Suggestions to Reduce Clinical Fibromyalgia Pain and Experimentally Induced Pain Produce Parallel Effects on Perceived Pain but Divergent Functional MRI-Based Brain Activity.

OBJECTIVE: Hypnotic suggestion is an empirically validated form of pain control; however, the underlying mechanism remains unclear. METHODS: Thirteen fibromyalgia patients received suggestions to alter their clinical pain, and 15 healthy controls received suggestions to alter experimental heat pain. Suggestions were delivered before and after hypnotic induction with blood oxygen level-dependent (BOLD) activity measured concurrently. RESULTS: Across groups, suggestion produced substantial changes in pain report (main effect of suggestion, F2, 312 = 585.8; p < .0001), with marginally larger changes after induction (main effect of induction, F1, 312 = 3.6; p = .060). In patients, BOLD response increased with pain report in regions previously associated with pain, including thalamus and anterior cingulate cortex. In controls, BOLD response decreased with pain report. All changes were greater after induction. Region-of-interest analysis revealed largely linear patient responses with increasing pain report. Control responses, however, were higher after suggestion to increase or decrease pain from baseline. CONCLUSIONS: Based on behavioral report alone, the mechanism of suggestion could be interpreted as largely similar regardless of the induction or type of pain experience. The functional magnetic resonance imaging data, however, demonstrated larger changes in brain activity after induction and a radically different pattern of brain activity for clinical pain compared with experimental pain. These findings imply that induction has an important effect on underlying neural activity mediating the effects of suggestion, and the mechanism of suggestion in patients altering clinical pain differs from that in controls altering experimental pain. Patient responses imply that suggestions altered pain experience via corresponding changes in pain-related brain regions, whereas control responses imply suggestion engaged cognitive control.

Effects of brief mindful acceptance induction on implicit dysfunctional attitudes and concordance between implicit and explicit dysfunctional attitudes.

Mindfulness-based interventions have been shown to be effective in alleviating depressive symptoms. While much work has examined the effects of mindfulness training on subjective symptoms and experiences, and less is known regarding whether mindfulness training may alter relatively uncontrollable cognitive processes associated with depressed mood, particularly implicit dysfunctional attitudes. The present study examined the effects of a brief mindful acceptance induction on implicit dysfunctional attitudes and degree of concordance between implicit and explicit dysfunctional attitudes in the context of sad mood. A total of 79 adult participants with elevated depressive symptoms underwent an autobiographical mood induction procedure before being randomly assigned to mindful acceptance or thought wandering inductions. Results showed that the effect of mindful acceptance on implicit dysfunctional attitude was significantly moderated by trait mindfulness. Participants high on trait mindfulness demonstrated significant improvements in implicit dysfunctional attitudes following the mindful acceptance induction. Those low on trait mindfulness demonstrated significantly worse implicit dysfunctional attitudes following the induction. Significantly greater levels of concordance between implicit and explicit dysfunctional attitudes were observed in the mindful acceptance condition versus the thought wandering condition. The findings highlight changes in implicit dysfunctional attitudes and improvements in self-concordance as two potential mechanisms underlying the effects of mindfulness-based interventions.

A double-blind study to evaluate the safety of recombinant human hemoglobin in surgical patients during general anesthesia.

OBJECTIVE: To evaluate recombinant human hemoglobin (rHb1.1) in patients undergoing surgery involving general anesthesia; examine rHb1.1 for toxicity, including renal dysfunction and hypertension; and measure plasma concentrations of rHb1.1 over time. DESIGN: Prospective, double-blinded, randomized, placebo-controlled study. SETTING: University medical center hospital. PARTICIPANTS: Eighteen patients having surgery under general anesthesia. INTERVENTIONS: One of 4 escalating doses of rHb1.1 or normal saline (control) was administered by continuous infusion to patients receiving general anesthesia for elective surgical procedures. Total rHb1.1 doses ranged from 4.7 to 25.6 g. MEASUREMENTS AND MAIN RESULTS: Clinical and laboratory data, including vital signs monitoring, hematology (white blood cell and reticulocyte count, hemoglobin, hematocrit, erythrocyte sedimentation rates, and coagulation values), renal function (serum creatinine and blood urea nitrogen), hepatic function (mean and indirect bilirubin), pancreatic function (serum amylase and lipase), and antibodies (IgG and IgM) to Escherichia coli protein, were collected at specified intervals for 7 days after infusion of rHb1.1. No serious adverse events occurred. The most frequently observed clinical event occurred during the first 24 hours after infusion and was primarily associated with surgery and anesthetic administration. A slightly higher incidence of hypertension, symptoms suggestive of pyrogenicity, mildly elevated total and indirect bilirubin, and elevated pancreatic enzymes was observed in rHb1.1 treatment groups when compared with control. Hypertension resolved within 7 hours, and laboratory values returned to normal levels by day 7. CONCLUSION: Although the elevations in pancreatic enzymes seen in some rHb1.1-treated patients remain unexplained, the safety profile of rHb1.1 appears to be acceptable. These results support the continued clinical evaluation and development of rHb1.1.

Transcutaneous cranial electrical stimulation (TCES): a review 1998.

The Transcutaneous Cranial Electrical Stimulation (TCES) technique appeared at the beginning of the 1960s and is aimed to act at the level of the central nervous system. The current, composed of high frequency pulses interrupted with a repetitive low frequency, is delivered through three electrodes (a negative electrode placed between the eyebrows while two positive electrodes are located in the retro-mastoid region). Due to the characteristics of the current delivered, shortcomings encountered with previous electrical stimulation techniques are avoided. The main property of TCES is to potentiate some drug effects, especially opiates and neuroleptics, during anesthetic clinical procedures. This potentiation effect permits drastic reduction of pharmacological anesthetic agent and reduces post-operative complications. Animal studies performed with TCES demonstrated that this stimulation releases 5-hydroxy-indol-acetic acid and enkephalins. Despite numerous clinical and animal studies performed with this technique for several decades, TCES mechanisms are not completely elucidated but results obtained without undesirable effect are encouraging signs to continue investigations of this particular technique.

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.

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.

The dose-response pharmacology of intrathecal sufentanil in female volunteers.

The pharmacologic effects of intrathecal sufentanil (ITS) beyond what is clinically administered (10 microg) are not known. We observed 18 healthy, young, adult female volunteers who received 12.5, 25, or 50 microg of ITS in a randomized, double-blind fashion for 11 h. Analgesia was assessed by pressure algometry at the tibia. Respiratory function was assessed by pulse oximetry, respiratory rate, arterial blood gas, the ventilatory response to CO2, and a respiratory intervention score (RIS). The incidence and severity of side effects also were documented. Serum sufentanil levels were measured for 4 h after ITS administration. We found that ITS produced statistically significant changes in algometry, doubling the pressure required to produce moderate pain. However, doses of ITS greater than 12.5 microg failed to produce proportionate increases in the duration or intensity of analgesia. All doses of ITS produced significant respiratory depression, but only the RIS was significantly related to ITS dose. Neither respiratory rate nor sedation reliably predicted hypoxemia. Supplemental oxygen by nasal cannula consistently prevented pulse oximeter readings below 90%. Serum sufentanil concentrations were related to ITS dose in a statistically significant manner, reached clinically significant concentrations, and followed a time course similar to analgesia and measures of respiratory depression. However, there was no significant increase in measured analgesia associated with the increases in serum sufentanil concentrations. We conclude that in our volunteer model of lower extremity pain, administering ITS in doses larger than 12.5 microg does not improve the speed of onset, magnitude, or duration of analgesia and only causes dose-related increases in serum sufentanil concentrations, which may augment respiratory depression.

Oral transmucosal back permeation of alfentanil in dogs--a novel method to determine blood alfentanil concentration.

This study explores a novel noninvasive method for monitoring blood alfentanil concentrations using a dog model. Alfentanil which "back" permeated across the oral mucosa from the systemic circulation was collected from the oral mucosal surface and quantitated. The levels of the "back" permeated alfentanil were found to closely reflect real time serum alfentanil concentrations. With further work, this finding may lead to a novel noninvasive method for monitoring real time serum alfentanil concentrations in its clinical applications.

A new method to evaluate cardiovascular response in anesthetized rats. Hypertension after variable intensity, brief electrical stimuli.

To establish and standardize a nociceptive response in anesthetized rats, the hypertensive responses to defined electrical and mechanical stimuli were studied. Rats (n = 7) were given etomidate, 3.8 mg/kg/hr intravenously (i.v.) 2 hr following carotid artery and jugular vein cannulation. At 15 min after beginning the infusion, four types of noxious stimuli were administered sequentially at 1-min intervals (14 stimuli total): Type 1: Square electrical waves, 125 cps, 1.6 msec, 2-sec train duration, varying current from 0.4 to 12 mA (11 stimuli); Type 2: A single 10-mA electrical stimulus, 5-sec train duration; Type 3: Tail clamping; and, Type 4: Skin incision. After each stimulus, maximum change in systolic blood pressure (delta SBP) was measured. delta SBP after the most intense stimuli was as follows: Type 1 (12 mA, 2 sec), 32.1 +/- 2.14 mmHg; Type 2 (10 mA 5 sec), 42.9 +/- 2.4 mmHg; Type 3 (tail-clamping), 34.3 +/- 3.3 mmHg; Type 4 (skin incision), 14.2 +/- 2.8 mmHg. For the multiple Type-2 stimuli, a relationship between current and delta SBP was present. The authors believe that characterized graded electrical stimulation will allow a more quantitative evaluation of the hypertensive response to noxious stimuli in etomidate anesthetized rats, as compared to observing a single response to a single stimulus. The characterization of the electrical stimulation by amplitude, frequency, and wave form makes research work on nociception under anesthesia easily reproducible.

Identification of a sorbitol permease in human erythrocytes.

Sorbitol, a polyol derived from glucose by the enzyme, aldose reductase, is a common organic solute in many cells. It plays a role in the osmotic regulation of epithelial cells and in the pathology of uncontrolled diabetes. To learn more about sorbitol transport, we measured D-[14C]sorbitol influx in human erythrocytes. Sorbitol influx at 37 degrees C was a linear function of sorbitol concentration over the range of 0.05-100 mM. The activation energy for sorbitol influx was 10.0 kcal/mol, and the Q10 over the range 10-50 degrees C was 1.8, higher than predicted for diffusion through an aqueous pore. Glucose transport inhibitors either had no effect (1 mM phloridzin) or minimally inhibited (approximately 35% inhibition by 10 microM cytochalasin B or 250 microM phloretin) sorbitol influx. Influx was stimulated twofold by 0.5 mM p-chloromercuribenzoic acid, an inhibitor of glucose transport, and this was reversed by 2 mM dithiothreitol. Sorbitol influx was neither Na dependent nor sensitive to changes in cell volume. Glucose, fructose, mannitol, myo-inositol, and gluconate, at four- to fivefold molar excesses over sorbitol, did not inhibit its influx. We conclude that there is a specific sorbitol transport pathway in human erythrocytes similar to the sorbitol permease in renal epithelial cells.

A new model to evaluate the hypertensive response to noxious stimuli in the anesthetized, spontaneously hypertensive rat.

We have developed a method to evaluate the hypertensive response after noxious stimuli in anesthetized rats. Anesthetic level, stimuli, and responses were standardized by using an etomidate infusion, a series of stimuli of increasing intensity applied to the tail, and measuring maximal changes in systolic blood pressure (delta SBP) after each stimulus. Normotensive Sprague Dawley rats (SD) (n = 7) were studied using an etomidate infusion of 4.2 mg.kg-1 x h-1. This method was then applied to spontaneously hypertensive rats (SHR) anesthetized with three rats of etomidate infusion: Group 1 (n = 8), 7.0 mg.kg-1 x h-1; Group 2 (n = 8), 5.6 mg.kg-1 x h-1; and Group 3 (n = 11), 4.2 mg.kg-1 x h-1. Under anesthesia, three types of noxious stimuli were applied to the tail at 1-min intervals (13 total): (a) Type 1:11 2-s electrical stimuli of increasing intensity (0.4-12 mA, to produce threshold to maximal responses); (b) Type 2: one intense, prolonged electrical stimulus (10 mA, 5 s); and (c) Type 3: tail-clamping. After each stimulus, delta SBP was measured. In the SHR, comparing single delta SBP responses to single noxious stimuli after each of the three most intense stimuli showed no statistically significant differences among the three anesthetic groups. In contrast, comparison of dose-response curves of multiple delta SBP responses to multiple Type 1 (2-s) stimuli demonstrated a significant difference among the three anesthetic groups of SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

The initial clinical experience of 1819 physicians in maintaining anesthesia with propofol: characteristics associated with prolonged time to awakening.

In October 1989, propofol underwent Phase IV Food and Drug Administration testing that involved 25,981 patients, 1722 institutions, and 1819 anesthesiologists. Participants were 18-80 yr of age and ASA physical status I-III; they could not have a continuing pregnancy or prior adverse anesthetic experience. Anesthesiologists completed detailed forms to describe their use of propofol in this three-step study: propofol for induction only (Step 1), for induction and then maintenance by intermittent bolus injection (Step 2), or for continuous infusion (Step 3). In early 1992, our group of anesthesiologists and epidemiologists analyzed the resulting data base. We evaluated data from 14,882 patients (8095 given bolus injections and 6787 given continuous infusion) to determine factors predicting prolonged time (> 15 min after cessation of all anesthesia) to awakening, one measure of recovery from anesthesia. The incidence of prolonged awakening was 6.8% (1016 patients); the median and mean (+/- SD) times to awakening were, respectively, 5 min and 7.2 +/- 7.3 min. The following variables were associated (P < 0.05) with prolonged awakening from propofol maintenance anesthesia: a total dose of propofol > 8 mg/kg, male gender, endotracheal intubation, age > 65 yr, abdominal surgery, continuous infusion of propofol, and concomitant use of isoflurane or benzodiazepines. These results support the clinical impression that recovery from propofol anesthesia is remarkably rapid; although the vast majority of physicians participating in this study were using propofol for maintenance for the first time, only 6.8% of patients had awakening times exceeding 15 min.

Effects on recovery when isoflurane is used to supplement propofol-nitrous oxide anesthesia.

During propofol-nitrous oxide (N2O) anesthesia, volatile anesthetics are frequently administered to treat signs of inadequate anesthesia and to decrease the possibility of intraoperative awareness. Because the clinical effects of this combination have not been examined rigorously, we used data from the 1989-90 Phase IV clinical trial with propofol to evaluate recovery from propofol-N2O anesthesia with and without supplementation with isoflurane. In this study involving 15,806 patients at 1722 institutions, propofol was administered for induction and maintenance of anesthesia with N2O for procedures lasting less than 60 min. At the discretion of the anesthesiologist, volatile anesthetics were administered as needed during maintenance of anesthesia (the incidence of use of inhaled anesthetics was 14.7% for isoflurane, 2.2% for enflurane, and 0.2% for halothane). Other intraoperative medications included opioid analgesics, muscle relaxants, and anticholinergic drugs. The present study concerns the subset of 7796 patients given propofol-N2O maintenance anesthesia (intermittent bolus or continuous infusion) with or without isoflurane supplementation for procedures lasting less than 60 min. Isoflurane was used more frequently for procedures lasting 30-60 min than for those less than 30 min. Nevertheless, the maintenance dose of propofol was significantly (P < 0.05) less with isoflurane (178 vs 235 mg). Adjunctive use of isoflurane prolonged the time to awakening and to becoming oriented, but discharge times were similar for the two groups. The incidence of postoperative nausea, vomiting, recall, and excitement did not differ between the two groups. We conclude that the addition of isoflurane to a propofol-N2O anesthetic does not alter recovery from anesthesia.

Hemodynamic effects of propofol: data from over 25,000 patients.

To investigate clinically important hypotension and bradycardia after induction of anesthesia with propofol, we analyzed data from a Phase IV stepwise study involving 25,981 patients, 1722 institutions, and 1819 anesthesiologists. In Step 1, propofol was used for induction only. In Step 2, propofol was used for induction and then maintenance by intermittent injection. In Step 3, an induction dose was followed by a maintenance infusion. Participants were to be 18-80 yr of age and ASA physical status I-III; they could not have a continuing pregnancy or prior adverse anesthetic experience. Detailed data on demographic, perioperative, and outcome variables were recorded on data collection forms. The overall incidence of hypotension (systolic blood pressure < 90 mm Hg) was 15.7%; 77% of the episodes were recorded within 10 min of induction of anesthesia with propofol. Bradycardia (heart rate < 50 beats/min) occurred in 4.8% of patients, with 42% of the episodes in the first 10 min. Only 1.3% of patients had both hypotension and bradycardia. The incidence of hypotension was significantly higher for the elderly, females, Caucasians, those undergoing abdominal and integumentary procedures, and those given propofol with opioids, benzodiazepines, or propranolol. Bradycardia was significantly more common when propofol was combined with opioids or chronically taken beta-adrenergic receptor-blocking drugs. Bradycardia and hypotension were not commonly associated. Giving this new drug by protocol, even inexperienced anesthesiologists incurred few adverse hemodynamic changes. Hemodynamic changes were transient and rarely (< 0.2%) required drug therapy. Cardiovascular changes and drug interactions were predictable and manageable based on knowledge of the pharmacology of propofol.

Adverse events in a multicenter phase IV study of propofol: evaluation by anesthesiologists and postanesthesia care unit nurses.

Phase II and III studies are tightly controlled trials investigating adverse effects before government approval of a new drug. However, because postapproval Phase IV studies involve a much larger and more complex population, the true nature of adverse effects can be seen. We analyzed Phase IV data for the new drug propofol with regard to the incidence of adverse events, and evaluations of such events by anesthesiologists versus postanesthesia care unit (PACU) nurses. Data pertained to 25,981 patients, 1722 institutions, and 1819 anesthesiologists giving propofol in three anesthetic regimens. Inclusion criteria were liberal: age, 18-80 yr; ASA physical status I-III; no continuing pregnancy; and no prior adverse anesthetic experience. Anesthesiologists and PACU nurses used data collection forms to record demographic, perioperative, and outcome variables; to evaluate recovery (excellent, good, or poor); and to describe adverse events. Adverse events were reported for 2813 patients (10.8%); the most common events were pain on injection (5.2%), hypotension (1.1%), nausea/vomiting (1.9%), and excitement (1.3%). The incidences of pain on injection and nausea/vomiting were approximately one-half and one-fifth, respectively, the values reported in earlier studies. Six hundred thirty-three patients (2.4%) had a "poor" recovery according to one or both of the evaluators (the anesthesiologist or PACU nurse). The PACU nurse was more influenced by nausea, vomiting, or postoperative pain; and the anesthesiologist was more influenced by postoperative confusion or delayed emergence from anesthesia. For only 0.6% of patients did both evaluators rate recovery as poor. Anesthesiologists gave more weight to intraoperative adverse events, and nurses to postoperative events.(ABSTRACT TRUNCATED AT 250 WORDS)

How do anesthesiologists select patients when introducing a new drug into practice?

As part of the marketing strategy for the anesthetic drug propofol (Diprivan), Stuart Pharmaceuticals began a Phase IV postmarketing study soon after the drug received Food and Drug Administration approval in 1989. We used data from this study to test the hypothesis that anesthesiologists would initially use propofol for young, relatively healthy patients and then, with experience, for older, sicker patients. The Phase IV study involved 1722 institutions, 1819 anesthesiologists, and 25,981 patients. The study incorporated three sequential steps, each to be tested in five patients. In Step 1, propofol was used for induction only; in Step 2, for induction and maintenance of anesthesia by intermittent injection; and, in Step 3, for induction and maintenance by continuous infusion. Inclusion criteria were age 18-80 yr and ASA physical status I-III. Exclusion criteria were continuing pregnancy and a previous adverse anesthetic experience. Physicians used standardized data collection forms to voluntarily compile detailed demographic, perioperative, and outcome variables for patients. Data were then evaluated by an independent, multicenter team of seven anesthesiologists and three epidemiologists to determine whether the first two patients selected to participate in each step (Patients 1 and 2, 6 and 7, and 11 and 12) were less sick, younger, or undergoing less invasive or shorter procedures than patients enrolled later in the same steps (Patients 4 and 5, 9 and 10, and 14 and 15). Physicians gave propofol first to patients with fewer concurrent diseases than are found in the general population (10% were hypertensive versus 16%; 3% were diabetic versus 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

Phase IV study of propofol: validation of the data set.

In 1989-1990, Stuart Pharmaceuticals conducted a Phase IV study of propofol on over 26,000 patients, later making the large data base available to a team of epidemiologists and anesthesiologists for analysis. We now describe the process of verifying the data to provide a sound basis for further analyses. Original data were collected by 1819 physicians at 1761 hospitals. In that study, anesthesia was induced by bolus injection of propofol and was maintained by inhaled drug and N2O-O2 (Step 1), or by propofol (either intermittent bolus injection [Step 2] or continuous infusion [Step 3]) and N2O-O2. Forty-six recorded variables described history, physical examination, course and quality of anesthesia and recovery, and adverse events. Data were scrutinized for inaccuracy or bias regarding adverse events, completeness of data, data entry, and violations of the study protocol. The initial data set pertained to 26,841 patients (10,698, Step 1; 8886, Step 2; and 7257, Step 3). Because we excluded data if 25% of the items were missing from the data set, 3.2% of the case reports were eliminated: the final data set used for subsequent analyses contained 25,981 patients (10,184, Step 1; 8672, Step 2; and 7125, Step 3). Inaccuracy of data entry was not excessive, and violations of study protocol were less frequent than in similar studies. The nature and frequency of adverse events were similar to those reported in Phase II and III clinical trials of propofol. Analysis showed that missing data occurred randomly and did not introduce obvious bias. We conclude that the data set was valid and most likely represents perioperative events occurring in similar patients; that Phase IV studies can be valuable because of the range of patients studied and the ability to detect even rare events; and that future Phase IV studies could be improved by more efficient design of data collection forms for both hypotheses to be tested and the entry of data onto forms.

The role of pharmacoepidemiology research in postmarketing surveillance and anesthesia practice/critical care medicine.

Despite tremendous efforts to ensure the safety and effectiveness of newly marketed medications, a number of these have had significant problems after introduction of the drug to the market. Such problems highlight the practical limitations of clinical trials performed to obtain FDA approval for marketing. Pharmacoepidemiology research methodologies provide a powerful mechanism for exploring the determinants of drug safety and effectiveness in broad-based populations and can serve as a scientific foundation for outcome research. Using these methodologies, largescale postmarketing surveillance studies similar to the type described in the accompanying articles would constitute an important way of confirming and identifying the determinants of drug safety and effectiveness in large, diverse patient populations.