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 Table of Contents  
Year : 2020  |  Volume : 34  |  Issue : 1  |  Page : 1-2

The dawn of a new era on research on precision medicine for pain and the scope of diagnostic biomarkers: Is it a “neurologic pain signature” and is it construct validation??

Department of Anaesthesiology and Pain Medicine, University College of Medical Sciences and GTB Hospital, University of Delhi, Delhi, India

Date of Web Publication16-Apr-2020

Correspondence Address:
Dr. Ashok Kumar Saxena
Flat No. 703, Parivar Apartments, I.P. Extension, Patparganj, Delhi - 110 092
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpn.ijpn_31_20

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How to cite this article:
Saxena AK, Malik A. The dawn of a new era on research on precision medicine for pain and the scope of diagnostic biomarkers: Is it a “neurologic pain signature” and is it construct validation??. Indian J Pain 2020;34:1-2

How to cite this URL:
Saxena AK, Malik A. The dawn of a new era on research on precision medicine for pain and the scope of diagnostic biomarkers: Is it a “neurologic pain signature” and is it construct validation??. Indian J Pain [serial online] 2020 [cited 2021 May 17];34:1-2. Available from: https://www.indianjpain.org/text.asp?2020/34/1/1/282547

As India celebrates another “National Science Day” on February 28, 2020, marking the discovery of the “Raman effect” by the great Indian physicist C. V. Raman, the first Asian to ever win the Noble Prize for achievements in science (won for physics in 1930); pain assessment and evaluation are still embarking on a journey of conundrum through various enigmatic pathways. That is why, “Biomarkers in Pain” shall always be in a great demand, simply because “Pain” is a “subjective” phenomenon, with objective roots, and it indicates perceived or actual damage to the organism.

Biomarkers are coming up as significant entities in conditions, where self-reporting of the patient and/or clinical judgment of the clinician are not reliable. In pain, the whole new process of exploration of a reliable blood biomarker is mainly because one cannot do a direct biopsy of the spinal tracts of pain transmission or that of brain somatosensory cortices of pain perception. Today, there are, at the most, around 15,000 biomarkers available globally for the identification of various diseases. Of these 15,000, the developing nations, like India, have around 110 indigenous biomarker kits, and for the rest of the biomarker estimation, the relevant kits have to be imported.

In the opinion of Niculescu et al., blood biomarkers constitute a kind of liquid biopsy.[1] MFAP3 gene expression had the great empirical evidence and was a strong predictor for pain in the independent cohorts, especially for pain in females and males with posttraumatic stress disorder.[1] Niculescu et al. also observed few additional biomarkers with the best overall convergent functional evidence for the prediction of pain, and these include G-protein subunit gamma 7 (GNG7), contactin 1 (CNTN1), lymphocyte antigen 9 (LY9), coiled-coil domain containing 144b (CCDC 144b), and guanylate binding protein 1 (GBP1).[1]

It is interesting to know that GNG7, with roles in signal pain transduction, is reduced in expression in high pain states, or in other words, it is a pain suppressor gene. Niculescu et al. observed that GNG7 is a strong predictor in the independent cohorts, especially for the future emergency department visits for pain.[1] Hur et al. noted its involvement in human diabetic neuropathy, while Gruber et al. observed its involvement in degenerating human annulus at the intervertebral disc.[2],[3] Interestingly, recently, Olausson et al. noted that the CNTN1, with contribution in the adhesion of neuronal cell, is reduced in expression in the cerebrospinal fluid (CSF) in women with chronic widespread pain.[4] In addition, Parisienet al. observed that CCDC 144B is reduced in expression in the blood in high pain states.[5] Moreover, Cao-Leiet al. noted that LY9 is elevated in expression in the blood in high pain states and also on exposure to stress.[6] In addition, GBP1 with interferon-induced signaling roles is elevated in expression in the blood in high pain states.[5],[7]

Goel et al. in this issue presented findings from a cross-sectional, observational, hospital-based study to observe frequency, patterns, and response to treatment related to various biomarkers (biological and psycho-social) in patients of chronic nonspecific pain syndrome (CNPS).[8] The authors enrolled a total of 129 patients of CNPS over 3 months and nine patients were lost to follow-up. Measurements of serum ferritin, Vitamin B12, and Vitamin D levels were done in all patients. The authors concluded that patients with absolute deficiency of ferritin had good outcome at 3 months and patients with high level of somatization on sensitization had significantly lower rate of treatment response at 3 months.[8]

As authors should do when presenting the results using longitudinal observational study, Goel et al. should have pointed out that it is not possible to draw causal conclusions from their findings.[8] This inclination toward causal language is very common in many, if not most correlation studies. It is essential for readers to constantly guard themselves against drawing causal conclusions from the findings of these studies, despite what the authors may at times imply.[8] Further, conventionally, biomarkers are from blood or CSF, or body tissues; however, psycho-social indices are usually not taken as biomarkers. Interestingly, in a well-designed randomized, double-blind, controlled study by Saxena et al., an important biomarker so-called serum brain-derived neurotrophic factor (BDNF) was found to be significantly decreased in patients of thoracic postherpetic neuralgia (PHN) before any kind of therapy and when compared with healthy volunteers.[9] Subsequently, in this study by Saxena et al., following an integrated multimodal approach using pregabalin therapy and pulsed radiofrequency (PRF) of intercostal nerves, there was a significant increase in the levels of serum BDNF in the PRF plus pregabalin group when compared to pregabalin therapy only group, at the end of 4th week of follow-up.[9] The rise in the serum BDNF levels plateaued after the 4th week in both the groups. These modulations in the BDNF levels indicate that the neuroprotective and compensatory process mediated by BDNF is mitigated in PHN patients before therapy. The rise in the BDNF levels posttreatment with pregabalin and PRF treatment may indicate decrease in PHN-mediated nerve injury and neuroplasticity.[9] However, even in this study, there were great many limitations such as small sample size of patients (only 60 patients), single-center data, and a follow-up of 3–4 months.

Like most of the other observational studies exploring the response treatment as related to various biomarkers, Goel et al. confirmed the importance of biofeedback or CBT in patients with high sensitization/somatization index.[8] Moreover, their finding that patients with high level of somatization or sensitization index had significantly lower rate of treatment response at 3 months is an important one. Further, one should also be vigilant when interpreting the results of such longitudinal, observational studies, to not necessarily rule out a factor that could potentially be important to helping out a patient improve. The outcomes are best identified by experiments that systemically alter or modify the variable in question and then determine or analyze the subsequent effect of a change in the variable on measures of important outcomes, such as patterns and response to treatment as in the present study.[8]

In the psychology of pain, “construct validity” is an important component to the perceived overall validity of the test. In fact, “construct validity” is the degree to which a test measures what it claims or purports to be measuring. In fact, the best construct is the one around which we can build the largest number of conclusions, in the most direct fashion. Last but not the least, the root cause for the observed effects may be due to confounding variables or covariates that have not been considered or measured. Like “unto this last” by John Ruskin, last does not just mean final (dictionary means to remain fresh and endure). Some ideas and ideals last forever. However, it is for certain and it is for sure that biomarkers in pain medicine shall open the door for personalized pain management and precision medicine for pain with objective diagnostics, novel targeted therapy, nutraceuticals, and personalized interventional pain management strategies.

  References Top

Niculescu AB, Le-Niculescu H, Levey DF, Roseberry K, Soe KC, Rogers J, et al. Towards precision medicine for pain: Diagnostic biomarkers and repurposed drugs. Mol Psychiatry 2019;24:501-22.  Back to cited text no. 1
Hur J, Sullivan KA, Pande M, Hong Y, Sima AA, Jagadish HV, et al. The identification of gene expression profiles associated with progression of human diabetic neuropathy. Brain 2011;134:3222-35.  Back to cited text no. 2
Gruber HE, Hoelscher GL, Ingram JA, Hanley EN Jr. Genome-wide analysis of pain-, nerve- and neurotrophin-related gene expression in the degenerating human annulus. Mol Pain 2012;8:63.  Back to cited text no. 3
Olausson P, Ghafouri B, Bäckryd E, Gerdle B. Clear differences in cerebrospinal fluid proteome between women with chronic widespread pain and healthy women - A multivariate explorative cross-sectional study. J Pain Res 2017;10:575-90.  Back to cited text no. 4
Parisien M, Khoury S, Chabot-Doré AJ, Sotocinal SG, Slade GD, Smith SB, et al. Effect of human genetic variability on gene expression in dorsal root ganglia and association with pain phenotypes. Cell Rep 2017;19:1940-52.  Back to cited text no. 5
Cao-Lei L, Massart R, Suderman MJ, Machnes Z, Elgbeili G, Laplante DP, et al. DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm. PLoS One 2014;9:e107653.  Back to cited text no. 6
Smith SB, Maixner DW, Fillingim RB, Slade G, Gracely RH, Ambrose K, et al. Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia. Arthritis Rheum 2012;64:584-93.  Back to cited text no. 7
Goel D, Garg S, Srivastav M, Gupta S, Kaur A. Biomarkers of chronic nonspecific pain syndrome: A cross-sectional hospital-based pilot study. Ind J Pain 2020;34:15-21.  Back to cited text no. 8
Saxena AK, Lakshman K, Sharma T, Gupta N, Banerjee BD, Singal A. Modulation of serum BDNF levels in postherpetic neuralgia following pulsed radiofrequency of intercostal nerve and pregabalin. Pain Manag 2016;6:217-27.  Back to cited text no. 9


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