanil 0.25-4.0 micrograms.kg-1.min-1 effectively controlled intraoperative responses while allowing for rapid emergence from anesthesia.

The iontophoresis of fentanyl citrate in humans.

BACKGROUND: Iontophoresis is a method of transdermal administration of ionizable drugs in which the electrically charged components are propelled through the skin by an external electric field. This study was designed to determine whether iontophoresis could be used to deliver clinically significant doses of fentanyl in humans and whether there is a charge-dose relation in the delivery of fentanyl by iontophoresis. METHODS: Five adult volunteers were tested three times on separate days, once receiving passive treatment of 0.0 mA for 2 h (0 mA.min), iontophoresis 1.0 mA for 2 h (120 mA.min), and iontophoresis 2.0 mA for 2 h (240 mA.min) in an open, randomized, crossover design. Respiratory rate, heart rate, blood pressure, and hemoglobin oxygen saturation were monitored throughout the study. Plasma fentanyl concentrations were measured several times before, during, and after iontophoresis. Plasma fentanyl concentrations were measured by radioimmunoassay. RESULTS: No fentanyl was detected after passive (0.0-mA) fentanyl delivery. The following results were obtained for the 1.0- and 2.0-mA deliveries, respectively. Mean times to detectable concentrations of plasma fentanyl were 33 and 19 min; mean times to maximum concentration were 122 and 119 min; maximum concentrations were 0.76 and 1.59 ng/ml (P = 0.010); mean areas under the curve of the plasma fentanyl concentration versus time relation were 233 and 474 ng.ml-1.min (P = 0.003); and mean elimination half-lives were 354 and 413 min (P = 0.326). Only minor adverse side effects related to iontophoresis occurred. However, typical opioid-related effects occurred frequently in the 1.0- and 2.0-mA administration groups. CONCLUSIONS: Clinically significant doses of fentanyl can be administered by iontophoresis for delivery periods of 2 h. A charge-dose relation exists after administration with currents of 1.0 and 2.0 mA. Future research into the iontophoresis of fentanyl as a method of potent opioid administration is indicated.

Buccal absorption of fentanyl is pH-dependent in dogs.

BACKGROUND: Analgesia and sedation have been achieved noninvasively by fentanyl administration through the oral and nasal mucosa. In theory, the transmucosal bioavailability and absorption of fentanyl could be improved by converting more fentanyl to the unionized form by adjusting the surrounding pH. The authors tested this hypothesis in dogs. METHODS: Under general anesthesia, each of six mongrel dogs was given fentanyl on repeated occasions, first intravenously (once), then by application to the buccal mucosa (six times). Buccal fentanyl administration was accomplished by placement of a pH-buffered solution of fentanyl into a specially constructed cell, which was clamped to the dog's buccal mucosa for 60 min. Fentanyl solutions with pHs of 6.6, 7.2, and 7.7 were studied to span a tenfold difference in the unionized fraction of fentanyl. Femoral arterial blood samples were sampled frequently and analyzed for fentanyl using a radioimmunoassay. Peak plasma concentration and the time of its occurrence for each buccal study were noted from the plasma concentration verses time profile. Terminal elimination half-life, bioavailability, and permeability coefficients were calculated using standard pharmacokinetic techniques. RESULTS: The variables peak plasma concentration, bioavailability, and permeability coefficient increased three- to fivefold as the pH of the fentanyl buccal solution increased and more fentanyl molecules became unionized. There was no difference in terminal elimination half-life after intravenous fentanyl (244 +/- 68 min) or buccal fentanyl administration (pH 7.7, 205 +/- 89 min; pH 7.2, 205 +/- 65 min; pH 6.6, 196 +/- 48 min). In all buccal studies regardless of pH, time to peak plasma concentration occurred within 10 min of removal of the fentanyl solutions from the buccal mucosa. CONCLUSIONS: The buccal absorption, bioavailability, and permeability of fentanyl are markedly increased as the pH of the fentanyl solution becomes more basic. Most likely, this is because of an increase in the fraction of unionized fentanyl.

Oral transmucosal fentanyl citrate premedication in patients undergoing outpatient dermatologic procedures.

BACKGROUND: Oral transmucosal fentanyl citrate (OTFC) is a novel lozenge dosage form of fentanyl used for premedication. Many dermatology patients undergoing surgical procedures could benefit from such a medication. OBJECTIVE: The study compared the safety and efficacy of 400-vs 800-micrograms dosage forms for their sedative and anxiolytic effects in adults undergoing a variety of dermatologic outpatient surgical procedures. METHODS: Patients received OTFC 30 minutes before the procedure. Vital signs, oxygen saturation, sedation, and anxiety scores were measured before OTFC administration and every 15 minutes thereafter. RESULTS: Significant sedation and anxiolysis developed in both dosage groups. No clinically significant changes in respiratory rate, heart rate, or blood pressure occurred during the study period. Common drug-induced side effects included dizziness, nausea, pruritus, and vomiting. CONCLUSION: OTFC is safe and effective for outpatient dermatologic procedures; however, the risk of opioid-related side effects must be carefully weighed against the benefits when deciding to use OTFC in an outpatient setting.

Fentanyl-induced rigidity and unconsciousness in human volunteers. Incidence, duration, and plasma concentrations.

BACKGROUND: Muscle rigidity frequently accompanies induction of anesthesia with opioids. The authors sought to determine whether unconsciousness and amnesia occur when humans develop rigidity and apnea after intravenous fentanyl (without other concomitant anesthetics). METHODS: The incidence and duration of rigidity and level of consciousness were evaluated and associated plasma concentrations of fentanyl were measured in 12 healthy adult male volunteers given only intravenous fentanyl. Fentanyl was infused at a rate of 150 micrograms/min until a total of 15 micrograms/kg had been administered. Arterial blood samples for fentanyl assay were drawn and responsiveness, heart rate (HR), and systolic and diastolic arterial blood pressures were determined at frequent intervals during and after infusion. If rigidity was accompanied by an Spo2 < 90%, positive pressure ventilation with 100% O2 with a mask was instituted until spontaneous ventilation resumed. RESULTS: The incidence of muscular rigidity was 50% (6/12). All subjects who developed rigidity were apneic, unresponsive, and had no recall of commands to breathe or of positive pressure ventilation. Subjects not developing rigidity remained awake and responsive. No subject developing rigidity required neuromuscular blockade to allow positive pressure ventilation and adequate oxygenation (Spo2 > 90%). When rigidity occurred, it started 3 +/- 0.9 (range 1-4) min after the peak plasma fentanyl concentration and lasted for 11.5 +/- 5.8 (range 7-23) min. Rigidity started at a plasma fentanyl concentration of 21.5 +/- 4.4 (range 16-28) ng/ml and ended at 6.9 +/- 1.5 (range 5.2-8.7) ng/ml. Baseline HR was less in the subjects who subsequently developed rigidity (56.7 +/- 7.8 vs. 67.2 +/- 7.8 P = 0.04). No differences in fentanyl plasma concentrations or predicted effect site concentrations for rigidity were detected between subjects who developed rigidity and those who did not. CONCLUSIONS: These findings support the hypothesis that unconsciousness occurs in the unstimulated subject during fentanyl-induced apnea and rigidity.

Absorption and bioavailability of oral transmucosal fentanyl citrate.

Oral transmucosal fentanyl citrate (OTFC) is a novel, noninvasive dosage form of fentanyl used to provide children and adults with sedation, anxiolysis, and analgesia. In order to determine the bioavailability and absorption of fentanyl from OTFC, 12 volunteers were given intravenous fentanyl citrate or OTFC 15 micrograms/kg on each of two occasions. On a third occasion, the authors assessed oral administration (gastrointestinal absorption) by giving eight of the same volunteers the same dose of a solution of fentanyl citrate to swallow. In each study, arterial blood samples were taken over 24 h for analysis of plasma fentanyl. After intravenous (iv) administration of fentanyl, clearance (mean +/- standard deviation) was 0.67 +/- 0.15 l/min; volume of distribution at steady state was 287 +/- 79 l; and the terminal elimination half-life was 425 +/- 102 min. Peak plasma concentrations of fentanyl were higher (3.0 +/- 1.0 vs. 1.6 +/- 0.6 ng/ml, P = 0.01) and occurred sooner (22 +/- 2.5 vs. 101 +/- 48.8 min, P = 0.003) after OTFC than after oral solution administration. Plasma concentrations of fentanyl after OTFC decreased rapidly, to less than 1.0 ng/ml within 75-135 min after the beginning of administration. Peak absorption rate was greater (11.1 +/- 4.3 vs. 3.6 +/- 2.1 micrograms/min, P = 0.004) and occurred much sooner after OTFC than after oral solution administration (19 +/- 2.6 vs. 87.5 +/- 38.1 min, P = 0.001). Systemic bioavailability was greater after OTFC administration than after the oral solution (0.52 +/- 0.1 vs. 0.32 +/- 0.1, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Oral transmucosal fentanyl citrate for premedication in paediatric outpatients.

Two doses (10-15 micrograms.kg-1, Group I, and 15-20 micrograms.kg-1, Group II) of oral transmucosal fentanyl citrate (OTFC) plus a placebo (Group III) were evaluated for premedication in 105 healthy children, aged 2 to 13 yr, undergoing short (less than 1 hr) operations in the hospital short-stay unit. The study was randomized and double-blinded and 91 of the 105 children also received droperidol, 25 micrograms.kg-1 IV, after induction of anaesthesia with halothane and N2O in oxygen. Both doses of OTFC produced significantly greater sedation (first present at 20 min) and anxiolysis (first present in Group I at 40 min) than the placebo. Recovery times were similar in the three groups and analgesic requirements in the recovery room were significantly lower in Group I than Group III. Both OTFC groups took longer to tolerate oral fluids in the postoperative discharge unit than the placebo group and this caused patients in Group I to have a delayed discharge from the hospital compared to Group III. Preoperative pruritus occurred significantly more frequently in Groups I and II (58 and 76 per cent, respectively) than Group III (23 per cent). Although the incidences of nausea and vomiting tended to be slightly higher in the OTFC groups in the preoperative holding and postoperative discharge units, the differences among the groups were not statistically significant. Likewise droperidol did not reduce the incidence of postoperative nausea or vomiting. The data indicate that OTFC may be a safe and effective premedicant in paediatric patients having short operations but delays discharge from the hospital (by 30-50 min) by delaying the time patients tolerate fluids early after operation.

Transdermal scopolamine reduces nausea and vomiting after outpatient laparoscopy.

The authors evaluated the effect of transdermal scopolamine on the incidence of postoperative nausea, retching, and vomiting after outpatient laparoscopy in a double-blind, placebo-controlled study. A Band-Aid-like patch containing either scopolamine or placebo was placed behind the ear the night before surgery. Anesthesia was induced with fentanyl (0.5-2 micrograms/kg iv), thiopental (3-5 mg/kg iv), and succinylcholine (1-1.5 mg/kg iv) and maintained with isoflurane (0.2-2%) and nitrous oxide (60%) in oxygen. Scopolamine-treated patients had less nausea, retching, and vomiting compared with placebo-treated patients (P = 0.0029). Severe nausea and/or vomiting was present in 62% of the placebo group but only 37% of those getting the scopolamine patch. Repeated episodes of retching and vomiting were also less frequent in the scopolamine group compared with the placebo group (23% vs. 41%; P = 0.0213) as was the need for additional antiemetic therapy (13% vs. 32%; P = 0.0013). Patients in the scopolamine group were also discharged from the hospital sooner (4 +/- 1.3 vs. 4.5 +/- 1.5 h; P = 0.0487). Side effects were more frequent among those patients treated with the scopolamine patch (91% vs. 45%; P less than 0.05) but were not troublesome. The authors conclude that transdermal scopolamine is a safe and effective antiemetic for outpatients undergoing laparoscopy.

Differences in magnitude and duration of opioid-induced respiratory depression and analgesia with fentanyl and sufentanil.

The magnitude and duration of analgesia and respiratory depression induced by fentanyl (1.0, 2.0, and 4.0 micrograms/kg) and sufentanil (0.1, 0.2, and 0.4 microgram/kg) after intravenous administration over 30 s were measured in 30 healthy young adult male volunteers divided into three groups and studied in a double-blind, randomized fashion. Each volunteer received one dose of fentanyl or sufentanil and no sooner than 48 h later, the corresponding equipotent dose of the other opioid. End-tidal CO2 and ventilatory and occlusion pressure responses to CO2 rebreathing were used to measure drug-induced respiratory effects. Analgesic effects were assessed by changes in the pain threshold to electric shock applied to the forearm. Plasma levels of fentanyl and sufentanil were measured by radioimmunoassay. Testing and sampling intervals were 5, 30, 60, 90, 120, 240, 300, and 360 min after drug administration. The magnitude and duration of depression of the ventilatory and occlusion pressure response were significantly less with sufentanil compared with fentanyl, irrespective of dose. Ventilatory and occlusion pressure responses returned to control values by 30 and 30 min, respectively, after sufentanil and by 240 and 120 min, respectively, after fentanyl. Statistically significant elevations of the pain threshold were, however, greater and longer lasting after sufentanil compared with fentanyl. Pain threshold returned to control values 180 min after sufentanil but only 90 min after fentanyl. These results suggest that sufentanil may provide better patient comfort with less respiratory depression than does fentanyl.

Oral transmucosal fentanyl citrate (lollipop) premedication in human volunteers.

The authors determined whether fentanyl incorporated into a candy lollipop, oral transmucosal fentanyl citrate (OTFC), would cross mucosal tissues of the mouth in sufficient quantities during and after dissolution to produce sedation and/or analgesia. Associated respiratory and circulatory changes, side effects, and plasma concentrations of fentanyl were also measured. The evaluations were done in 28 adult volunteers who received fentanyl citrate in doses of 5, 4, 2, 1, and 0.5 mg in OTFC and rapidly sucked the lollipops (N = 20) or allowed them to passively dissolve (N = 8). Rapid consumption of OTFC resulted in more rapid onset of a pleasant feeling (first subjective sensation) but not more rapid onset of objective sedation or analgesia than passive dissolution. There was a significant correlation between dose of OTFC and magnitude of sedation (P less than 0.001, Spearman rank correlation = -0.82). Higher doses of OTFC produced greater and longer lasting analgesia and respiratory depression and a higher incidence of nausea and vomiting than lower doses, but pruritus (33%-87%) was not related to the dose of OTFC. Heart rate and arterial blood pressures were not changed by any dose of OTFC. The data indicate that low doses of OTFC (0.5 and 1 mg, equivalent to 5-20 micrograms.kg-1 of fentanyl citrate) produce analgesia and sedation with minimal side effects and little respiratory depression in adult volunteers and deserve further evaluation in patients.