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.
Condition or disease |
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Chronic Pain |
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).
Study Type : | Observational |
Estimated Enrollment : | 162 participants |
Observational Model: | Cohort |
Time Perspective: | Prospective |
Official Title: | Sensory Abnormalities in Post-surgical Peripheral Neuropathy: A Comparison of Subjects With and Without Severe Pain Using Normative Data |
Estimated Study Start Date : | July 1, 2019 |
Estimated Primary Completion Date : | February 1, 2020 |
Estimated Study Completion Date : | February 1, 2021 |
Group/Cohort |
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P-GHR
Patients with persistent severe pain after groin hernia repair.
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NP-GHR
Patients without pain after groin hernia repair.
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NP
Healthy non-operated controls
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Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
Sampling Method: | Non-Probability Sample |
INCLUSION CRITERIA:
All study subjects must meet all the following criteria to be eligible to enroll in the study:
In addition, for study subjects without pain after GHR (NP-GHR):
EXCLUSION CRITERIA:
Any study subject, who meets one or more of the following criteria, is not suitable for inclusion in this study:
In addition, for healthy non-operated study subjects (NP):
In addition, for study subjects without pain after GHR (NP-GHR):
Contact: Mads U Werner, MD DMSc | 28257703 ext 45 | mads.u.werner@gmail.com |
Denmark | |
Multidisciplinary Pain Center 7612, Neuroscience Center, Rigshospitalet, Blegdamsvej 9 | Recruiting |
Copenhagen O, Denmark, 2100 | |
Contact: Mads U Werner, MD DMSc +45 28257703 mads.u.werner@gmail.com | |
Principal Investigator: Elisabeth K Jensen, MB |
Tracking Information | |||||||||
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First Submitted Date | May 25, 2019 | ||||||||
First Posted Date | May 29, 2019 | ||||||||
Last Update Posted Date | June 4, 2019 | ||||||||
Estimated Study Start Date | July 1, 2019 | ||||||||
Estimated Primary Completion Date | February 1, 2020 (Final data collection date for primary outcome measure) | ||||||||
Current Primary Outcome Measures |
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Original Primary Outcome Measures | Same as current | ||||||||
Change History | |||||||||
Current Secondary Outcome Measures |
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Original Secondary Outcome Measures | Same as current | ||||||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
Descriptive Information | |||||||||
Brief Title | Sensory Abnormalities in Post-surgical Peripheral Neuropathy | ||||||||
Official Title | Sensory Abnormalities in Post-surgical Peripheral Neuropathy: A Comparison of Subjects With and Without Severe Pain Using Normative Data | ||||||||
Brief Summary |
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. |
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Detailed Description |
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). |
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Study Type | Observational | ||||||||
Study Design | Observational Model: Cohort Time Perspective: Prospective |
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Target Follow-Up Duration | Not Provided | ||||||||
Biospecimen | Not Provided | ||||||||
Sampling Method | Non-Probability Sample | ||||||||
Study Population | Study subjects with pain after GHR (P-GHR) (n=54) Study subjects without pain after GHR (NP-GHR) (n=54) Healthy non-operated study subjects (NP) (n=54) | ||||||||
Condition | Chronic Pain | ||||||||
Intervention | Not Provided | ||||||||
Study Groups/Cohorts |
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Publications * |
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||||
Recruitment Status | Unknown status | ||||||||
Estimated Enrollment |
162 | ||||||||
Original Estimated Enrollment | Same as current | ||||||||
Estimated Study Completion Date | February 1, 2021 | ||||||||
Estimated Primary Completion Date | February 1, 2020 (Final data collection date for primary outcome measure) | ||||||||
Eligibility Criteria |
INCLUSION CRITERIA: All study subjects must meet all the following criteria to be eligible to enroll in the study:
In addition, for study subjects without pain after GHR (NP-GHR):
EXCLUSION CRITERIA: Any study subject, who meets one or more of the following criteria, is not suitable for inclusion in this study:
In addition, for healthy non-operated study subjects (NP):
In addition, for study subjects without pain after GHR (NP-GHR):
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Sex/Gender |
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Ages | 18 Years to 65 Years (Adult, Older Adult) | ||||||||
Accepts Healthy Volunteers | Yes | ||||||||
Contacts | Contact information is only displayed when the study is recruiting subjects | ||||||||
Listed Location Countries | Denmark | ||||||||
Removed Location Countries | |||||||||
Administrative Information | |||||||||
NCT Number | NCT03966677 | ||||||||
Other Study ID Numbers | H-16034340 | ||||||||
Has Data Monitoring Committee | Yes | ||||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement |
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Responsible Party | mads u werner, University of Copenhagen | ||||||||
Study Sponsor | University of Copenhagen | ||||||||
Collaborators | Not Provided | ||||||||
Investigators | Not Provided | ||||||||
PRS Account | University of Copenhagen | ||||||||
Verification Date | May 2019 |