Chronic pain affects 25% to 37% of children and adolescents,39,51 30% of whom have co-occurring obesity.50 These comorbid diseases are associated with impaired health-related quality of life, such that, across physical, emotional, social, and school domains, the impairment is greater than either disease alone.21 As one example, the likelihood of experiencing impaired physical functioning is at least 2 times greater for youth with chronic pain and obesity compared with chronic pain alone, and at least 6 times greater than youth with obesity alone.21 Furthermore, although youth with chronic pain and healthy weight show significant improvement in functional disability associated with multidisciplinary pain management, chronic pain with obesity is associated with treatment failure, such that these patients do not improve over time.52 Obesity is a risk factor for some of the most debilitating pain conditions including osteoarthritis,18,19,55 migraine and chronic daily headaches,2,42 fibromyalgia,38 and musculoskeletal pain.56 Although less evidence exists, pediatric obesity has been identified as a risk factor for these conditions.10,43,58 Although mechanisms for this interaction of co-occurring chronic pain and obesity are complex and multifactorial, inflammation is currently viewed as a key link in the causal pathway.5,44 Specifically, pain- and obesity-driven elevations in inflammatory cytokines exert their effects through multiple peripheral and central pathways. As 2 primary examples, inflammatory cytokines modulate nociception and can trigger structural and biochemical changes, ultimately contributing to joint deterioration.5,12,15,28,36,37,44,46
Soluble urokinase plasminogen activator receptor (suPAR) has been proposed as a useful biomarker for chronic inflammation.1,22 Soluble uPAR is a protein that is cleaved and released from membrane-bound uPAR, which is expressed on cells of the immune system.24 Variations in serum suPAR have been associated with cancer, cardiovascular disease, type 2 diabetes, and mortality.14,17,24,32,33,41,47
Overweight and obesity, both of which have also been associated with inflammation, may have increased serum suPAR.26,32,33,45,54 We are aware of 2 studies evaluating suPAR in children with obesity that showed conflicting results.4,29 We are not aware of systematic studies of the independent effect of chronic pain on suPAR dynamics. Because, as described above, there are significant interactions between obesity and chronic pain in children, the purpose of this study was to perform a preliminary, exploratory study of suPAR in serum samples from a group of male and female adolescents without or with chronic pain and/or obesity that are a subset of a larger, ongoing study.
Adolescents (13–17 years, n = 146) were recruited for a larger trial focused on endogenous pain control. This project was approved by the Children's Wisconsin Institutional Review Board and written consent provided by participants and parents. Recruitment of 4 groups was based on presence/absence of chronic pain and presence/absence of obesity: (1) Healthy Controls (normal weight and no pain); (2) Obese (no pain); (3) Chronic Pain with Healthy Weight; and (4) Chronic Pain and Obesity. The 2 groups with chronic pain were recruited from a multidisciplinary pain clinic at Children's Wisconsin (formerly called Children's Hospital of Wisconsin). The 2 groups without chronic pain were recruited from an outpatient clinic within the Children's Wisconsin system and located in the same community.
2.1. Inclusion/exclusion criteria
Almost all criteria were extracted from information associated with the medical appointment visit in the electronic medical record before approaching participants. With the exception of diagnoses, self-reported information was confirmed with the medical provider and family before consent discussion. Medical providers inquired directly about the use of medicinal marijuana/cannabidiol and use of illicit street drugs.
2.2. Inclusion criteria
Thirteen to 17 years old, English speaking, and, if taking psychotropic or long-acting analgesics, doses had to be stable (defined as ≥ 1 week of medication use). Inclusion in the groups without obesity required a BMI of fifth to <85th percentile, based on age and sex.30 Inclusion in the groups with obesity required a BMI ≥95th percentile, based on age and sex.30 Subjects for the 2 nonpain groups answered screening questions before a consent discussion: (1) “Do you have any chronic illness?” Subjects who responded “yes” were excluded; (2) “Over the past 3 months, have you had pain?” Response options included “not at all,” “rarely,” “sometimes,” “frequently,” and “all the time.” Subjects who responded “sometimes,” “frequently,” or “all the time” were excluded. Self-reported days with pain (PFSD1) and usual pain intensity (PFSD2) over the past 2 weeks were used to evaluate potential between-group differences in pain characteristics.48
2.3. Exclusion criteria
Type 1 or Type 2 diabetes mellitus and/or metabolic syndrome, documented hypertension, cancer-related pain, sickle cell disease, and inflammatory conditions (eg, rheumatoid arthritis, fibromyalgia, irritable bowel syndrome, celiac disease, Crohn disease, ulcerative colitis, and lupus), or the use of metformin, Accutane, corticosteroids, asthma inhalers (daily use within the past 2 weeks or ≥12 times in the past month or use within 12 hours of blood draw), medicinal marijuana/cannabidiol, immune-modulating medications, or self-reported use of illicit “street drugs.”
A total of 179 subjects were consented, with 33 lost to follow-up, resulting in 146 subjects who completed the study. A total of 339 were excluded for the following reasons: Weight status (43.1%, with all but 3 of these adolescents having an overweight status), excluded medications (18.0%), chronic pain in the no pain groups (11.2%), a subset with medical complications, untreated mental health concerns, or other reasons (10.6%), excluded pain/medical condition (10.0%), physically unable to participate in the larger trial (6.2%), or other drug use (0.9%). Seven adolescents declined to hear about the study (8.3%), and 77 declined participation after being approached. Most of these declinations were due to the blood draw required (35.1%), followed by disinterest in research, distance to travel or other reasons (33.8%), with a subset of passive declines (31.1%).
2.4. Serum soluble urokinase plasminogen activator receptor assay
Blood (12 mL) was drawn from an arm vein into serum separating tubes, allowed to clot at room temperature for 30 to 60 minutes, and centrifuged (4°C) for 15 minutes at 1000 g and serum frozen at −80°C until analysis. Serum suPAR was measured by enzyme immunoassay from R&D Systems (DUP00; Minneapolis, MN) as described previously.54 The samples were diluted 5-fold before assay and assayed in duplicate. The sensitivity of the assay without dilution of the serum is <33 pg/mL, which translates to <0.2 ng/mL with the 5-fold dilution of serum. The intraassay and interassay precisions are 2% to 8%.
2.5. Statistical analysis
Data were analyzed using nonparametric Kruskal–Wallis one-way analysis of variance, exact Mann–Whitney tests for pairwise comparisons, and Fisher–Freeman–Halton exact test (SPSS v26, IBM Corporation, Somers, NY, and Cytel StatXact v8, Cambridge, MA). Cohen's d was calculated to estimate effect size, based on the Kruskal–Wallis H31(with d = 0.20, 0.50, or 0.80 interpreted as a small, medium, or large effect size, respectively).7 No adjustments were made for multiple comparisons. P < 0.05 was considered significant; unadjusted values are given. Data are presented as mean (SD) or median (25%-75%).
Table 1 shows the demographic and anthropometric data for the 4 groups of subjects. There was no significant difference in the ages (P > 0.39) or sex (P > 0.29) between the 4 groups. There was a significant difference in the racial distribution of the groups with significantly more African Americans and Native Americans in the Chronic Pain & Obese group compared to Healthy Controls and Obese Alone groups (P < 0.009). As expected, BMI was significantly greater in the Obese and Chronic Pain & Obese Groups compared to the Healthy Controls and Chronic Pain/Healthy Weight groups, but there was no difference within the nonobese groups and within the obese groups. Self-reported days with pain and worst pain intensity over the past 2 weeks (PFSD1 and PFSD2, respectively) were significantly greater in the Chronic Pain/Healthy Weight and Chronic Pain & Obese groups compared to the Healthy Controls and Obese Alone groups, but not different within the no chronic pain groups or within the chronic pain groups. Pain location was condensed to best represent between group differences. The majority of participants in both chronic pain groups presented with headache/migraine pain, followed by extremity pain (Chronic Pain group) and abdominal pain. “Other” pain conditions were condensed into a single category (included back pain and joint pain).
Serum suPAR (Fig. 1) concentration was in the expected range in the Healthy Control group.4,29 Serum suPAR was not related to either chronic pain alone or obesity alone. However, there was a significant, classic interaction between pain and obesity on suPAR (P = 0.046) reflected in a significant increase in serum suPAR in the Chronic Pain & Obese group compared to the other 3 groups (P values shown in Fig. 1). The differences in suPAR are characterized as a small-medium (Cohen's d = 0.4) effect size. There was no difference between males and females with respect to chronic pain/obesity on serum suPAR (P > 0.17), although pain intensity (PFSD1) seemed to differ between males and females for the chronic pain only group (data not shown; unadjusted P = 0.003). We also did a subanalysis in the Pain/Healthy Weight and Pain & Obese groups to explore whether headache/migraine could be a covariate. We found no such interaction with suPAR in the Pain/Healthy group with vs without headache (2.2 [1.8–2.4] ng/mL (n = 27) vs 2.2 [2.0–2.3] ng/mL (n = 10), respectively P = 0.918) or with suPAR in the Pain & Obese group with vs without headache (2.4 [2.1–2.7] ng/mL (n = 25) vs 2.9 [2.0–3.2] ng/mL (n = 3), respectively; P = 0.391).
The purpose of this study was to perform an exploratory study of serum suPAR in male and female adolescents without and with chronic pain and/or obesity. We found a classic, significant interaction between chronic pain and obesity in that neither condition increased suPAR, but the combination of chronic pain and obesity did. This augmentation of suPAR by the combination of pain and obesity was subtle with an increase in the median of 0.3 ng/mL. Although the effect size was small-medium, given that even small differences in levels of various biomarkers can make critical differences to health, the implications of this augmentation cannot be determined until future research defines cutoff values for the effects of suPAR.
As a biomarker of inflammation and immune system activation, increases in suPAR have been associated with obesity and insulin resistance.17,24,26,32,33,45 Furthermore, it is considered a marker and may be a predictor of outcomes in a variety of cardiovascular diseases associated with inflammation.1,14,17,22,32,41,47,54
It is possible that the higher percentage of non-White subjects in the Pain & Obese group (29%) compared to the other groups (5%–14%) could have been a contributing factor to the subtle augmentation of serum suPAR observed. Many more subjects are needed to evaluate this novel conjecture. That said, there is no evidence in the literature so far of any relationship of race/ethnicity with serum suPAR concentration in adult and pediatric patients with kidney disease or peripheral artery disease.3,25,49 In a comprehensive study using the Framingham Risk Score for cardiovascular disease prediction, the authors bemoan the lack of information on ethnicity and socioeconomic status in the evaluation of suPAR.32 In fact, evaluation of serum suPAR in a very large cohort of subjects from different racial and ethnic groups may provide insight in potential mechanisms for differences in the interaction of obesity and pain. This is particularly so because other biomarkers may be altered by and reflect differences in race and ethnicity with respect to pain and obesity.11,20,23
Obesity in adolescents is increasing in frequency and severity.8 Furthermore, we have shown that adolescents with obesity and chronic pain have a higher incidence of impaired functioning in multiple domains.21 Therefore, we hypothesized that serum suPAR may be useful as a marker of the interaction between these 2 conditions. The 2 studies of which we are aware that measured serum suPAR in adolescents with obesity alone have been conflicting.4,29 More importantly, we are unaware of systematic studies of suPAR in conditions of chronic pain in any age group.
Inflammatory biomarkers, now including suPAR, may provide insight into the mechanisms underlying the co-occurrence of chronic pain and obesity.5,9,42 For example, serum biomarkers have been used to characterize pain conditions and their symptomatology,13,40 predict pain intensity,34 diagnose pain conditions,6 identify the etiology of painful conditions,57 identify relationships between pain, obesity, and comorbid psychobehavioral conditions35 and, critically, distinguish between groups based on the presence of pain.53 Such advancements are needed because we know little about adequate management of chronic pain with comorbid obesity.27 Of note, we did not find an association of headache/migraine with suPAR in the 2 pain groups. It is also important to point out that we excluded fibromyalgia and inflammatory bowel disease from our cohort, primarily to avoid confounds due to inflammation associated with these conditions. Furthermore, these conditions can be difficult to quickly diagnose, and difficult to distinguish whether these conditions have any underlying autoimmune components. One of the ways that suPAR may be useful is as an additional biomarker in the evaluation and diagnosis of these complex pain conditions. More research is necessary to further explore the potential of suPAR as a biomarker in pediatric populations.
Given our results, suPAR shows promise as a new inflammatory biomarker of the co-occurrence of chronic pain and obesity. Because it is possible that suPAR may be more stable than C-reactive protein, it may serve as a more reliable, less volatile integrated index of treatment response, particularly in children. As an example of its potential to assess treatment response, it has been suggested that obesity-driven inflammation in those with chronic pain may respond to nutritional interventions.15,16
In conclusion, we have demonstrated in this initial, exploratory study an interaction of chronic pain and obesity to increase serum suPAR in male and female adolescents. This is further evidence that these 2 conditions have an inflammatory process as a characteristic. We plan to add suPAR to our panel of inflammatory biomarkers in adolescents and to determine whether suPAR can be used to evaluate the effectiveness of therapeutic approaches such as nutritional interventions as well as to evaluate mechanisms of racial and ethnic differences in the interaction of obesity and pain.
The authors have no conflicts of interest to declare.
This project was funded in part by the Advancing a Healthier Wisconsin Endowment and the Advocate Aurora Research Institute. This work could not have been done without the support of the Children's Wisconsin Pediatric Translational Research Unit. The authors thank Nina Linneman and Taylor Brockman for their assistance with study coordination and subject recruitment.
. Backes Y, van der Sluijs KF, Mackie DP, Tacke F, Koch A, Tenhunen JJ, Schultz MJ. Usefulness of suPAR
as a biological marker in patients with systemic inflammation
or infection: a systematic review. Intensive Care Med 2012;38:1418–28.
. Bigal ME, Tsang A, Loder E, Serrano D, Reed ML, Lipton RB. Body mass index
and episodic headaches: a population-based study. Arch Intern Med 2007;167:1964–70.
. Bock ME, Price HE, Gallon L, Langman CB. Serum soluble urokinase-type plasminogen activator receptor levels and idiopathic FSGS in children
: a single-center report. Clin J Am Soc Nephrol 2013;8:1304–11.
. Can U, Buyukinan M, Yerlikaya FH. Serum levels of soluble urokinase plasminogen activator receptor as a new inflammatory marker in adolescent obesity. Indian J Med Res 2017;145:327–33.
. Cao H. Adipocytokines in obesity and metabolic disease. J Endocrinol 2014;220:T47–59.
. Cibere J, Zhang H, Garnero P, Poole AR, Lobanok T, Saxne T, Kraus VB, Way A, Thorne A, Wong H, Singer J, Kopec J, Guermazi A, Peterfy C, Nicolaou S, Munk PL, Esdaile JM. Association of biomarkers
with pre-radiographically defined and radiographically defined knee osteoarthritis in a population-based study. Arthritis Rheum 2009;60:1372–80.
. Cohen J Statistical power analysis for the behavioral sciences. Hillsdale: Erlbaum Associates, 1988.
. Collaborators GBDO, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Arnlov J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Furst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabares-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13–27.
. De Jongh RF, Vissers KC, Meert TF, Booij LH, De Deyne CS, Heylen RJ. The role of interleukin-6 in nociception and pain. Anesth Analg 2003;96:1096–103.
. Deere KC, Clinch J, Holliday K, McBeth J, Crawley EM, Sayers A, Palmer S, Doerner R, Clark EM, Tobias JH. Obesity is a risk factor for musculoskeletal pain in adolescents: findings from a population-based cohort. PAIN 2012;153:1932–8.
. Djuric Z, Bird CE, Furumoto-Dawson A, Rauscher GH, Ruffin MTt, Stowe RP, Tucker KL, Masi CM. Biomarkers
of psychological stress in health disparities research. Open Biomark J 2008;1:7–19.
. Dodet P, Perrot S, Auvergne L, Hajj A, Simoneau G, Decleves X, Poitou C, Oppert JM, Peoc'h K, Mouly S, Bergmann JF, Lloret-Linares C. Sensory impairment in obese patients? Sensitivity and pain detection thresholds for electrical stimulation after surgery-induced weight loss, and comparison with a nonobese population. Clin J Pain 2013;29:43–9.
. Dray A. Inflammatory mediators of pain. Br J Anaesth 1995;75:125–31.
. Edsfeldt A, Nitulescu M, Grufman H, Gronberg C, Persson A, Nilsson M, Persson M, Bjorkbacka H, Goncalves I. Soluble urokinase plasminogen activator receptor is associated with inflammation
in the vulnerable human atherosclerotic plaque. Stroke 2012;43:3305–12.
. Elma O, Yilmaz ST, Deliens T, Clarys P, Nijs J, Coppieters I, Polli A, Malfliet A. Chronic musculoskeletal pain and nutrition: where are we and where are we heading? PM R 2020. doi: 10.1002/pmrj.12346. doi:10.1002/pmrj.12346 [Epub ahead of print].
. Elma O, Yilmaz ST, Deliens T, Coppieters I, Clarys P, Nijs J, Malfliet A. Do nutritional factors interact with chronic musculoskeletal pain? A systematic review. J Clin Med 2020;9:702.
. Eugen-Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, Petersen J, Pielak T, Moller LN, Jeppesen J, Lyngbaek S, Fenger M, Olsen MH, Hildebrandt PR, Borch-Johnsen K, Jorgensen T, Haugaard SB. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010;268:296–308.
. Gandhi R, Perruccio AV, Rizek R, Dessouki O, Evans HM, Mahomed NN. Obesity-related adipokines predict patient-reported shoulder pain. Obes Facts 2013;6:536–41.
. Gandhi R, Takahashi M, Smith H, Rizek R, Mahomed NN. The synovial fluid adiponectin-leptin ratio predicts pain with knee osteoarthritis. Clin Rheumatol 2010;29:1223–8.
. Goodman E, McEwen BS, Huang B, Dolan LM, Adler NE. Social inequalities in biomarkers
of cardiovascular risk in adolescence. Psychosom Med 2005;67:9–15.
. Hainsworth KR, Davies WH, Khan KA, Weisman SJ. Co-occurring chronic pain and obesity in children
and adolescents: the impact on health-related quality of life. Clin J Pain 2009;25:715–21.
. Hamie L, Daoud G, Nemer G, Nammour T, El Chediak A, Uthman IW, Kibbi AG, Eid A, Kurban M. SuPAR
, an emerging biomarker in kidney and inflammatory diseases. Postgrad Med J 2018;94:517–24.
. Harris KM, Schorpp KM. Integrating biomarkers
in social stratification and health research. Annu Rev Sociol 2018;44:361–86.
. Haupt TH, Kallemose T, Ladelund S, Rasmussen LJ, Thorball CW, Andersen O, Pisinger C, Eugen-Olsen J. Risk factors associated with serum levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor in a general population. Biomark Insights 2014;9:91–100.
. Hayek SS, Landsittel DP, Wei C, Zeier M, Yu ASL, Torres VE, Roth S, Pao CS, Reiser J. Soluble urokinase plasminogen activator receptor and decline in kidney function in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2019;30:1305–13.
. Heraclides A, Jensen TM, Rasmussen SS, Eugen-Olsen J, Haugaard SB, Borch-Johnsen K, Sandbaek A, Lauritzen T, Witte DR. The pro-inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR
) is associated with incident type 2 diabetes among overweight but not obese individuals with impaired glucose regulation: effect modification by smoking and body weight status. Diabetologia 2013;56:1542–6.
. Janke EA, Collins A, Kozak AT. Overview of the relationship between pain and obesity: what do we know? Where do we go next? J Rehabil Res Dev 2007;44:245–62.
. Koch A, Zacharowski K, Boehm O, Stevens M, Lipfert P, von Giesen HJ, Wolf A, Freynhagen R. Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients. Inflamm Res 2007;56:32–7.
. Kosecik M, Dervisoglu P, Koroglu M, Isguven P, Elmas B, Demiray T, Altindis M. Usefulness of soluble urokinase plasminogen activator receptor (suPAR
) as an inflammatory biomarker in obese children
. Int J Cardiol 2017;228:158–61.
. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 2002;11:1–190.
. Lenhard W, Lenhard A. Calculation of effect sizes: psychometrica, 2016. doi: 10.13140/RG.2.2.17823.92329. Available at: https://www.psychometrica.de/effect_size.html
. Accessed May 4, 2020.
. Lyngbaek S, Marott JL, Sehestedt T, Hansen TW, Olsen MH, Andersen O, Linneberg A, Haugaard SB, Eugen-Olsen J, Hansen PR, Jeppesen J. Cardiovascular risk prediction in the general population with use of suPAR
, CRP, and Framingham Risk Score. Int J Cardiol 2013;167:2904–11.
. Lyngbaek S, Sehestedt T, Marott JL, Hansen TW, Olsen MH, Andersen O, Linneberg A, Madsbad S, Haugaard SB, Eugen-Olsen J, Jeppesen J. CRP and suPAR
are differently related to anthropometry and subclinical organ damage. Int J Cardiol 2013;167:781–5.
. Massengale M, Lu B, Pan JJ, Katz JN, Solomon DH. Adipokine hormones and hand osteoarthritis: radiographic severity and pain. PLoS One 2012;7:e47860.
. Menzies V, Lyon DE, Elswick RK Jr, Montpetit AJ, McCain NL. Psychoneuroimmunological relationships in women with fibromyalgia. Biol Res Nurs 2013;15:219–25.
. Narouze S, Souzdalnitski D. Obesity and chronic pain: opportunities for better patient care. Pain Manag 2015;5:217–19.
. Narouze S, Souzdalnitski D. Obesity and chronic pain: systematic review of prevalence and implications for pain practice. Reg Anesth Pain Med 2015;40:91–111.
. Okifuji A, Donaldson GW, Barck L, Fine PG. Relationship between fibromyalgia and obesity in pain, function, mood, and sleep. J Pain 2010;11:1329–37.
. Perquin CW, Hazebroek-Kampschreur AA, Hunfeld JA, Bohnen AM, van Suijlekom-Smit LW, Passchier J, van der Wouden JC. Pain in children
and adolescents: a common experience. PAIN 2000;87:51–8.
. Perruccio AV, Mahomed NN, Chandran V, Gandhi R. Plasma adipokine levels and their association with overall burden of painful joints among individuals with hip and knee osteoarthritis. J Rheumatol 2014;41:334–7.
. Persson M, Engstrom G, Bjorkbacka H, Hedblad B. Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the Malmo Diet and Cancer Study. Atherosclerosis 2012;220:502–5.
. Peterlin BL. The role of the adipocytokines adiponectin and leptin in migraine. J Am Osteopath Assoc 2009;109:314–17.
. Pinhas-Hamiel O, Frumin K, Gabis L, Mazor-Aronovich K, Modan-Moses D, Reichman B, Lerner-Geva L. Headaches in overweight children
and adolescents referred to a tertiary-care center in Israel. Obesity (Silver Spring) 2008;16:659–63.
. Ray L, Lipton RB, Zimmerman ME, Katz MJ, Derby CA. Mechanisms of association between obesity and chronic pain in the elderly. PAIN 2011;152:53–9.
. Rohde C, Polcwiartek C, Andersen E, Vang T, Nielsen J. Effect of a physical activity intervention on suPAR
levels: a randomized controlled trial. J Sci Med Sport 2018;21:286–90.
. Ruiz-Fernandez C, Francisco V, Pino J, Mera A, Gonzalez-Gay MA, Gomez R, Lago F, Gualillo O. Molecular relationships among obesity, inflammation
and intervertebral disc degeneration: are adipokines the common link? Int J Mol Sci 2019;20:2030.
. Rundgren M, Lyngbaek S, Fisker H, Friberg H. The inflammatory marker suPAR
after cardiac arrest. Ther Hypothermia Temp Manag 2015;5:89–94.
. Salamon KS, Davies WH, Fuentes MR, Weisman SJ, Hainsworth KR. The pain frequency-severity-duration scale as a measure of pain: preliminary validation in a pediatric chronic pain sample. Pain Res Treat 2014;2014:653592.
. Samman Tahhan A, Hayek SS, Sandesara P, Hajjari J, Hammadah M, O'Neal WT, Kelli HM, Alkhoder A, Ghasemzadeh N, Ko YA, Aida H, Gafeer MM, Abdelhadi N, Mohammed KH, Patel K, Arya S, Reiser J, Vaccarino V, Sperling L, Quyyumi A. Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes. Atherosclerosis 2017;264:108–14.
. Santos M, Murtaugh T, Pantaleao A, Zempsky WT, Guite JW. Chronic pain and obesity within a pediatric interdisciplinary pain clinic setting: a preliminary examination of current relationships and future directions. Clin J Pain 2017;33:738–45.
. Stanford EA, Chambers CT, Biesanz JC, Chen E. The frequency, trajectories and predictors of adolescent recurrent pain: a population-based approach. PAIN 2008;138:11–21.
. Stoner AM, Jastrowski Mano KE, Weisman SJ, Hainsworth KR. Obesity impedes functional improvement in youth
with chronic pain: an initial investigation. Eur J Pain 2017;21:1495–504.
. Symons FJ, ElGhazi I, Reilly BG, Barney CC, Hanson L, Panoskaltsis-Mortari A, Armitage IM, Wilcox GL. Can biomarkers
differentiate pain and no pain subgroups of nonverbal children
with cerebral palsy? A preliminary investigation based on noninvasive saliva sampling. Pain Med 2015;16:249–56.
. Torino C, Pizzini P, Cutrupi S, Postorino M, Tripepi G, Mallamaci F, Reiser J, Zoccali C, Group PW. Soluble urokinase plasminogen activator receptor (suPAR
) and all-cause and cardiovascular mortality in diverse hemodialysis patients. Kidney Int Rep 2018;3:1100–9.
. Tukker A, Visscher TL, Picavet HS. Overweight and health problems of the lower extremities: osteoarthritis, pain and disability. Public Health Nutr 2009;12:359–68.
. Vincent HK, Adams MC, Vincent KR, Hurley RW. Musculoskeletal pain, fear avoidance behaviors, and functional decline in obesity: potential interventions to manage pain and maintain function. Reg Anesth Pain Med 2013;38:481–91.
. Vuolteenaho K, Koskinen A, Moilanen E. Leptin - a link between obesity and osteoarthritis. applications for prevention and treatment. Basic Clin Pharmacol Toxicol 2014;114:103–8.
. Widhalm HK, Marlovits S, Welsch GH, Dirisamer A, Neuhold A, van Griensven M, Seemann R, Vecsei V, Widhalm K. Obesity-related juvenile form of cartilage lesions: a new affliction in the knees of morbidly obese children
and adolescents. Eur Radiol 2012;22:672–81.