This Editorial View accompanies the following article: Granot M, Lowenstein L, Yarnitsky D, Tamir A, Zimmer EZ: Postcesarean section pain prediction by preoperative experimental pain assessment. Anesthesiology 2003; 98:1422–6.

SOME individuals seem to be highly sensitive to pain, whereas others seem to be surprisingly insensitive. A quantitative characterization of an individual's basal pain sensitivity holds the potential to be of significant clinical utility if it could help predict the magnitude of pain that a clinical procedure would evoke in that individual. The current issue of Anesthesiology includes an article describing a reasonably strong correlation between a simple preoperative assessment of pain to an experimental stimulus and the amount of pain experienced after a standardized surgery (cesarean section). 1The purpose of this editorial is to discuss the validity of these preoperative measures and the implications of the authors’ observations to further clinical research and, ultimately, clinical practice.

Measurement of Individual Differences in Pain Sensitivity

Historically, pain sensitivity has been defined as the difference between threshold and tolerance, 2but this definition is problematic. 3Thresholds are generally insensitive to analgesic manipulations and are subject to significant response biases, whereas tolerance is highly dependent on the motivation of the subject. 3Magnitude estimates of a single, fixed, supra-threshold stimulus provide a simple, yet straightforward way to characterize pain sensitivity. 4However, the use of supra-threshold responses as a measure of pain sensitivity has been limited because of inadequate methods of psychophysically assessing the subjective magnitude of pain and the lack of devices capable of delivering supra-threshold noxious stimuli in a well-controlled fashion. Moreover, the interpretation of interindividual differences in magnitude estimates is hampered by questions about differences in the manner in which each individual reports his or her experience or uses the rating scales. 5Thus, the potential to characterize and subsequently use information about a patient's pain sensitivity to guide treatment decisions has long remained unrealized.

Several factors, however, have currently opened the door for fundamental studies examining the relationship between a patient's basal pain sensitivity and the pain he or she experiences after a clinical manipulation. First, magnitude estimation techniques for assessing pain intensity and pain unpleasantness have slowly but steadily matured over the past 25 years. 6Visual analog scales, in particular, have been heavily validated and have been shown to produce reproducible, internally consistent, ratio-scale measures of both pain intensity and pain unpleasantness. 6–9Second, computerized, feedback control thermal stimulators are now commercially available, and some have been approved by the Food and Drug Administration for human use.

Brain imaging studies provide strong evidence that subjective ratings of pain magnitude are closely related to objectively measured neural activity in a number of cerebral cortical and subcortical regions involved in the processing of pain. In within-individual  studies using either positron emission tomography or functional magnetic resonance imaging, brain regions such as the thalamus, primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex, prefrontal cortex, and insular cortex have been shown to exhibit increasing activation as subjective ratings of pain increase across different intensities of stimulation. 10–12More important, emerging functional magnetic resonance imaging studies indicate that interindividual  differences in subjective reports of pain magnitude are closely related to the degree of activation in several brain regions important in the processing of pain. 4Using a visual analog scale, individuals who rate a fixed noxious thermal stimulus as very painful activate the primary somatosensory cortex, anterior cingulate cortex, and prefrontal cortex more frequently and more significantly than those who report that the same stimulus is only mildly painful. Taken together, these objective correlates of the subjective experience confirm that interindividual differences in subjective pain magnitude ratings do indeed reflect interindividual differences in the pain experience.

The current investigation by Granot et al.  is on the vanguard of studies examining the clinical implications of interindividual differences in pain sensitivity. 1In a preoperative session, they assessed both thermal pain thresholds and supra-threshold visual analog scale responses to a fixed set of noxious thermal stimuli in women who were scheduled to undergo elective cesarian section. Postoperative visual analog scale ratings of both resting pain and pain evoked by standing or sitting were significantly correlated with preoperative pain evoked by a supra-threshold 48°C heat stimulus. In contrast, no statistically reliable relationship was detected between preoperative pain thresholds and postoperative pain, consistent with earlier notions that thresholds are of limited utility in defining pain sensitivity. 3 

In identifying this statistically reliable relationship between a preoperative, controlled noxious stimulus and postoperative pain, Granot et al.  have provided a key piece of evidence that basal pain sensitivity can be related to postoperative pain. It is important to note that this study lacked controls to assess interindividual differences in scale use. Thus, there is a possibility that some individuals would make consistently high ratings or consistently low ratings of any stimulus, and that a nontrivial percentage of the observed relationship between experimental and clinical pain might be attributable to this factor rather than to differences in basal pain sensitivity. However, our own findings examining the neural correlates of interindividual differences in the subjective experience of pain would argue strongly against such an interpretation. 4Nevertheless, follow-up studies should include magnitude ratings of visual, auditory, or other nonpainful stimuli to explicitly assess this potential confound.

Clinical Implications of Differences in Pain Sensitivity

Differences in pain report to a supra-threshold stimulus are real, are large, reflect differences in brain activation rather than differences in stoicism, and, as noted by Granot et al. , correlate with pain after surgery. 1There remains much left to learn regarding the truth of the above clauses and their implications to clinical research and practice. Why does report to a supra-threshold stimulus, but not the threshold itself, correlate with postoperative pain? Do doses of analgesics or other manipulations that diminish report to supra-threshold stimuli in the normal individual predict doses and efficacy in patients after surgery? Are studies in animals that typically rely on measurement of threshold responses to test analgesics after surgery fundamentally flawed in their ability to predict efficacy in the clinic? These are a few of the obvious questions to be addressed.

More important from a practical standpoint is whether the correlation between report to experimental pain and the subsequent postoperative pain experience equates to an equally impressive correlation with analgesic drug use. Clearly, the many factors that determine individual differences in pain sensitivity may not overlap with those that determine individual differences in sensitivity to the therapeutic and side effects of analgesics. We need several, preferably large, follow-up studies to the current report to determine whether results of preoperative testing can predict analgesic drug consumption postoperatively.

Should there be a strong predictive value in preoperative pain testing and postoperative use of analgesics, several additional questions should be examined. Patient-controlled anesthesia is said to be easily titrated by the patient to effective analgesia, yet small changes in the dose available with each button press results in the inability to achieve analgesia (small incremental dose) or to avoid heavy sedation and respiratory depression. 13Knowing in advance the rough range of analgesic dose required for treatment of postoperative pain could allow more effective analgesia with patient-controlled anesthesia by personalizing the prescription for dose and perhaps lock out interval. An even bigger improvement in analgesia might be obtained with less frequently titrated methods of providing postoperative analgesia, such as intermittent injections or oral medications.

In summary, Granot et al.  highlight the real possibility that simple preoperative tests can predict individual differences in pain experience after surgery. The time is ripe for exploiting this observation: we have the tools to quantify individual differences in pain sensitivity with ease, and emerging literature suggests that there are cortical substrates responsible for these differences. Perhaps we are at the beginning of a move toward routine preoperative pain assessment, just as 15 years ago we were at the beginning of a move away from routine preoperative chest radiographs and electrocardiograms.

Granot M, Lowenstein L, Yarnitsky D, Tamir A, Zimmer EZ: Post-cesarean pain prediction by preoperative experimental pain assessment. A nesthesiology 2003; 99: 1422–6
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