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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.
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Abstract |
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Introduction |
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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).
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Methods |
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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.
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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.
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Results |
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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).
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Discussion |
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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 GABAA 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.
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Footnotes |
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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 has been cited by other articles:
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  B. Singler, A. Troster, N. Manering, J. Schuttler, and W. Koppert Modulation of Remifentanil-Induced Postinfusion Hyperalgesia by Propofol Anesth. Analg., June 1, 2007; 104(6): 1397 - 1403. [Abstract] [Full Text] [PDF]
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K. P. Ng and J. F. Antognini Isoflurane and Propofol Have Similar Effects on Spinal Neuronal Windup at Concentrations that Block Movement Anesth. Analg., December 1, 2006; 103(6): 1453 - 1458. [Abstract] [Full Text] [PDF]
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A. W. Merrill, L. S. Barter, U. Rudolph, E. I. Eger II, J. F. Antognini, M. I. Carstens, and E. Carstens Propofol's effects on nociceptive behavior and spinal c-fos expression after intraplantar formalin injection in mice with a mutation in the gamma-aminobutyric acid-type(A) receptor beta3 subunit. Anesth. Analg., August 1, 2006; 103(2): 478 - 83, table of contents. [Abstract] [Full Text] [PDF]
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