The concept of normality is a cornerstone in medical practice and research. As an example, in clinical chemistry, a laboratory value based on a patient plasma sample, exceeding the +/- 1.96 x standard deviation (SD) range, referenced from a normative material, is per definition outside the normal range (the reference interval). Obviously, a number of reasons for this deviation may exist. The sample value could reflect a "true" pathological condition, but could just as well also be caused by error, e.g., technical measurement error, drug-interaction error, random error, or, reflect a value occurring in 5% of the healthy population. Conversely, a sample value in the normal range evidently does not exclude a pathological condition.
The reference interval is calculated from a large number of healthy subjects sampled across age, anthropometrics, ethnicity and gender. Normative reference intervals are certainly of help particularly in the screening of subjects, but may be of limited value in the detailed assessment of pathophysiological processes. Also, increasing the number of analyses in a subject expands the risk of making a type I error (acquiring "false" positive results). The likelihood of one or more type I errors in the analysis of 10 different laboratory values in one subject, is impressive 46% ([1 - 0.95^10] =0.46). It is well-known that multiple measurements are commonly performed in medical practice and research, but corrected significance levels are not always used.
Quantitative sensory testing (QST) is defined as perceptually quantifiable responses to graded chemical (capsaicin), electrical, mechanical (pressure, punctate, vibratory, and light touch) or thermal (cool, warmth, cold pain, and heat pain) stimuli. Thus, QST is a psychophysical method primarily assessing small nerve fiber function in the skin. The method is ubiquitously used for the assessment of peripheral neuropathies, e.g., chemotherapy-induced neuropathy, painful diabetic polyneuropathy, post-herpetic neuralgia, and post-surgical neuropathy. Sensory mapping and QST are essential tools in grading definite or probable neuropathic pain as stated in the definition: "Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory test." During the last decade, the German Research Network on Neuropathic Pain (DFNS) has acquired normative sensory data from healthy individuals using a standardized testing protocol. Clearly, a deviating sensory response from a patient with a painful peripheral neuropathy could be evaluated by use of these normative data and eventually be classified as an abnormal response.
But, other alternatives exist, that hypothetically might provide an improved diagnostic specificity and sensitivity. First, in unilateral sensory deficits (mono-neuropathies), assessments at the contralateral side are possible, allowing a comparison with the pathological side. The within-subject variances (WSV) are often significantly smaller than the between-subject variances (BSV) in QST-assessments. In a normative study including thermal assessments (n = 100), the WSV and the BSV ranged between 18-23% and 77-82% of the total variance, respectively. Correspondingly, in a study of patients with the post-thoracotomy pain syndrome, the estimated WSV and BSV were 5-28% and 72-95%, respectively. Thus, scenarios using the subject as own control may reduce data variability, and improve diagnostic efficacy. However, the use of a contralateral homologous area as a control area in sensory testing has been questioned by several authors. The occurrence of mirror image sensory dysfunction (MISD) may affect contralateral assessments, requiring a neutral control area in the subject. Second, instead of using healthy controls in pain studies, use of pain-free patients (e.g. post-groin hernia repair, post-thoracotomy) as controls have been recommended in persistent post-surgical pain studies.
In spite of the importance of selecting an optimally controlled research design, the research group is only aware of one QST-study, adressing the control-group problem, i.e., a study including patients with complex regional pain syndrome type I (CRPS I) restricted to one extremity. The study examined the validity of using the contralateral side as control compared to using normative data from healthy individuals. The study recommended that the contralateral side in CPRS I patients should be used as a control.
Thus it may be inferred, that following approaches are available evaluating sensory data from an anticipated pathological site: an empirical approach (á priori set reference values); an absolute approach (comparing the subject's pathological side with normative data); and a relative approach (comparing the subject's side-to-side differences with normative data).
| Condition | Chronic Pain |
|---|---|
| Clinical Study Identifier | NCT03966677 |
| Sponsor | University of Copenhagen |
| Last Modified on | 18 September 2023 |
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