Table 1.
Selected Characteristics of Reviewed Studies on the Metabolomics of Chronic Pain Conditions (N = 19).
| Authors (Year) | Pain Type | Purpose | Tissue | Sample | Metabolomic Approach | Main Findings | Pain Assessment |
|---|---|---|---|---|---|---|---|
| Adams et al. (2012) | OA | To use global metabolic profiling to identify a distinct metabolic profile for cultured human synovial tissue from patients with end-stage OA compared to patients with little or no evidence of disease | Synovial tissue | 11 patients with late OA, 11 with little or no evidence of OA | UHLC/MS/MS, UHLC/MS/MS, & GC/MS | 105 compounds detected across all samples, with11 differing significantly between late-OA and no-OA groups. Levels of seven metabolites (pro-hydroxyproline, acetylcarnitine, myo-inositol, N-acetylornithine, succinate, glutamine, and urea) where higher and levels of 4 (gamma-glutamylleucine, 4-methyl-2-oxopentanonoate, 5-oxoproline, and phenylacetylglycine) were lower in late-OA compared with the no-OA group. | None |
| Caboni et al. (2014) | FM | To investigate the metabolic profile of patients with FM. Focused on plasma lipidome | Blood | 22 females with FM, 21 healthy controls | LC-Q-TOF/MS, GC/MS | 7 molecules (PC[14:0/0:0], PC[16:0/0:0], 1-[9E-hexadecenoyl]-sn-glycero-3-phosphocholine, 1-heptadecanoyl-sn-glycero-3-phosphocholine, 1-[9Z-octadecenoyl]-sn-glycero-3-phosphocholine, 1-[2E,4E-octadecadienoyl]-sn-glycero-3-phosphocholine, and 1-[4Z,7Z,10Z,13Z, 16Z,19Z-docosahexaenoyl]-sn-glycero-3-phosphocholine) showed significant loading differences between FM and control groups. Docking analysis revealed that lysophosphatidylcholine and platelet-activating factor-like factors may play a role on FMs | None |
| Mickiewicz et al. (2015) | OA | To use an integrated metabolomics approach to describe a broader and more detailed metabolic pattern for potential use in early OA diagnosis | Knee synovial fluid | 55 patients with OA, synovial fluid from 13 normal cadaveric knee joints | 1H NMR, GC/MS | 11 metabolites distinguished OA samples from controls. Two metabolites (fructose and citrate) were increased, and 9 metabolites (malate, methionine, O-acetylcarnitine, N-phenylacetylglycine, ethanol, creatine, ethanolamine, 3-hydroxybutyrate and hexanoylcarnitine) were decreased in OA samples compared to controls. | None |
| De Jong et al. (2016) | OA | To characterize the immune cells present in synovium from the knee of OA patients and their association with pain | Synovial tissue | 40 patients with OA of the knee undergoing total knee-replacement surgery | LC/MS | Fatty acids released by joint adipocytes enhanced the release of CD4+ T cells, which were abundant in synovial tissue and associated with VAS pain in patients with end-stage knee OA. CD4+ T cells also correlated with BMI. | VAS |
| Finco et al. (2016) | NP/ NC | To assess whether urinary metabolomic profiles can differentiate between neuropathic and nociceptive pain, as diagnosed using current clinical protocols | Urine | 12 patients with NC, 25 patients with NP, and 37 healthy controls | 1H NMR | Results showed an upregulation of phosphocholine and sphingomyelin associated with NP. Also, the urine of patients with NP had higher levels of choline and phosphocholine, citrate, alanine and taurine when compared with those with NC. | None |
| Parker et al. (2016) | IC, BPS, CP, CPPS | To discover urinary biomarkers in females with IC/BPS who underwent extensive urologic and non-urologic phenotyping in the MAPP Research Network’s central clinical protocol, the Trans-MAPP Epidemiology, and Phenotyping Study | Urine | 40 female patients with IC/BPS, 40 age-matched healthy female controls | LC/MS | Six biomarkers were capable of discriminating between patients with IC/BPS and controls, including Etio-S, a sulfoconjugated 5-β-reduced isomer of testosterone. Etio-S was highly associated with IC/BPS, predicting IC/PBS with a specificity of 87.4% and sensitivity of 91.2% (p < 0.0001). | GPI, BPI |
| Smolenska et al. (2016) | RA | To explore differences in levels of amino acids and nicotinamide metabolites between patients with RA and controls and examine the effects of age, disease activity and duration, and treatment affect these levels. | Blood | 46 adults with RA, 19 healthy controls | LC/MS | Plasma concentrations of six metabolites (arginine, aspartic acid, glutamic acid, serine, phenylalanine, and threonine) were higher and of one (lysine) was lower in RA patients. VAS score was positively correlated with levels of four metabolites (alanine, arginine, proline, and serine) and negatively correlated with two (glutamic acid and histidine). | VAS |
| Zielman et al. (2016) | Mig | To identify differences in biochemical characteristics of different subtypes of Mig (i.e., Mig with aura, Mig without aura, and hemiplegic Mig) | CSF | 91 patients with Mig (19hemiplegic, 39 with aura, and 33 without aura), 45 healthy controls | 1H NMR | 2 metabolites, 2-hydroxybutyrate and 2-hydroxyisovalerate, discriminated between patients with hemiplegic Mig and healthy controls. | None |
| Malatji et al. (2017) | FM | To identify biomarkers for objective diagnosis of FM | Urine | 18 women with FM, 41controls (11 1st-degree relative of subjects, 10 unrelated and age matched, 20 randomly selected, young, healthy subjects) | 1H NMR | Of the 21 endogenous and exogenous metabolites identified and quantified, taurine, TMAO, and succinic acid were significantly increased in patients with FM compared with controls. | FIQR |
| Mantyselka et al. (2017) | MSP | To examine whether ornithine levels differ among subjects with persistent musculoskeletal pain compared with other subjects in the population. | Blood | 76 patients with PP, 221 with NPP, and 61 no-pain controls | UHLC, LC/MS | Ornithine levels were significantly elevated in men and women with PP compared to those with NPP and no-pain controls. The concentration of ornithine was highest in women with PP. Differences in citrulline levels trended toward significance in women, with higher levels in those with PP compared to no-pain controls and those with NPP (lowest levels). | None |
| Shin et al. (2017) | Mig | To identify metabolites that could be used as potential biomarkers for the diagnosis of Mig | Serum | 11 patients with Mig and 9 controls | NMR | Compared with controls, patients with Mig had significantly lower levels of 2-hydroxybutyrate, phenylalanine, isocitrate and citrate were significantly lower, and significantly higher levels of lactate and valine. These 5 metabolites may have diagnostic power for Mig. Model validation demonstrated good diagnostic accuracy with an area under the receiver operating characteristic (ROC) curve of 94.1%. | None |
| Xu et al. (2017) | OA | To explore potential mechanisms of osteophyte formation by detecting metabolic variations between extracts of osteophyte cartilage tissues and uninvolved control cartilage tissues | Cartilage | Cartilage from osteophytes in 32 patients with OA and cartilage from lateral posterior femoral condyle in 34 controls without OA | UHLC-MS/MS | 28 endogenous metabolite variations including amino acids (phenylalanine, proline, arginine, and leucine), sulfonic acids (taurine and hypotaurine) glycerophospholipids (phosphatidyl choline and phosphatidyl ethanolamine), and fatty acids (vaccenyl carnitine and muconic acid) differentiated patients in the osteophyte group from those in the control group. Among these metabolites, 25 were elevated and 3 were decreased in the osteophyte group. Pathway analysis revealed that phenylalanine, proline, arginine, taurine, and hypotaurine metabolism were associated with osteophyte formation. | None |
| Livshits et al. (2018) | MSP | To use omics approaches to identify molecular genetic factors underlying the heritability of frailty and its genetic correlation with CWP | Blood | 3626 female twins | Multi-omics | Genomic regions involved in neurological pathways were associated with frailty and its covariation with CWP. After correction for multiple testing, FI score was associated with 51 metabolites, including amino acids (glutamate, proline, and N-acetyl glycine), carbohydrates (mannose), and lipids (glycerol, 2-linoleoylglycero-phosphocholine, and epiandrosterone sulphate). Also, levels of epiandrosterone sulphate and uridine were significantly associated with CWP. | None |
| Trbojevic-Akmacic et al. (2018) | CLBP | To identify changes in total plasma N-glycosylation pattern connected with CLBP to provide potential insight into the pathogenic mechanisms of the disease | Blood | 1128 patients with CLBP, 760 healthy controls | HILIC/UHLC | Changes in plasma N-glycome level in patients with CLBP compared to controls were consistent with changes observed in N-linked glycosylation, which are usually in chronic inflammation. Among patients with CLBP, chromatographic peaks corresponding to high-branching glycans increased and those corresponding to low-branching glycans decreased compared with controls. | None |
| Hackshaw et al. (2019) | FM | To develop simple, rapid, sensitive, robust methods for diagnosis of FM based on highly characteristic mid-IR and Raman “fingerprint” from peripheral blood samples combined with supervised pattern recognition techniques |
Blood | 30 patients with FM, 20 patients with RA, 23 patients with SLE, 19 patients with OA | Vibrational (IR and Raman) spectroscopy, UHLC | FT-IR spectral data dominated by strong vibration modes for water, glucose, polysaccharides, lipids and proteins correlated with pain intensity in FM (log-transformed FIQR scores), while the Raman spectral data dominated by vibration modes for aromatic amino acids, glycans, collagens and minerals correlated with disease severity in FM (log-transformed FIQR scores). Findings show that vibrational spectroscopy can distinguish among FM, RA, and SLE. UHLC findings distinguished FM from RA and SLE, however, known compounds or fragments were not identified. | MPI |
| Malatji et al. (2019) | FM | To perform an exploratory metabolomics study to (1) elucidate the global urinary metabolite profile of patients with FM, and (2) explore the potential of metabolite biomarkers for diagnosis of FM | Urine | 18 women with FMS, 42 controls (11 1st-degree relatives of subjects, 10 unrelated, age-matched women, 20 randomly selected, young, healthy controls) | 1H NMR | Levels of 14 metabolites (sorbose, phosphoric acid, glutaric acid, threonic acid, tagatose, oxalic acid, erythropentonic acid, rhamnose, arabinose, 4-BHA, 2,3,4-trihydroxybutyl-L, 2-keto-1-gluconic acid, 2-D-3,5-DHPL, and 3-D-ribohexonic acid) were significantly increased in the urine of patients with FM compared with controls. | FIQ, IHCQ |
| Menzies et al. (2020) | FM | To identify differences in levels of plasma metabolites between women with and without FM | Blood | 20 women with FM, 20 age-matched healthy controls | LC/MS | 1,462 known metabolites and unknown spectral features differed significantly between groups. PCA of the known metabolites revealed 71 significant metabolites with FC > 2 (n = 48) or FC < 0.5 (n = 23). Significant metabolites are involved in energy, lipid, and amino acid metabolism. | None |
| Onderwater et al. (2019) | Mig | To identify a plasma metabolomic signature for Mig | Blood | 2800 patients with Mig, 7353 healthy controls | 1H NMR | Levels of apoA1 and the ratio of free cholesterol to HDL were decreased in Mig patients compared with controls. Overall, apoA1 levels were lower in males than females, and global analysis showed a general decrease in HDL-associated metabolites in females with Mig compared with males with Mig. Males with Mig had decreased levels of omega-3 fatty acids, compared with male controls. | None |
Note. 1H NMR = proton nuclear magnetic resonance; apoA1 = apolipoprotein A1; BMI = body mass index; BPI = Brief Pain Inventory; BPS = bladder pain syndrome; CLBP = chronic low-back pain; CP = chronic prostatitis; CPPS = chronic pelvic pain syndrome; CSF = cerebrospinal fluid; CWP = chronic widespread pain; Etio-S = etiocholan3α-ol-17-one sulfate; FC = fold-change; FI = Frailty Index; FIQR = Fibromyalgia Impact Questionnaire; FT-IR = Fourier transform infrared; FM = fibromyalgia; GC = gas chromatography; GPI = Genitourinary Pain Index; HDL = high-density lipoprotein cholesterol; HILIC = hydrophilic interaction liquid chromatography; IC = interstitial cystitis; IHCQ = in-house clinical questionnaire; IR = infrared vibrational spectroscopy; LC = liquid chromatography; MAPP = Multidisciplinary Approach to the Study of Chronic Pelvic Pain; Mig = migraine; MPI = McGill Pain Index; MS = mass spectrometry; MSP = musculoskeletal pain; NC = nociceptive pain; NMR = nuclear magnetic resonance; NP = neuropathic pain; NPP/PP = nonpersistent pain/persistent pain; OA = osteoarthritis; PCA = principal component analysis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TMAO = trimethylamine N-oxide; TOF-MS = time-of-flight mass spectrometry; UHLC = ultrahigh liquid chromatography; VAS = visual analog scale.