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The Effects of Propofol on Pain Intensity and Unpleasantness

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The Effects of Propofol on Pain Intensity and Unpleasantness
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FROELICH, MACHAEL A. ( Author, Primary )
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2008

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Analgesia ( jstor )
Anesthesia ( jstor )
Anesthetics ( jstor )
Blood ( jstor )
Dosage ( jstor )
Pain ( jstor )
Pain perception ( jstor )
Placebos ( jstor )
Psychomotor disorders ( jstor )
Ratings ( jstor )

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University of Florida
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University of Florida
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Copyright Machael A. Froelich. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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4/30/2005
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73174645 ( OCLC )

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THE EFFECTS OF PROPOFOL ON PAIN INTENSITY AND UNPLEASANTNESS By MICHAEL A. FROELICH A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2004

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Copyright 2004 by Michael A. Froelich, MD

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This document is dedicated to my family.

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ACKNOWLEDGMENTS I thank the Lord for my wife Kimberly and children Raphaela, Morgan and Raphael. They are the delight of my life. I also want to thank my parents for their continuous support for their family and their strength in pursuing life’s challenges. I also would like to express my appreciation for the efforts of Marc Heft, Marian Limacher and Don Price who took time out of their busy schedule to work with me on this thesis. I would like to thank Mike Robinson, Doug Theriaque and Jon Schuster for their valuable scientific contributions, Eve Johnson for her editorial support and Nik Gravenstein for his support as chairman and advisor. iv

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TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES............................................................................................................vii LIST OF FIGURES.........................................................................................................viii ABSTRACT.......................................................................................................................ix CHAPTER 1 INTRODUCTION......................................................................................................1 The Concept of Anesthesia........................................................................................1 Anesthesia and Sedation............................................................................................2 Anesthesia and Analgesia..........................................................................................3 Sedation During Painful Medical Procedures............................................................4 Propofol......................................................................................................................4 Previous Studies.........................................................................................................5 Specific Aims and Study Hypothesis.........................................................................6 2 MATERIALS AND METHODS...............................................................................7 Study Subjects............................................................................................................7 Sample Size Determination................................................................................7 Screening............................................................................................................7 Enrollment..........................................................................................................8 Inclusion criteria......................................................................................8 Exclusion criteria .....................................................................................8 Demographics....................................................................................................8 Randomization and Blinding.....................................................................................8 Randomization...................................................................................................8 Subject Blinding.................................................................................................9 Thermal Pain Stimulation..........................................................................................9 TSA II Neuro Sensory Analyzer........................................................................9 Stimulation Temperatures................................................................................10 Thermal Pain Stimulation Sequence................................................................10 Control of Psychomotor Impairment (“Number Rating”)...............................11 v

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Computer-Assisted Continuous Infusion (CACI)............................................12 Effect Site Concentrations...............................................................................13 Blood Levels (LC-MS)....................................................................................13 Subject Monitoring..................................................................................................13 Data Analysis...........................................................................................................14 Descriptive Statistics........................................................................................14 Overall Test......................................................................................................14 Post Hoc Analysis............................................................................................14 Other Analyses.................................................................................................14 3 RESULTS.................................................................................................................15 Main Effects.............................................................................................................15 Psychomotor Impairment.........................................................................................16 Pairwise Comparisons..............................................................................................17 Interaction Analysis.................................................................................................17 Secondary Analysis..................................................................................................17 Prediction of Pain Rating Using Propofol Blood Levels.................................17 Pain Ratings Before and After the Study.........................................................18 4 DISCUSSION..........................................................................................................19 Key Findings............................................................................................................19 Study Limitations.....................................................................................................19 Variation in Sedation Levels............................................................................19 Psychomotor Impairment and Pain Rating......................................................20 Variability of Pain Perception..........................................................................20 Propofol Injection Pain....................................................................................20 Pain Ratings Before and After the Study.................................................................21 Clinical Implications................................................................................................21 Study Design and the Existing Literature................................................................22 Summary..................................................................................................................23 APPENDIX SUPPLEMENTAL TABLES............................................................................................24 LIST OF REFERENCES...................................................................................................29 BIOGRAPHICAL SKETCH.............................................................................................32 vi

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LIST OF TABLES Table page 3-1 ANOVA Tables on Pain Ratings.............................................................................16 3-2 Pairwise Comparison of Mean Pain Ratings............................................................17 A-1 Summary of VAS Ratings........................................................................................24 A-2 Descriptive Statistics (Intensity Rating)...................................................................25 A-3 Descriptive Statistics (Unpleasantness Ratings)......................................................26 A-4 Pairwise Comparisons of Intensity Ratings.............................................................27 A-5 Pairwise Comparisons of Unpleasantness Ratings...................................................28 vii

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LIST OF FIGURES Figure page 2-1 Illustration of The Research Setup.............................................................................9 2-2 Illustration of Thermal Pain Stimulation Probe on Subject’s Forearm....................10 2-3 Sample Testing Sequence for One Subject..............................................................11 3-1 Bar Graph Of VAS Ratings......................................................................................15 viii

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Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science THE EFFECTS OF PROPOFOL ON PAIN INTENSITY AND UNPLEASANTNESS By Michael A. Froelich May 2004 Chair: Marian Limacher, MD Major Department: Clinical Investigation In this study, the effect of propofol, a widely used sedative-hypnotic drug, on pain perception, was examined. Eighteen subjects received propofol in two sedative concentrations, which were balanced and randomized in order. Painful stimulation temperatures (45, 47, and 49C) were presented in random order and non-painful 31 o C stimuli were presented on alternate trials. The sedative–hypnotic drug propofol was administered as a target-controlled infusion at an effect site concentration of 0.5 g/ml for mild sedation and 1.0 g/ml for moderate sedation. Subjects rated both pain intensity and unpleasantness higher than baseline when sedated with propofol. The average pain intensity scores were 28/100 for placebo, 35/100 for mild and 40/100 for moderate sedation. Pain unpleasantness scores were 23/100 for placebo, 29/100 for mild and 33/100 for moderate sedation. This effect is unexpected and ix

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illustrates that there may be an important difference in subjective pain experienced by a patient and the level of analgesia perceived by a health care provider in sedated patients. This finding calls further attention to the need for adequate analgesia in patients sedated with propofol. x

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CHAPTER 1 INTRODUCTION Sedation and analgesia are the main components of the traditional conceptualization of anesthesia. This concept can be extended to include unconsciousness, amnesia, antinociception and autonomic stability. An ongoing area of research is dedicated to characterizing drugs used in anesthesia with respect to their ability to affect the individual components that constitute the anesthetic state. Intravenous sedative drugs are used commonly in anesthetic practice but very little is known about their effect on pain perception. This document describes the findings of research on the effects of propofol, an intravenous sedative-hypnotic drug, on pain perception. The Concept of Anesthesia Classic anesthesia theories were based on unitary, non-specific mechanisms of anesthetic actions. It was assumed that one anesthetic could be replaced freely by another, and in the case of anesthetic combinations, the anesthetic effect of such mixtures was expected to be additive (1). In 1986, Pinsker (2) postulated anesthesia as a concept with three components: paralysis, unconsciousness, and attenuation of the stress response. In his theory, any drug or combination of drugs that provided these three conditions reversibly could be used in anesthesia. 1 This classic concept was based on the anesthetic needs of the patient–being pain free and unaware of the stressful surgical environment–and the surgical need of keeping the patient from moving during an operation. However, this picture was rather simplified, and new theories have further developed the anesthesia concept. Recent advances in pharmacology have led to the development of drugs that target desired anesthetic effects

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2 pharmacology have led to the development of drugs that target desired anesthetic effects while minimizing untoward drug effects on cardiopulmonary function. Anesthesiologists began to study the main goals of sedative-hypnotic drugs: loss of consciousness, amnesia and their effect on memory (3, 4). Other anesthetic goals are autonomic stability and antinociception. Anesthesia and Sedation Sedation and hypnosis are terms to describe a continuum of decreased levels of alertness, ranging from mild sedation to general anesthesia. The American Society of Anesthesiology has defined these states as follows (5): Minimal sedation (anxiolysis). Minimal sedation (anxiolysis) is a drug-induced state during which patients respond normally to verbal commands. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are unaffected. Moderate sedation ("Conscious sedation"). Moderate sedation/analgesia ("conscious sedation") is a drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained. Deep sedation. Deep sedation is a drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. The ability to independently maintain ventilatory function may be impaired. Patients may require assistance in maintaining a patent airway, and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

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3 General anesthesia. General anesthesia is a drug-induced loss of consciousness during which patients are not arousable, even by painful stimulation. The ability to independently maintain ventilatory function is often impaired. Patients frequently require assistance in maintaining a patent airway, and positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired. Anesthesia and Analgesia Analgesia is the treatment used to induce antinociception. Antinociception refers to inhibition of the nociceptive (i.e. pain perception sensation) processing in the nervous system. In adequate anesthesia, the role of antinociception is crucial: it makes surgical operations possible, and it reduces immediate and long-term negative consequences related to those procedures. With inappropriate analgesia, nociception can cause unfavorable responses of the autonomic nervous system and involuntary movements in the patient. Unfortunately, the effect of nociceptive stimuli upon the unconscious patient is not completely understood. In 1987, Prys-Roberts (6) discussed the definition of pain depending on consciousness and raised a noteworthy point: If pain is to be considered as a "conscious perception of noxious stimulus,” then "a state of anesthesia" could be defined as drug-induced unconsciousness, in which the patient neither perceived nor recalled pain. If this concept were true, analgesia would not be necessary as long as the absence of consciousness was maintained. If, on the other hand, the unconscious experience of pain was to have an untoward effect on the patient, then more emphasis would have to be placed on the adequacy of intraoperative analgesia.

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4 Sedation During Painful Medical Procedures The use of intravenous sedative-hypnotic drugs for monitored anesthesia care is widespread. Intravenous drugs in this pharmacological category are benzodiazepines, short-acting barbiturates and propofol. Examples for the use of these drugs are for preoperative anxiolytics, as sedatives in the intensive care unit and for many short medical procedures. The use of propofol has been described in the emergency room as a sedative for many short, but painful procedures such as anoscopy, fracture reduction, abscess incision, or cervical dilatation and curettage (7, 8). Propofol is also used extensively for sedation of intubated patients in the intensive care unit (9). Other applications include various non-surgical diagnostic procedures that require sedation, such as gastrointestinal endoscopy and bronchoscopy (10). Despite their widespread application, little data exist on the effects of sedative hypnotics on pain perception. Propofol The drugs used to produce the anesthetic components mentioned previously are very heterogeneous in structure, mode of administration and pharmacological effect. In recent years, emphasis has been on the development of intravenous drugs that can produce sedation and hypnosis in a dose-dependent fashion. The most popular of the intravenous sedative-hypnotics is propofol (2,6-Diisopropylphenol). Propofol was commercially introduced in the United States in 1989. It is the first of a new class of intravenous anesthetic agents, the alkyl phenols, and is approved for the induction and maintenance of anesthesia in more than 50 countries. Propofol is used for all levels of sedation as outlined above. In our study, we use minimal (mild) sedation and moderate sedation to test the effect of propofol on pain perception.

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5 Previous Studies The sedative-hypnotic pharmacology, pharmacokinetic, pulmonary and cardiovascular profiles of propofol are well described (11), however, there is only sparse and somewhat conflicting literature on the effect of propofol on pain perception in humans. In 1995, Wilder-Smith studied the change in thermal pain detection thresholds in healthy patients scheduled for orthopedic surgery under epidural anesthesia who received thiopentone and propofol (12). Patient reaction time to a probe delivering temperatures from a neutral to painful range was recorded. The reaction time for thermal pain perception did not increase significantly at either a low dosage (0.5 mg/kg bolus and 1 mg/kg/hr infusion) or high dosage (0.5 mg/kg bolus and 5 mg/kg/hr infusion) range in the 15 subjects who received propofol. Anker-Mller et al. (13) found significant increases in pain detection thresholds associated with argon laser stimulation after an intravenous bolus of 0.25 mg/kg propofol. These results have led some physicians to believe that painful conditions could be treated with small bolus doses of propofol (14), a strategy that has been frowned upon by other clinicians who maintain that propofol should not be used to treat inadequate analgesia (15). Indeed, there is evidence that points towards hyperalgesic effects of propofol (16, 17). In a study involving 12 human volunteers, Peterson-Felix et al. (17) demonstrated that propofol in subhypnotic doses has hyperalgesic effects on mechanical pressure pain, while pain perception in response to electrical or heat stimulation appeared unaltered. Whether propofol affects pain perception is not just an academic question. A recent discussion in the anesthesiology literature (14, 15) illustrates this point. In the following,

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6 TerRiet et al. (15) respond to a suggestion made by Lau et al. that inadequate pain relief resulting in patient movement may be treated by deepening a patient’s level of sedation: Too often, in our opinion, patients receive propofol, at a time when an analgesic would serve them better. Many times, our surgical colleagues insist that propofol, or “that white stuff,” “works much better.” They seem to believe that propofol is a miracle drug, without side effects, and appropriate for every patient in every circumstance. They seem to think propofol can replace adequate analgesia obtained by infiltration with local anesthesia. Unfortunately, educating them is sometimes difficult. However, this prestigious journal should certainly provide our fellow anesthesia providers with correct information regarding appropriate use of certain drugs, including the effects they do not exert. (p. 1455) This comment illustrates a lack of consensus for the best approach to manage a patient who moves in response to a painful stimulation. Most clinicians would agree that adequate analgesia is at least as important as sedation in the conscious patient. If sedative-hypnotic drugs alter pain perception, then the amount of supplementary analgesia would depend on the type of sedative drug used and perhaps also on the dose administered. Specific Aims and Study Hypothesis The primary aim of this study was to test if the visual analogue scale (VAS) pain rating differs among sedation levels (placebo, mild, moderate sedation) achieved with propofol. The second aim was to test if the VAS pain rating depended on the pain rating objective (pain dimensions with two levels: intensity versus unpleasantness). The hypothesis tested was that propofol increases pain perception, the statistical null hypothesis that propofol has no effect on pain perception..

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CHAPTER 2 MATERIALS AND METHODS Study Subjects Sample Size Determination Sample size calculations were performed for the primary outcome related to VAS pain intensity ratings, as baseline data were available in the literature. These calculations assume a moderate within-subject correlation of .75, alpha=0.05, and two-tailed tests. We calculated that 12 subjects would need to be tested to detect an 8-point difference in VAS pain intensity ratings at 80% power. Screening After study approval was issued by the Health Center Institutional Review Board, 18 healthy subjects were recruited by public advertisement. Each subject was scheduled for a screening appointment. After informed consent was obtained, the subject’s history, physical examination, and complete blood count and chemistry panel were collected. Female subjects were scheduled for a urine pregnancy test on the day of the study. The study procedure was explained in detail to volunteers. To insure that subjects could tolerate thermal pain, several test stimuli were given and subjects were asked to rate the pain intensity and unpleasantness on a visual analog scale. 7

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8 Enrollment Inclusion criteria Volunteers were included if their medical screening indicated no health concerns and they were able to follow study instructions. Exclusion criteria Exclusion criteria were any medical condition that could affect the study procedure or potentially put the subject at risk. Examples of exclusion conditions were obesity, pregnancy, sleep apnea, moderate or severe bronchial asthma, and cardiovascular problems such as hypertension. Subjects taking any drugs or substances that would alter their pain perception were excluded. Demographics Ultimately, seven female and 11 male subjects were enrolled. None of the subjects were obese their BMI ranged from 17.7 – 25.2 kg/m 2 and their ages ranged from 19 to 28 years. Randomization and Blinding Randomization Subjects underwent a three-period crossover study involving random assignment to drug (mild or moderate propofol) or placebo. Within each of these three treatment periods, three temperature stimuli (45C, 47C, 49C) were randomly administered in a set of three replicates (nine measurements per period). All subjects received both levels of drug as well as placebo. Four replicates of a 3X3 Greco-Latin squares design were employed to achieve approximate balance to both drug and temperature assignments, and SAS 6.1 software (Cary, NC) was used to perform the randomization. Figure 2-1 shows a graphical representation of a stimulation sequence for one subject.

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9 Figure 2-1. Illustration of the experimental laboratory: The research subject is sitting in a comfortable chair. There are intravenous lines in the right and left brachial veins (covered by towels). One line is used for the propofol infusion. The propofol infusion pump is behind the subject (not shown here) and separated by a curtain. Subject Blinding Subjects were blinded with respect to their treatment. The intravenous line leading to the intravenous catheter was covered to avoid any visual clues that would help subjects learn about their treatment. Also, the IV pole equipped with both carrier and propofol infusion was placed behind the subject and visually separated by a curtain. Thermal Pain Stimulation TSA II Neuro Sensory Analyzer We used the TSA-II Neuro Sensory Analyzer (Medoc, Ltd., Ramat-Yishai, Israel) for the administration of thermal pain stimuli. This device consists of a computer-driven heat exchanger that regulates the temperature of a water circuit. The circuit perfuses a 30 by 30 mm thermode, which was attached to the forearm (Figure 2-2). The TSA-II Neuro Sensory Analyzer is controlled using a personal computer-based stimulation software which we programmed to a staircase test algorithm.

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10 Figure 2-2. This is the thermal pain stimulation thermode being applied to the subject’s forearm. Stimulation Temperatures Stimulus temperatures were 45, 47 and 49 C, temperature levels that have been shown to activate A and C fibers. After each of the thermal pain stimuli, presented in random order, subjects were asked to rate sensations with a mechanical slide algometer. Subjects were instructed to rate the perceived pain intensity and unpleasantness using visual analog scales with end-points of “no pain sensation,” “most intense pain sensation imaginable” and “not at all unpleasant,” “most unpleasant imaginable” as described by Price et al(18). Thermal Pain Stimulation Sequence Four, 4 second square-wave painful target temperatures (45, 47and 49C) alternating with a neutral temperature (31C) were programmed. The ramp-up temperature rise was 10C/sec. The three target temperatures were randomly assigned within each testing period and were maintained for 4 seconds, followed by a 30-second interval during which pain ratings took place. This cycle of three painful stimuli, each followed by the subjects pain rating, was performed three times under each study condition (placebo, mild and moderate propofol drug levels),

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11 providing a total of 27 measurements for each subject. After each thermal stimulus, the skin contact site was changed in a systematic fashion to avoid redness of the skin and stimulus habituation. This testing sequence is depicted in Figure 2-3. This subject was randomly allocated to receive mild sedation first, followed by placebo (no drug) and moderate sedation. During each drug condition, the subject is exposed to three sets of three painful temperatures (45, 47 and 49C). After each thermal pain stimulus the temperature drops to a neutral temperature (31C) and subjects are asked to rate pain intensity and unpleasantness. Figure 2-3. Sample Testing Sequence for One Subject. At each propofol condition painful thermal stimuli were applied to the right forearm (R) alternating with the left forearm (L), the sequence of the three painful stimulation temperatures is shown in the lower section of the figure. Control of Psychomotor Impairment (“Number Rating”) Controlling for psychomotor impairment is important when the visual analog scale (VAS) for pain rating is used by sedated subjects. At the beginning of each testing sequence, subjects were asked to perform a task intended to test cognitive and

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12 psychomotor ability. Rather than rating a painful thermal stimulus, subjects were given a random numbers using the VAS scale which has no gradation visible to subjects; however, the flip side of the rating scale has a gradation which allows the study administrator to obtain an exact reading of the rating. For this test, subjects were told that the VAS scale ranges from zero to 100. Random numbers were limited to a range of 20 and 80, thus avoiding the extremes of the scale that might be more difficult to use. The difference of the intended number rating by subjects and the actual number (visible to the study administrator) was calculated for each propofol condition. If the difference of intended versus actual number rating was significantly larger during the sedation conditions compared to the placebo (control) subjects’ psychomotor ability would be considered impaired. This method of testing psychomotor impairment has not been formally studied but was used based on face validity and the lack of a better applicable test. Propofol Administration and Control of Propofol Levels Computer-Assisted Continuous Infusion (CACI) CACI is an infusion system that allows the anaesthetist to select the target blood concentration required for a particular effect and then to control depth of anaesthesia by adjusting the requested target concentration. The main advantage of using CACI is its ability to change the blood concentration more rapidly when compared to the standard infusion pump, which uses linear infusion kinetics. This infusion algorithm is based on a three compartment pharmacologic model. The central compartment represents blood or plasma, the second compartment represents the highly perfused tissues like the heart and brain, and the third compartment represents the poorly perfused tissues such as fat and bone. After a bolus dose, there is a rapid,

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13 initial distribution phase which represents distribution of the dose to highly perfused organs such as the brain (effect site). This is followed by a slower, second phase representing redistribution to less well-perfused tissues such as muscle. Significant metabolism occurs during the second phase. Recovery from anaesthesia is due to extensive redistribution from the brain and to metabolic clearance. The infusion of propofol followed the three-compartment target site infusion model adjusted for age, as proposed by Schnider et al. (19). This model is included in the software STANPUMP developed by Steven L. Shafer, M.D. This personal computer-based program was used in this study to drive a Graseby 3400 infusion pump (Graseby Medical Limited, Watford, United Kingdom). Effect Site Concentrations The effect site concentrations were 0.5 g/mL and 1.0 g/mL. These doses are in the lower therapeutic range and produce mild and moderate sedation respectively. Based on the short context sensitive half life of propofol, a time frame of 20 minutes was deemed sufficient to establish a new plateau effect site concentration for all possible drug concentration changes in this study. Blood Levels (LC-MS) Blood samples to determine propofol levels were obtained prior to each pain testing sequence. Samples were analyzed using liquid chromatography–mass spectroscopy (LC-MS) (20) Subject Monitoring All subjects were monitored according to the standards for basic anesthetic monitoring recommended by the American Society of Anesthesiologists (21). After

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14 completion of the study, subjects were monitored according to the standards for postanesthetic care recommended by the American Society of Anesthesiologists. Data Analysis Descriptive Statistics Demographic data were expressed as means plus/minus standard deviation. Overall Test The methodology utilized was parametric analysis of variance. The dependent variables for all analyses were intensity and unpleasantness scores. For the treatment comparisons, we obtained 54 dependent observations (18 subjects times 3 treatments) by averaging each subject’s response over temperature and phase. This averaging process improved the power as compared to analyses that do not do this averaging. To limit the errors of multiple testing, we first ran randomized block analyses for treatment differences, treating the subject as the block. Post Hoc Analysis For each of the dependent variables, if the three treatment F-statistic was non-significant at p < .05, all statistical comparisons would cease. If significant, pairwise comparisons of treatments and secondary 3-group analysis of the individual temperatures were done. This secondary 3-way analysis further determined if pairwise analysis within temperature would be necessary. Other Analyses Other analyses, which are viewed as diagnostic, were also completed. We looked at the interaction between temperature and experimental group, asking if the mean difference between treatments depended upon temperature.

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CHAPTER 3 RESULTS Main Effects We found overall statistically significant differences in pain intensity and unpleasantness ratings among study conditions (Figure 3-1 and Table 3-1). Pain intensity was rated significantly higher under mild (p=0.01) and moderate (p<0.001) sedation when compared to the placebo condition. In a similar fashion, pain unpleasantness was rated significantly higher under mild (p=0.003) or moderate sedation (p<0.001) when compared to the placebo condition. * * * * * * * * Figure 3-1. This bar graph displays VAS ratings as means standard deviation. Significantly different ratings are labeled with *p< 0.05; ** p<0.005. 15

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16 Table 3-1. ANOVA tables on pain ratings: pain ratings are based on a univariate general linear model with pain ratings as dependent variable and sedation group and subjects as independent variable. Effect sizes are displayed as partial eta squared; 42% (intensity) and 39% (unpleasantness) of variations on pain ratings can be explained by propofol sedation. Dependent Variable: VAS Intensity Rating Source DF Sum of Squares Mean Square F Value Partial Eta Squared Subject 17 13892 817 15.94 (p<.001) 0.89 Sedation Group 2 1263 631 12.32(p<.001) 0.42 Error 34 1743 51 Dependent Variable: VAS Unpleasant Rating Source DF Sum of Squares Mean Square F Value Partial Eta Squared Subject 17 12946 762 17.85 (p<.001) 0.90 Sedation Group 2 913 457 10.70 (p<. 001) 0.39 Model 19 13859 729 17.1 Error 34 1450 43 We noted a large variability in pain rating which is reflected in the large effect size parameter (partial eta squared) for the subjects in the ANOVA table shown (Table 3-1). Psychomotor Impairment Subjects’ psychomotor ability to use the sliding scale under propofol sedation was not impaired. The difference between numbers given to subjects and numerical values of VAS ratings of subjects did not significantly increase with sedation. Thus, mean differences between presented 0-100 numbers and 0-100 VAS ratings were 4.3 (3.3 SD) for the placebo condition, 4.7 (2.9 SD) for mild sedation, and 5.6 (3.5 SD) for moderate sedation. These mean differences were very low and did not differ statistically (ANOVA, p=0.48).

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17 Pairwise Comparisons Mean VAS scores increased by 12 points on a scale ranging from 0 to 100 for intensity, and by 10 points for unpleasantness when placebo was compared to moderate sedation. Table 3-2. Pairwise Comparison of Means Averaged over Temperature. Variable N Mean Std Dev Pr > |t| Intensity Moderate Placebo 18 11.8 11.4 <. 001 Mild – Placebo 18 6.8 10.1 0.011 Moderate – Mild 18 5 8.6 0.026 Unpleasantness Moderate – Placebo 18 10 9.91 <. 001 Mild – Placebo 18 5.9 7.2 0.0028 Moderate – Mild 18 4.1 10.3 0.11 Interaction Analysis We looked at the interaction between temperature and experimental group and did not uncover a significant interaction. We also studied the role of order of treatments to see if the analysis might need to take that into account, but no significant order effect was uncovered. Secondary Analysis Prediction of Pain Rating Using Propofol Blood Levels The finding of increased pain ratings with propofol sedation was confirmed by a secondary analysis that was based on the correlation of pain VAS ratings and plasma propofol levels (random effects analysis). Propofol levels, predicted with the target

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18 controlled infusion (Stanpump ), were significantly correlated to blood levels obtained by LC-MS; the correlation coefficient equals 0.778. Pain Ratings Before and After the Study We also compared a separate set of pain ratings before and after the study. These ratings did not differ significantly. However, we observed a non-significant trend of lower pain ratings after the study when compared to before the study (p=0.107).

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CHAPTER 4 DISCUSSION Key Findings This study shows that propofol at effect site concentrations of 0.5 g/mL and 1.0 g/mL increases both pain intensity and pain unpleasantness. The observed changes are significant and of moderate statistical effect size (eta squared = 0.42). The hyperalgesic effects of propofol may well be clinically significant if they are systematically present in large numbers of patients. These concentrations of propofol chosen in our study equal linear infusion rates – usually applied in clinical practice of 25 and 50 g/kg/min. These concentrations of propofol are used for sedation during regional anesthesia, uncomfortable diagnostic procedures such as endoscopies, reposition of dislocated joints, or interventional procedures in radiology where sedation is desired (7, 8). The finding of dose dependent hyperalgesia underscores the importance of assuring appropriate analgesia if sedation with propofol is used and certainly argues against the treatment of pain with additional doses of propofol as proposed by some clinicians (14). Study Limitations Variation in Sedation Levels A potential limitation of our study is the variation in sedation levels among subjects. However, the prospective randomized and balanced treatment assignment was used to minimize these differences as well as minor pharmacokinetic differences in drug washout among subjects. 19

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20 Psychomotor Impairment and Pain Rating We were also concerned about oversedation that might affect the subjects’ ability to perform pain rating. Unfortunately, most investigators do not attempt to address this potential confounding variable (12, 13). We have used the “number rating test” to control for psychomotor impairment as a potentially confounding factor. This test, while not well established, has reasonable face validity. Variability of Pain Perception We observed a significant variability in subjects’ pain rating when subjects were exposed to identical stimulation temperatures. The observation of pain rating variability is consistent with previous reports by Coghill et al (22) who demonstrated that there are large differences in pain rating by volunteers and that those differences correlate with differences in intensity of brain activation patterns using functional magnetic resonance imaging. Because of this variability, one might argue that stimuli should be normalized using pain threshold measurements. However, there are important advantages of using unadjusted suprathreshold pain. First, normal human variability in pain sensitivity is captured and second, suprathreshold pain is the more relevant to assess clinical pain. In our data analysis, we have statistically controlled for this source of variability. Propofol Injection Pain Another potential confounding factor for the assessment of pain in patients receiving propofol is its potential to cause burning upon injection. Fortunately, none of our subjects reported propofol injection pain, a fact that we attributed to the careful selection of the injection site using a large caliber vein. We also alternated between

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21 forearms twice and received consistent ratings within subjects. Thus, the pain rating appeared to be unaffected by the possible local irritant effects of propofol. Pain Ratings Before and After the Study We observed a trend toward lower pain scores when comparing baseline VAS ratings to VAS scores obtained after the propofol infusion had been terminated and the infusion line had been disconnected. This trend toward lower pain ratings may reflect lower situational anxiety, a known cause for increased pain perception (23), at the end of the study session compared to the beginning. Clinical Implications Our results are limited to observations in subjects who have maintained consciousness or are easily arousable, i.e. moderately sedated. This design takes into consideration that pain is the conscious experience of a noxious event. One might also state that the experience of pain in the patient with a depressed level of consciousness is equally important. In fact, critically ill patients do report a high number of unpleasant events that they believe took place before they regained consciousness (24). This is frequently interpreted as a need for better assessment and treatment of sedation (often accomplished by means of a propofol infusion) in the critically ill patient. Thus, the need for adequate analgesia in the sedated patient may be of equal or even higher importance when considering the possible hyperalgesic effect of the sedative medication. This suggestion is accentuated by the observation that more than half of the patients in the ICU actively recall pain (25) and underscores the importance of adequate analgesia in patients who are being sedated with propofol. Similar considerations apply for many endoscopic procedures, procedures in interventional radiology and the

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22 emergency room, and some office-based surgical procedures performed under local anesthesia with sedation. Study Design and the Existing Literature The reason for the conflicting results in studies evaluating the effect of propofol on pain perception may, at least in part, be attributed to study design and methods. We therefore chose an experimental model of pain and a rating scale that has been extensively used in both clinical and experimental contexts (18, 26-28). In particular, the combined use of mechanical VAS and contact heat-induced pain has been shown to provide ratio scale measures of pain and internally consistent measures of experimental and clinical pain when patients rate both forms of pain (18, 26, 28). This method is also predictive of changes in clinical pain intensity. For example, conventional analgesic treatments such as opioid administration have been shown to produce similar magnitudes of pain reduction in both clinical and this form of experimental pain (28). At the time of preparation of this thesis an independent group of investigators published data corroborating our findings. Hofbauer et al (29) also studied the effect of propofol on pain perception and found increased pain ratings at the mild sedation dose (0.5 g/mL) when compared to placebo control. At a dose of 1.5 g/mL they found lower pain ratings but were unable to obtain meaningful pain ratings responses from about one third of their subjects. This study was limited by the lack of control for psychomotor impairment but added some interesting information about activation of the anterior cingulate gyrus (ACC) of the brain. Using positron emission tomography (PET) the same investigators showed increased regional blood flow to the ACC that correlates with increased pain perception when subjects were mildly sedated.(29)

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23 Summary In summary, these findings indicate that propofol in mild to moderate sedative doses increases pain intensity and unpleasantness. This finding calls attention to the need for adequate analgesia in sedated patients and stimulates the ongoing discussion about the pharmacologic profile of anesthetic drugs and their mechanism of action. Further research is necessary to further delineate the effect of sedative-hypnotic drugs on pain perception and to determine the effects of higher, hypnotic doses on pain experience.

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APPENDIX SUPPLEMENTAL TABLES Table A-1. Summary of VAS Ratings: This table summarizes visual analogue scale (VAS) ratings under different sedation conditions. The first part of the table displays VAS ratings on pain intensity. The second part of the table displays pain unpleasantness ratings. Intensity Exp. Group Quartiles Mean (SD) Placebo 14.4 29.4 40.0 27.80 (15.62) Mild 19.8 33.6 47.6 34.62 (17.82) Moderate 26.3 38.8 51.1 39.60 (18.92) Unpleasantness Exp. Group Quartiles Mean (SD) Placebo 8.2 25.0 33.6 23.23 (14.85) Mild 12.7 27.1 46.2 29.14 (17.82) Moderate 14.7 34.2 46.9 33.25 (17.57) 24

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25 Table A-2. Descriptive Statistics: Descriptive Statistics for Intensity Ratings, Averaged over Phase Exp Group Temp N Quartiles Mean Std Dev 45 18 8.67 18.33 32.67 20.09 13.93 Mild 47 18 17.33 34 40.67 31.44 17.81 49 18 33.33 56.67 70 52.33 24.83 45 18 12.67 21.33 32 25.09 15.48 Moderate 47 18 20.67 34.67 60.67 38.48 24.37 49 18 44 52.33 72.67 55.22 23.95 45 18 7.33 10.67 24 14.72 12.97 Placebo 47 18 11 25 32.67 22.11 13.47 49 18 25.33 47.33 68.67 46.57 25.38

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26 Table A-3. Descriptive Statistics: Descriptive Statistics for Unpleasantness Ratings, Averaged over Phase Exp Group Temp N Quartiles Mean Std Dev 45 18 4 18.33 27.33 16.98 12.6 Mild 47 18 12 26 36.67 25.26 16.08 49 18 22 43.67 68 45.19 27.45 45 18 12 20.67 30 20.94 11.82 Moderate 47 18 18.67 25.67 52.67 32.8 21.38 49 18 19.33 46 71.33 46 27.11 45 18 1.33 8.33 14 11.3 11.94 Placebo 47 18 8 15.33 30 16.78 13.2 49 18 14 46.33 62.67 41.61 25.95

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27 Table A-4. Pairwise Comparisons of Intensity Ratings: At each temperature, the three group p-values are: @45 (p<.001) @47 (p<.001) @49 (p=.39), this table shows differences of treatment groups (placebo, mild or moderate sedation) for each temperature. Variable (@45) Mean Std Dev Pr > |t| Moderate-Placebo 10.4 10.5 0.0006 Mild-Placebo 5.4 10.9 0.0528 Moderate-Mild 5 10.6 0.0608 Variable (@47) Mean Std Dev Pr > |t| Moderate-Placebo 16.4 18.8 0.0018 Mild-Placebo 9.3 11.8 0.0038 Moderate-Mild 7 15.7 0.0748 Variable (@49) Mean Std Dev Pr > |t| Moderate-Placebo 8.6 14.8 0.024 Mild-Placebo 5.8 14.7 0.1144 Moderate-Mild 2.9 11.3 0.2934

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28 Table A-5. Pairwise Comparisons of Unpleasantness Ratings: At each temperature, the three group p-values are : @45 (p<.001) @47 (p<.001) @49 (p=.39), this table shows differences of treatment groups (placebo, mild or moderate sedation) for each temperature. Variable (@45) Mean Std Dev Pr > |t| Moderate-Placebo 9.6 7.2 <0.0001 Mild-Placebo 5.7 10.1 0.0288 Moderate-Mild 4.0 9.8 0.1030 Variable (@47) Mean Std Dev Pr > |t| Moderate-Placebo 16.0 19.2 0.0026 Mild-Placebo 8.5 9.4 0.0013 Moderate-Mild 7.5 16.2 0.0655 Variable (@49) Mean Std Dev Pr > |t| Moderate-Placebo 4.4 16.5 N/A Mild-Placebo 3.6 11.9 N/A Moderate-Mild 0.8 14.1 N/A

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LIST OF REFERENCES 1. Kissin I. A concept for assessing interactions of general anesthetics. Anesth Analg 1997; 85:204-210. 2. Pinsker MC. Anesthesia: a pragmatic construct, letter. Anesth Analg 1986; 65:819-820. 3. Ghoneim, M (Ed). Awareness during anesthesia (textbook). Butterworth-Heinemann Publishers, 2001 (ISBN 0-7506-7201-3). 4. Veselis RA, Reinsel RA, Feshchenko VA. Drug-induced amnesia is a separate phenomenon from sedation: electrophysiologic evidence. Anesthesiology 2001; 95: 896-907. 5. Definitions of general anesthesia and levels of sedation/analgesia. Standards, guidelines and statements. American Society of Anesthesiologists, Parke Ridge, IL 2003. 6. Prys-Roberts C. Anaesthesia: a practical or impractical construct? Br J Anaesth 1987;11:1341-1345. 7. Havel CJ Jr, Strait RT, Hennes H. A clinical trial of propofol vs midazolam for procedural sedation in a pediatric emergency department. Acad Emerg Med 1999; 6:989-97. 8. Swanson ER, Seaberg DC, Mathias S. The use of propofol for sedation in the emergency department. Acad Emerg Med 1996; 3:234-8. 9. Chamorro C, de Latorre FJ, Montero A, Sanchez-Izquierdo JA, Jareno A, Moreno JA, Gonzalez E, Barrios M, Carpintero JL, Martin-Santos F, Otero B, Ginestal R. Comparative study of propofol versus midazolam in the sedation of critically ill patients: results of a prospective, randomized, multicenter trial. Crit Care Med 1996; 24:932-9. 10. Carlsson U, Grattidge P. Sedation for upper gastrointestinal endoscopy: a comparative study of propofol and midazolam. Endoscopy 1995; 27:240-3. 11. Deegan RJ. Propofol: a review of the pharmacology and applications of an intravenous anesthetic agent. Am J Med Sci. 1992 Jul;304(1):45-9. 29

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30 12. Wilder-Smith OH, Kolletzki M, Wilder-Smith CH. Sedation with intravenous infusions of propofol or thiopentone. Effects on pain perception. Anaesthesia 1995; 50:218-22. 13. Anker-Mller E, Spangsberg N, Arendt-Nielsen L, Schultz P, Kristensen MS, Bjerring P. Subhypnotic doses of thiopentone and propofol cause analgesia to experimentally induced acute pain. Br J Anaesth 1991; 66:185-58. 14. Lau WC, Green CR, Faerber GJ, Tait AR, Golembiewski JA. Determination of the effective therapeutic dose of intrathecal sufentanil for extracorporeal shock wave lithotripsy. Anesth Analg 1999; 89:889-92. 15. TerRiet MF, Jacobs JS, Lewis MC, DeSouza GJ. Propofol and analgesia. Anesth Analg 2000; 90:1455. 16. Ewen A, Archer DP, Samanani N, Roth SH. Hyperalgesia during sedation: effects of barbiturates in the rat. Can J Anaesth 1995; 42:532-40. 17. Petersen-Felix S, Arendt-Nielsen L, Bak P, Fischer M, Zbinden AM. Psychophysical and electrophysiological responses to experimental pain may be influenced by sedation: comparison of the effects of a hypnotic (propofol) and an analgesic (alfentanil). Br J Anaesth 1996; 77:165-71. 18. Price DD, Long S, Harkins SW. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales of pain. Pain 1994; 56:217-26. 19. Schnider TW, Minto CF, Gambus PL, Andresen C, Goodale DB, Shafer SL, Youngs EJ. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology 1998; 88:1170-82. 20. Lim CK, Lord G. Current developments in LC-MS for pharmaceutical analysis. Biol Pharm Bull 2002; 25:547-57. 21. Basic anesthetic monitoring. Standards, guidelines and statements. American Society of Anesthesiologists, Parke Ridge, IL 2003. 22. Coghill RC, McHaffie JG, Yen YF. Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci USA. 2003;100:8538-42. 23. Keogh E, Cochrane M. Anxiety sensitivity, cognitive biases, and the experience of pain. J Pain. 2002 Aug;3(4):320-9. 24. Rundshagen I, Schnabel K, Wegner C, am Esch S. Incidence of recall, nightmares, and hallucinations during analgosedation in intensive care. Intensive Care Med 2002; 28:38-43.

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31 25. Puntillo KA. Pain experiences of intensive care unit patients. Heart Lung 1990; 19:526-33. 26. Price DD, Harkins SW. Combined use of experimental pain and visual analogue scales in providing standardized measurement of clinical pain. Clin J Pain 1987; 3:18. 27. Price DD, Harkins SW, Baker C: Sensory-affective relationships among different types of clinical and experimental pain. Pain 1987; 28:297-300. 28. Price DD, Harkins SW, Rafii A, Price CA. Simultaneous comparison of fentanyl's analgesic effects on experimental and clinical pain. Pain 1986 Feb;24:197-203. 29. Hofbauer RK, Fiset P, Plourde G, Backman SB, Bushnell MC. Dose-dependent effects of propofol on the central processing of thermal pain. Anesthesiology 2004;100:386-94.

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BIOGRAPHICAL SKETCH Michael Froelich, MD, attended medical school at the University of Vienna in Austria. After a year of postgraduate education in the management of infectious disease, he started his internship training in Augsburg, Germany, in the Department of Anesthesia and Intensive Care Medicine. In 1991 he moved to Atlanta, where he completed one year of internship training in the Departments of Pediatrics and Internal Medicine and three years of residency training in the Department of Anesthesiology. In 1995-96 he completed his training as fellow in the Division of Obstetric Anesthesia at the Brigham and Women’s Hospital in Boston, MA. After a two year faculty appointment at the Ludwig Maximilians University in Munich, Germany, he was appointed Assistant Professor of Anesthesiology at the University of Florida starting in March 1998. Three years later, Dr. Froelich enrolled in the Advanced Postgraduate Program in Clinical Investigation (APPCI) to obtain formal training in the conduct of clinical research. Dr. Froelich published the first German textbook on obstetric anesthesia in 2000. He has published several articles related to the care of pregnant women. In 2001 he was appointed Chief of the Division of Obstetric Anesthesia, and in March 2004 he received an appointment as Joint Assistant Professor of Obstetrics and Gynecology at the University of Florida. His clinical focus also includes pediatric liver transplantation where he performed the anesthesia for the liver transplant in the youngest (36 week gestational age) liver transplant recipient in North America, the first liver transplantation 32

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33 in an infant on extracorporeal membrane oxygenation and the first EXIT (ex utero intrapartum treatment) procedure at the University of Florida. Dr. Froelich is certified by the American Board of Anesthesiology, the European Academy of Anesthesiology and Critical Care Medicine, and the National Board of Echocardiography. He serves as a senator for the University of Florida and is the cochair of the University Minority Mentoring Program at the University of Florida. In continuation of his training in clinical investigation, Dr. Froelich plans to become actively involved in research efforts in evaluation of brain imaging methods as tools to enhance our understanding of anesthesia and analgesia.