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PAIN MEDICINE

The Effect of Propofol on Thermal Pain Perception

From the Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, the Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, University of Florida College of Dentistry, and Department of Clinical Health and Psychology, University of Florida College of Health Related Professions, Gainesville, Florida

Address correspondence and reprint requests to Michael A. Frölich, MD, MS, Department of Anesthesiology, 619 South 19th Street, Birmingham, AL 35249-6810. Address e-mail to froelich{at}uab.edu.

	Abstract

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We studied the effect of propofol, a widely used sedative-hypnotic drug, on pain perception. Eighteen subjects received propofol in two sedative concentrations that were balanced and randomized in order. Painful (45°C, 47°C, and 49°C) stimulation temperatures were presented in random order, and nonpainful 31°C stimuli were presented on alternate trials. We used a target-controlled infusion and chose effect site concentrations of 0.5 µg/mL for mild sedation and 1.0 µg/mL for moderate sedation. Using a visual analog scale, subjects rated both pain intensity and unpleasantness higher when sedated with propofol. The average pain intensity was 28/100 for placebo, 35/100 for mild, and 40/100 for moderate sedation. Pain unpleasantness was 23/100 for placebo, 29/100 for mild, and 33/100 for moderate sedation. This effect was unexpected and may be explained by a difference of subjective pain experience by a patient and the perceived level of analgesia by a health care provider in sedated patients. This finding calls further attention to the need for adequate analgesia in patients sedated with propofol.

	Introduction

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The use of propofol as an IV sedative for monitored anesthesia care is widespread. It is used in the emergency room as a sedative for many short but painful procedures such as anoscopy, fracture reduction, abscess incision, or cervical dilation and curettage (1,2). It is used extensively for sedation of tracheally intubated patients in the intensive care unit (3). Other applications include various nonsurgical diagnostic procedures, such as gastrointestinal endoscopy and bronchoscopy, which require sedation (4). Although the sedative- pharmacokinetic profile of propofol is well described, there is only sparse and somewhat conflicting literature on the effect of propofol on pain perception.

A discussion in the anesthesiology literature illustrates that this is not just an academic question (5,6). Authors discussed whether inadequate analgesia, often manifested as restlessness in the sedated patient, should be treated with supplemental bolus doses of propofol or analgesic medication. The widespread use of propofol for many medical and surgical procedures and for sedation in the intensive care environment underscores the clinical relevance of this question. We therefore decided to assess the effect of propofol sedation on pain perception using a well established model that is reliable, reproducible, and accurately predictive of changes and intensities of clinical pain (7).

	Methods

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After approval by the institutional review board 18 healthy subjects were recruited by public advertisement. Each subject was scheduled for a screening appointment. After informed consent was obtained, subject history, physical examination, and a complete blood count and chemistry panel were obtained. Female subjects were scheduled for a urine pregnancy test on the day of the study. The study procedure was explained in detail to volunteers. Several thermal pain stimuli were given and subjects were asked to rate the pain intensity and unpleasantness on a visual analog scale (VAS). Volunteers were included if their medical screening was unremarkable and they were able to follow study instructions. Exclusion criteria were any medical condition that could affect the study procedure or potentially put the subject at risk. Examples of exclusion conditions are obesity, 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 not allowed to participate in this study. Ultimately, 7 female and 11 male subjects were enrolled. None of the subjects was obese (weight range, 43 to 90 kg), their height ranged from 156 to 193 cm, and their age ranged from 19 to 28 yr.

Stimulus temperatures were 45°C, 47°C, 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 (VAS) whose end points are "no pain sensation," "most intense pain sensation imaginable," and "not at all unpleasant," "most unpleasant imaginable" (7). 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 x 30 mm thermode, which was attached to the forearm. The TSA-II Neuro Sensory Analyzer is controlled using a personal computer-based stimulation software that we programmed to a staircase test algorithm. Four, 4 s square wave painful target temperatures (45°C, 47°C, and 49°C) alternating with a neutral temperature (31°C) were programmed. The ramp-up temperature increase was 10°C/s. The three target temperatures were randomly assigned within each testing period and were maintained for 4 s, followed by a 30 s interval during which pain ratings took place. This cycle of 3 painful stimuli, each followed by the subject pain rating, was performed 3 times under each study condition (placebo, mild and moderate propofol drug levels), providing a total of 27 measurements for each subject. After each thermal stimulus, the skin contact site was moved by 3 cm within the upper section of the forearm in a systematic fashion to avoid redness of the skin and stimulus habituation.

Subjects underwent a three period crossover study involving randomization to drug (mild or moderate propofol) or placebo. Within each of these 3 treatment periods, 3 temperature stimuli (45°C, 47°C, 49°C) were randomly administered in a set of 3 replicates (nine measurements per period). All subjects received both levels of drug as well as placebo. Figure 1 shows a graphical representation of a stimulation sequence for one subject. Four replicates of a 3 x 3 Greco-Latin squares design were used to achieve approximate balance to both drug and temperature assignments, and SAS 6.1 software (Cary, NC) was used to perform the randomization.

View larger version (26K): [in this window] [in a new window]   Figure 1. Example of thermal pain testing sequence. 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.

Subjects were blinded with respect to their treatment. The IV line leading up to the IV catheter was covered to avoid any visual clues that would help subjects to learn about their treatment. During the placebo condition, the propofol target-controlled infusion was set to zero and thus did not infuse. The crystalloid carrier infusion was maintained. Also, the IV pole equipped with both carrier and propofol infusion was placed behind the subject and visually separated by a curtain. Two research nurses were involved; the nurse responsible for the administration of thermal pain stimuli and the recording of VAS ratings, for obvious reasons, had access to the thermal testing sequence. Another nurse, who recorded vital signs and withdrew blood at the appropriate times, was not informed about the testing sequence.

Controlling for psychomotor impairment is important when the 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 psychomotor ability. Rather than rating a painful thermal stimulus, subjects were given a random number using the VAS scale, which has no gradation visible to subjects; however, the flip side of the rating scale has a gradation that allows the study administrator to obtain an exact reading of the rating.

For this test, subjects were told that the VAS scale ranged from 0 to 100 mm. Random numbers were limited to a range of 20 and 80 mm, 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.

The infusion of propofol followed the three-compartment target site infusion model adjusted for age proposed by Schnider et al. (8). This model is included in the software STANPUMP by Steven L. Shafer, MD. This personal computer-based program was used to drive a Graseby 3400 Infusion pump (Graseby Medical Limited, Watford, United Kingdom). The effect site concentrations were 0.5 µg/mL and 1.0 µg/mL. These doses are in the lower therapeutic range and will produce mild and moderate sedation. Based on propofol’s short context sensitive half-life, a time frame of 20 min was deemed sufficient to establish a new plateau effect site concentration for all possible drug concentration changes in this study. Thus, the propofol infusion was set to deliver one of the three propofol conditions (no infusion, mild and moderate sedation). Twenty minutes after each rate adjustment thermal testing is performed (Fig. 1). Blood samples to determine propofol levels were obtained before each pain testing sequence. Samples were analyzed using liquid chromatography-mass spectroscopy (9).

All subjects were monitored according to the standards of the American Society of Anesthesiologists using pulse oximetry, electrocardiogram (ECG), and noninvasive blood pressure in addition to inspection of subject’s breathing and circulation (10).

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 0.75, = 0.05, and two-tailed tests. We calculated that 12 subjects would need to be tested to detect an 8 mm difference in VAS pain intensity ratings at 80% power. We decided to enroll a total of 18 patients to compensate for potential missing data, but we were able to gather a complete set of data.

The methodology used was a repeated-measures parametric analysis of variance, which is described in detail as follows. The dependent variables for all analyses were intensity and mean unpleasantness VAS ratings. For the treatment comparisons, we calculated each patient’s global mean score for each treatment, yielding 54 dependent observations (18 subjects x 3 treatments). 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 conducted randomized block analyses for three-way treatment differences, with the subject used as the block. For each of the dependent variables, if the three treatment F-statistic was nonsignificant at P < 0.05, all statistical comparisons would cease. If significant, pairwise comparisons of treatments and secondary 3-group analysis within each of the individual temperatures would be done. This secondary 3-way analysis further determined if pairwise treatment comparisons within temperature would be necessary. 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. No significant interactions were uncovered. Finally, as a diagnostic, we studied the role of the order of the treatments to see if the analysis might need to take that into account, but no significant order effect was uncovered.

	Results

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We found overall statistically significant differences in pain intensity and unpleasantness ratings among study conditions (Tables 1 and 2 and Fig. 2). Pain intensity was rated significantly higher under mild (P = 0.01) and moderate (P < 0.001) sedation when compared with 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 with the placebo condition. Mean VAS scores increase by 12 points on a scale ranging from 0 to 100 for intensity and by 10 points for unpleasantness when comparing placebo and moderate sedation.

View larger version (25K): [in this window] [in a new window]   Figure 2. Visual analogue scale (VAS) pain ratings comparing placebo to mild and moderate sedation. The bar graphs displays VAS Ratings as means ± sd. Significantly different ratings are labeled with aP = 0.011, bP < 0.001, cP = 0.026, xP = 0.003, yP < 0.001.

Subjects’ general cognitive ability 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 (see also "number rating test" in Methods). 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 small and did not differ statistically (analysis of variance, P = 0.48).

The finding of increased pain ratings with propofol sedation were confirmed by our secondary analysis that was based on the correlation of pain VAS ratings and plasma propofol levels (random effects analysis). Propofol plasma levels showed a significant positive association with pain ratings (Table 3).

	Discussion

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We have demonstrated that propofol, at an effect site concentration of 0.5 µg/mL and 1.0 µg/mL, increases both pain intensity and pain unpleasantness. Most anesthesiologists are more accustomed to linear infusion rates; the sedative doses chosen in this study would approximately equal linear infusion rates of 25 and 50 µg · kg^–1 · min^–1. These concentrations of propofol are used for sedation during regional anesthesia, uncomfortable diagnostic procedures, such as endoscopies, reposition of a dislocated joint, or interventional procedures in radiology where sedation is desired (2).

Some reports describing the effects of propofol on pain perception in humans were published in 1995 (11). The change in thermal pain detection thresholds was studied in healthy patients scheduled for orthopedic surgery under epidural anesthesia who received thiopentone or propofol. Thresholds did not increase significantly, either for a small (0.5 mg/kg bolus and 1 mg · kg^–1 · h^–1 infusion) or large (0.5 mg/kg bolus and 5 mg · kg^–1 · h^–1 infusion) dosage range in 15 subjects who received propofol. Anker-Møller et al. (12) found significant increases in pain detection thresholds associated with argon laser stimulation after an IV 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 (5), a strategy that has been frowned upon by many other clinicians who maintain that propofol should not be used to treat inadequate analgesia (6). Indeed, there is evidence that points toward hyperalgesic effects of propofol (13,14). In a study involving 12 volunteers, Petersen-Felix et al. (14) demonstrated that propofol in subhypnotic doses has hyperalgesic effects on mechanical pressure pain, whereas pain perception in response to electrical or heat stimulation appeared unaltered.

The finding that propofol increases pain perception is somewhat counterintuitive. Patients sedated with propofol appear less responsive to painful stimuli to observers and one might even assume analgesic properties of the sedative drug. Yet, based on this study, we have to recognize that subjective pain experience may in fact be increased. Hyperalgesic effects of propofol may not be well recognized if patients are simply not able to recall a painful and/or unpleasant procedure. The hyperalgesic effects may well be clinically significant if they are systematically present in large numbers of patients. This underscores the importance of assuring appropriate analgesia if propofol sedation is chosen as adjuvant medication and certainly argues against the treatment of pain with additional doses of propofol as proposed by some clinicians (5).

Additional evidence for hyperalgesic properties of sedative-hypnotic medications is provided by animal studies. Ewen et al. (13) describe the hyperalgesic effects of barbiturates and propofol in the rat, thus indicating that hyperalgesia may be a property of different anesthetics when administered in subhypnotic doses. A proposed mechanism for this effect is the modulation of the central gamma aminobutyric acid (GABA)_A ionophore by drugs such as barbiturates (15) This modulation of GABA_A receptors may well be the pathophysiologic mechanism for a central sensitization of noxious stimuli by propofol. This factor might play a major role for the development of pain after medical procedures performed with propofol sedation and may help to explain why sedated critically ill patients report frequent unpleasant events, which they thought had taken place before they regained consciousness (16). In fact, more than half of the patients in the intensive care unit actively recall pain (17). Similar considerations apply for many endoscopic procedures, procedures in interventional radiology, the emergency room, and some office-based surgical procedures performed under local anesthesia with sedation.

The proposed mechanism leading to central mechanism of noxious stimuli by propofol may also be present at larger, hypnotic doses of propofol. Although pain is considered the unpleasant sensory and emotional experience associated with actual or potential tissue damage, there may be important implications of enhanced processing of noxious stimuli during propofol anesthesia as a state during which the subjective experience of such a stimulus is presumably suppressed. The study of this hypothesis might be an interesting area of future research.

A potential limitation of our study is the variation in sedation levels among subjects. However, the prospective randomized and balanced treatment assignment should have helped to minimize these differences as well as minor pharmacokinetic differences in drug washout among subjects. We were also concerned about oversedation that might affect the subjects’ ability to perform pain rating. Unfortunately, some investigators do not attempt to address this potential confounding variable (12). We have used the "number rating test" to compare our subjects’ ability to use the mechanical slide algometer under different sedation conditions. We believe that this test, although not well established, has reasonable face validity.

We observed a significant variability in subjects’ pain rating when exposed to identical stimulation temperatures. Based on this finding, one might argue that stimuli should be normalized using pain threshold measurements. However, there are important advantages of using unadjusted suprathreshold pain; first, normal variability in pain sensitivity is captured, and second, suprathreshold pain is the more relevant to assess clinical pain.

A potential confounding factor for the assessment of pain in patients receiving propofol is its ability to cause burning on injection. Fortunately, none of our subjects reported propofol injection pain, a fact that we attributed to the careful selection of the injection site at a large caliber vein. We also changed forearms two times and received consistent rating within subjects. Thus, pain rating appeared to be unaffected by the possible local irritant effects of propofol.

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 rating scale that have been extensively used in both clinical and experimental contexts (7,18–20). 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 both forms of pain are rated by pain patients (7,18,20). 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 (20).

In summary, our 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 continuing discussion about the pharmacologic profile of anesthetic drugs and their mechanism of action. Further research is necessary to determine the effects of larger, hypnotic doses on pain experience.

	Footnotes

 
Supplemental material available at anesthesia-analgesia.org.

Supported, in part, by funds of National Institutes of Health K-30 and GCRC MO1-RR00082 at the University of Florida.

Accepted for publication July 26, 2004.

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This Article Abstract Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Frölich, M. A. Articles by Heft, M. W. Search for Related Content PubMed PubMed Citation Articles by Frölich, M. A. Articles by Heft, M. W.