Table 3.
Primary and secondary biomarkers.
| Domain | Category | Primary biomarker | Secondary biomarkers |
|---|---|---|---|
| Patient-reported outcomes and behavior | Pain | General pain intensity Local pain intensity Widespread body pain Movement-evoked pain Pain trajectory |
Pain duration Pain impact/quality of life Pain interference |
| Psychological | Anxiety Depression Pain catastrophizing Fear of movement |
Personality traits: Neuroticism Agreeableness Conscientiousness Openness Extraversion |
|
| Other | Disability Perceived physical function Performance physical function (KA) Sleep Cognitive dysfunction Trauma history Resilience Social support |
Physical activity Multisensory sensitivity Expectation Global impression of change Fatigue Neuropathic pain symptoms Acute pain Fibromyalgia diagnostic criteria |
|
| Patient characteristics | Age Sex/gender Ethnicity/race Education Relationship status Income Disability insurance Comorbidities Opioid use Opioid likeability Opioid or other substance misuse Other treatments—pharmacologic Other treatments—nonpharmacologic Smoking Surgery and hospital stay details |
||
| Omics | Proteomics | C-reactive protein Soluble glycoprotein 130 Tumor necrosis factor-alpha Interleukin-6 Interleukin-12 |
Interferon-gamma Interleukin-17 Interleukin-1beta Heparin-binding epidermal growth factor Monocyte chemoattractant protein-1 (MCP-1/CCL2) Interleukin-4 Interleukin-5 Interleukin-10 Interleukin-13 Brain derived neurotrophic factor Nerve growth factor Leptin Adiponectin |
| Genetics | Catechol-O-methyltransferase haplotype (rs4680) Mu-opioid receptor (rs1799971) ATP-binding cassette subfamily B1 (rs1045642) Brain-derived neurotrophic factor (rs6265, rs1491850) |
Interleukin-6 (rs2069845) Interleukin-13 (rs1295686) Tumor necrosis factor-alpha (rs18800610) Serotonergic signaling pathway (rs9316233, rs4776783, rs12439516, rs2276008, rs6928, rs3813928) T-cell receptor pathway (rs10500205, rs216535, rs306083, rs3797739, rs2070995, rs3756612, rs815815, rs790250) Voltage-gated potassium channel subunit KV9.1 (rs734784) Nuclear receptor subfamily-3 group-C member 1 (rs2963155) GTP cyclohydrolase 1 (rs998259) |
|
| Extracellular RNA | miR-223-3p | ||
| Lipidomics | Palmitoylethanolamide (NAE 16:0), an endocannabinoid 2-Arachidonoylglycerol sphingomyelin (d18:1/16:0) Ceramide (d18:1/16:0) Phosphoinositol (18:0/20:4) |
||
| Metabolomics | Threonic acid Nonanoic acid Hypoxanthine, a marker for redox status, ischemia Inosine, a purine marker for adenosine metabolism Kynurenic acid, a tryptophan/serotonin metabolite |
||
| Quantitative sensory testing | Pressure pain threshold (surgical site) Temporal summation (surgical site) Conditioned pain modulation |
Pressure pain threshold (control site) Temporal summation (control site) Pressure cuff pain sensitivity Dynamic mechanical allodynia (brush-evoked pain at the surgical site) |
|
| Brain imaging | Gray matter volume of medial prefrontal cortex Structural integrity in Am-NAc-mPFC network Core default mode network (DMN) (vmPFC/CC)—somatosensory (dplNS/S1) Core DMN (vmPFC/CC)—Nac/ventral striatum Core DMN (vmPFC/CC)—Anterior/middle insula Hub disruption Evoked response (pressure cuff) in neurologic pain signature Evoked response (pressure cuff) in Frontostriatal systems related to descending/central pain modulation and self-regulation (vmPFC, NAc) |
Gray matter density Gray matter morphometry Gray matter volume hippocampus Gray matter volume of amygdala Node degree—Hippocampus, dlPFC Lateral thalamus functional connectivity with periaqueductal gray Fractional anisotropy in superior longitudinal fasciculus, internal and external capsule Local pattern responses in nociceptive regions Local pattern responses in context-related regions Response to pain offset in reward systems |
Am, amygdala; ATP, adenosine trisphosphate; CC, cingulate cortex; dlPFC, dorsolateral prefrontal cortex; dpINS, dorsoposterior insula; GTP, guanosine trisphosphate, KA, knee arthroplasty; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; S1, somatosensory cortex 1; vmPFC, ventromedial prefrontal cortex.