Semin Musculoskelet Radiol 2020; 24(04): 441-450
DOI: 10.1055/s-0040-1713607
Review Article

Identifying Musculoskeletal Pain Generators Using Clinical PET

Daehyun Yoon
1   Division of Musculoskeletal Radiology, Department of Radiology, Stanford University School of Medicine, Stanford, California
Feliks Kogan
1   Division of Musculoskeletal Radiology, Department of Radiology, Stanford University School of Medicine, Stanford, California
Garry E. Gold
1   Division of Musculoskeletal Radiology, Department of Radiology, Stanford University School of Medicine, Stanford, California
Sandip Biswal
1   Division of Musculoskeletal Radiology, Department of Radiology, Stanford University School of Medicine, Stanford, California
› Author Affiliations


Identifying the source of a person's pain is a significant clinical challenge because the physical sensation of pain is believed to be subjective and difficult to quantify. The experience of pain is not only modulated by the individual's threshold to painful stimuli but also a product of the person's affective contributions, such as fear, anxiety, and previous experiences. Perhaps then to quantify pain is to examine the degree of nociception and pro-nociceptive inflammation, that is, the extent of cellular, chemical, and molecular changes that occur in pain-generating processes. Measuring changes in the local density of receptors, ion channels, mediators, and inflammatory/immune cells that are involved in the painful phenotype using targeted, highly sensitive, and specific positron emission tomography (PET) radiotracers is therefore a promising approach toward objectively identifying peripheral pain generators. Although several preclinical radiotracer candidates are being developed, a growing number of ongoing clinical PET imaging approaches can measure the degree of target concentration and thus serve as a readout for sites of pain generation. Further, when PET is combined with the spatial and contrast resolution afforded by magnetic resonance imaging, nuclear medicine physicians and radiologists can potentially identify pain drivers with greater accuracy and confidence. Clinical PET imaging approaches with fluorine-18 fluorodeoxyglucose, fluorine-18 sodium fluoride, and sigma-1 receptor PET radioligand and translocator protein radioligands to isolate the source of pain are described here.

Publication History

Article published online:
29 September 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.

  • References

  • 1 Pizzo P. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research. Washington, DC: Institute of Medicine of the National Academies; 2011: 1-4
  • 2 Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain 2015; 16 (08) 769-780
  • 3 Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain 2012; 13 (08) 715-724
  • 4 Groenewald CB, Essner BS, Wright D, Fesinmeyer MD, Palermo TM. The economic costs of chronic pain among a cohort of treatment-seeking adolescents in the United States. J Pain 2014; 15 (09) 925-933
  • 5 Waddell G. 1987 Volvo award in clinical sciences. A new clinical model for the treatment of low-back pain. Spine 1987; 12 (07) 632-644
  • 6 Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994; 331 (02) 69-73
  • 7 Borenstein DG, O'Mara Jr JW, Boden SD. , et al. The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic subjects : a seven-year follow-up study. J Bone Joint Surg Am 2001; 83 (09) 1306-1311
  • 8 Elfering A, Semmer N, Birkhofer D, Zanetti M, Hodler J, Boos N. Risk factors for lumbar disc degeneration: a 5-year prospective MRI study in asymptomatic individuals. Spine 2002; 27 (02) 125-134
  • 9 Carragee EJ, Alamin TF, Miller JL, Carragee JM. Discographic, MRI and psychosocial determinants of low back pain disability and remission: a prospective study in subjects with benign persistent back pain. Spine J 2005; 5 (01) 24-35
  • 10 Stafford MA, Peng P, Hill DA. Sciatica: a review of history, epidemiology, pathogenesis, and the role of epidural steroid injection in management. Br J Anaesth 2007; 99 (04) 461-473
  • 11 Ropper AH, Zafonte RD. Sciatica. N Engl J Med 2015; 372 (13) 1240-1248
  • 12 Mixter WJ, Barr JS. Rupture of the intervertebral disc with involvement of the spinal canal. N Engl J Med 1934; 211 (05) 210-215
  • 13 Visser LH, Nijssen PG, Tijssen CC, van Middendorp JJ, Schieving J. Sciatica-like symptoms and the sacroiliac joint: clinical features and differential diagnosis. Eur Spine J 2013; 22 (07) 1657-1664
  • 14 Kirschner JS, Foye PM, Cole JL. Piriformis syndrome, diagnosis and treatment. Muscle Nerve 2009; 40 (01) 10-18
  • 15 Ergun T, Lakadamyali H. CT and MRI in the evaluation of extraspinal sciatica. Br J Radiol 2010; 83 (993) 791-803
  • 16 van der Windt DA, Simons E, Riphagen II. , et al. Physical examination for lumbar radiculopathy due to disc herniation in patients with low-back pain. Cochrane Database Syst Rev 2010; (02) CD007431
  • 17 el Barzouhi A, Vleggeert-Lankamp CL, Lycklama à Nijeholt GJ. , et al; Leiden-The Hague Spine Intervention Prognostic Study Group. Magnetic resonance imaging in follow-up assessment of sciatica. N Engl J Med 2013; 368 (11) 999-1007
  • 18 Koes BW, van Tulder MW, Peul WC. Diagnosis and treatment of sciatica. BMJ 2007; 334 (7607): 1313-1317
  • 19 Englund M, Guermazi A, Gale D. , et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med 2008; 359 (11) 1108-1115
  • 20 Needell SD, Zlatkin MB, Sher JS, Murphy BJ, Uribe JW. MR imaging of the rotator cuff: peritendinous and bone abnormalities in an asymptomatic population. AJR Am J Roentgenol 1996; 166 (04) 863-867
  • 21 Sher JS, Uribe JW, Posada A, Murphy BJ, Zlatkin MB. Abnormal findings on magnetic resonance images of asymptomatic shoulders. J Bone Joint Surg Am 1995; 77 (01) 10-15
  • 22 Cohade C, Wahl RL. Applications of positron emission tomography/computed tomography image fusion in clinical positron emission tomography-clinical use, interpretation methods, diagnostic improvements. Semin Nucl Med 2003; 33 (03) 228-237
  • 23 Cipriano PW, Yoon D, Gandhi H. , et al. 18F-FDG PET/MRI in chronic sciatica: early results revealing spinal and nonspinal abnormalities. J Nucl Med 2018; 59 (06) 967-972
  • 24 Biswal S, Behera D, Yoon DH. , et al. [18F]FDG PET/MRI of patients with chronic pain alters management: early experience. EJNMMI Phys 2015; 2 (Suppl. 01) A84
  • 25 Ferrata P, Carta S, Fortina M, Scipio D, Riva A, Di Giacinto S. Painful hip arthroplasty: definition. Clin Cases Miner Bone Metab 2011; 8 (02) 19-22
  • 26 Hayter CL, Gold SL, Koff MF. , et al. MRI findings in painful metal-on-metal hip arthroplasty. AJR Am J Roentgenol 2012; 199 (04) 884-893
  • 27 Fritz J, Lurie B, Miller TT, Potter HG. MR imaging of hip arthroplasty implants. Radiographics 2014; 34 (04) E106-E132
  • 28 Barlow BT, Ortiz PA, Fields KG, Burge AJ, Potter HG, Westrich GH. Magnetic resonance imaging predicts adverse local tissue reaction histologic severity in modular neck total hip arthroplasty. J Arthroplasty 2016; 31 (10) 2325-2331
  • 29 Burge AJ, Gold SL, Lurie B. , et al. MR imaging of adverse local tissue reactions around rejuvenate modular dual-taper stems. Radiology 2015; 277 (01) 142-150
  • 30 Tang K, Boonen A, Verstappen SM. , et al. Worker productivity outcome measures: OMERACT filter evidence and agenda for future research. J Rheumatol 2014; 41 (01) 165-176
  • 31 Ma VY, Chan L, Carruthers KJ. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil 2014; 95 (05) 986-995.e1
  • 32 Xie F, Tanvejsilp P, Campbell K, Gaebel K. Cost-effectiveness of pharmaceutical management for osteoarthritis pain: a systematic review of the literature and recommendations for future economic evaluation. Drugs Aging 2013; 30 (05) 277-284
  • 33 Piert M, Zittel TT, Becker GA. , et al. Assessment of porcine bone metabolism by dynamic. J Nucl Med 2001; 42 (07) 1091-1100
  • 34 Messa C, Goodman WG, Hoh CK. , et al. Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry. J Clin Endocrinol Metab 1993; 77 (04) 949-955
  • 35 Kogan F, Broski SM, Yoon D, Gold GE. Applications of PET-MRI in musculoskeletal disease. J Magn Reson Imaging 2018; 48 (01) 27-47
  • 36 Kobayashi N, Inaba Y, Tateishi U. , et al. Comparison of 18F-fluoride positron emission tomography and magnetic resonance imaging in evaluating early-stage osteoarthritis of the hip. Nucl Med Commun 2015; 36 (01) 84-89
  • 37 Draper CE, Fredericson M, Gold GE. , et al. Patients with patellofemoral pain exhibit elevated bone metabolic activity at the patellofemoral joint. J Orthop Res 2012; 30 (02) 209-213
  • 38 Kobayashi N, Inaba Y, Tateishi U. , et al. New application of 18F-fluoride PET for the detection of bone remodeling in early-stage osteoarthritis of the hip. Clin Nucl Med 2013; 38 (10) e379-e383
  • 39 Lee JW, Lee SM, Kim SJ, Choi JW, Baek KW. Clinical utility of fluoride-18 positron emission tomography/CT in temporomandibular disorder with osteoarthritis: comparisons with 99mTc-MDP bone scan. Dentomaxillofac Radiol 2013; 42 (02) 29292350
  • 40 Kogan F, Fan AP, McWalter EJ, Oei EHG, Quon A, Gold GE. PET/MRI of metabolic activity in osteoarthritis: a feasibility study. J Magn Reson Imaging 2017; 45 (06) 1736-1745
  • 41 Gamie S, El-Maghraby T. The role of PET/CT in evaluation of Facet and Disc abnormalities in patients with low back pain using (18)F-Fluoride. Nucl Med Rev Cent East Eur 2008; 11 (01) 17-21
  • 42 Jenkins NW, Talbott JF, Shah V. , et al. [18F]-Sodium fluoride PET MR-based localization and quantification of bone turnover as a biomarker for facet joint-induced disability. AJNR Am J Neuroradiol 2017; 38 (10) 2028-2031
  • 43 Mabray MC, Brus-Ramer M, Behr SC. , et al. (18)F-Sodium fluoride PET-CT hybrid imaging of the lumbar facet joints: tracer uptake and degree of correlation to CT-graded arthropathy. World J Nucl Med 2016; 15 (02) 85-90
  • 44 Kogan F, Fan AP, Monu U, Iagaru A, Hargreaves BA, Gold GE. Quantitative imaging of bone-cartilage interactions in ACL-injured patients with PET-MRI. Osteoarthritis Cartilage 2018; 26 (06) 790-796
  • 45 Savic D, Pedoia V, Seo Y. , et al. Imaging bone-cartilage interactions in osteoarthritis using [18F]-NaF PET-MRI. Mol Imaging 2016; 15: 1-12
  • 46 Blake GM, Siddique M, Frost ML, Moore AE, Fogelman I. Quantitative PET imaging using (18)F sodium fluoride in the assessment of metabolic bone diseases and the monitoring of their response to therapy. PET Clin 2012; 7 (03) 275-291
  • 47 Hawkins RA, Choi Y, Huang SC. , et al. Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET. J Nucl Med 1992; 33 (05) 633-642
  • 48 Khalighi MM, Fan A, Delso G. , et al. Image-based arterial input function estimation for cerebral blood flow measurement on a PET/MR scanner. J Nucl Med 2016; 57 (Suppl. 02) 1627
  • 49 Haddock B, Fan AP, Jørgensen NR, Suetta C, Gold GE, Kogan F. Kinetic [18F]-fluoride of the knee in normal volunteers. Clin Nucl Med 2019; 44 (05) 377-385
  • 50 Zamanillo D, Romero L, Merlos M, Vela JM. Sigma 1 receptor: a new therapeutic target for pain. Eur J Pharmacol 2013; 716 (1-3): 78-93
  • 51 Ortíz-Rentería M, Juárez-Contreras R, González-Ramírez R. , et al. TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain. Proc Natl Acad Sci U S A 2018; 115 (07) E1657-E1666
  • 52 Kim FJ, Kovalyshyn I, Burgman M, Neilan C, Chien CC, Pasternak GW. Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding. Mol Pharmacol 2010; 77 (04) 695-703
  • 53 Roh DH, Yoon SY, Seo HS. , et al. Sigma-1 receptor-induced increase in murine spinal NR1 phosphorylation is mediated by the PKCalpha and epsilon, but not the PKCzeta, isoforms. Neurosci Lett 2010; 477 (02) 95-99
  • 54 Kim HW, Roh DH, Yoon SY. , et al. Activation of the spinal sigma-1 receptor enhances NMDA-induced pain via PKC- and PKA-dependent phosphorylation of the NR1 subunit in mice. Br J Pharmacol 2008; 154 (05) 1125-1134
  • 55 Kim HW, Kwon YB, Roh DH. , et al. Intrathecal treatment with sigma1 receptor antagonists reduces formalin-induced phosphorylation of NMDA receptor subunit 1 and the second phase of formalin test in mice. Br J Pharmacol 2006; 148 (04) 490-498
  • 56 Roh DH, Kim HW, Yoon SY. , et al. Intrathecal injection of the sigma(1) receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain. Anesthesiology 2008; 109 (05) 879-889
  • 57 Díaz JL, Zamanillo D, Corbera J. , et al. Selective sigma-1 (sigma1) receptor antagonists: emerging target for the treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem 2009; 9 (03) 172-183
  • 58 Jerčić L, Kostić S, Vitlov Uljević M, Vukušić Pušić T, Vukojević K, Filipović N. Sigma-1 receptor expression in DRG neurons during a carrageenan-provoked inflammation. Anat Rec (Hoboken) 2019; 302 (09) 1620-1627
  • 59 Kwon SG, Roh DH, Yoon SY. , et al. Role of peripheral sigma-1 receptors in ischaemic pain: potential interactions with ASIC and P2X receptors. Eur J Pain 2016; 20 (04) 594-606
  • 60 Shen B, Behera D, James ML. , et al. Visualizing nerve injury in a neuropathic pain model with [18F]FTC-146 PET/MRI. Theranostics 2017; 7 (11) 2794-2805
  • 61 James ML, Shen B, Zavaleta C. , et al. [18F]FTC-146: A new ultra selective PET radioligand for imaging sigma-1 receptors in living subjects. J Med Chem 2012; 55 (19) 8272-8282
  • 62 Hjørnevik T, Cipriano PW, Shen B. , et al. Biodistribution and radiation dosimetry of 18F-FTC-146 in humans. J Nucl Med 2017; 58 (12) 2004-2009
  • 63 James ML, Shen B, Nielsen CH. , et al. Evaluation of σ-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET. J Nucl Med 2014; 55 (01) 147-153
  • 64 Yoon D, Cipriano P, Hjørnevik T. , et al. Management of complex regional pain syndrome (CRPS) with [18F]FTC-146 PET/MRI. Proc Intl Soc Mag Res Med 2017; 1164
  • 65 Cipriano PW, Lee SW, Yoon D. , et al. Successful treatment of chronic knee pain following localization by a sigma-1 receptor radioligand and PET/MRI: a case report. J Pain Res 2018; 11: 2353-2357
  • 66 Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009; 32: 1-32
  • 67 Tsuda M. Microglia-mediated regulation of neuropathic pain: molecular and cellular mechanisms. Biol Pharm Bull 2019; 42 (12) 1959-1968
  • 68 Shinoda M, Hayashi Y, Kubo A, Iwata K. Pathophysiological mechanisms of persistent orofacial pain. J Oral Sci 2020; 62 (02) 131-135
  • 69 Hu P, Bembrick AL, Keay KA. , et al. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun 2007; 21 (05) 599-616
  • 70 Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003; 2 (12) 973-985
  • 71 Brody AL, Okita K, Shieh J. , et al. Radiation dosimetry and biodistribution of the translocator protein radiotracer [(11)C]DAA1106 determined with PET/CT in healthy human volunteers. Nucl Med Biol 2014; 41 (10) 871-875
  • 72 Garvey LJ, Pavese N, Politis M. , et al. Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART. AIDS 2014; 28 (01) 67-72
  • 73 Golla SS, Boellaard R, Oikonen V. , et al. Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients. J Cereb Blood Flow Metab 2015; 35 (05) 766-772
  • 74 Owen DR, Guo Q, Kalk NJ. , et al. Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study. J Cereb Blood Flow Metab 2014; 34 (06) 989-994
  • 75 Imamoto N, Momosaki S, Fujita M. , et al. [11C]PK11195 PET imaging of spinal glial activation after nerve injury in rats. Neuroimage 2013; 79: 121-128
  • 76 Cropper HC, Johnson EM, Haight ES. , et al. Longitudinal translocator protein-18 kDa-positron emission tomography imaging of peripheral and central myeloid cells in a mouse model of complex regional pain syndrome. Pain 2019; 160 (09) 2136-2148
  • 77 Albrecht DS, Ahmed SU, Kettner NW. , et al. Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. Pain 2018; 159 (05) 968-977
  • 78 Loggia ML, Chonde DB, Akeju O. , et al. Evidence for brain glial activation in chronic pain patients. Brain 2015; 138 (Pt 3): 604-615
  • 79 Albrecht DS, Forsberg A, Sandström A. , et al. Brain glial activation in fibromyalgia —a multi-site positron emission tomography investigation. Brain Behav Immun 2019; 75: 72-83
  • 80 Alshelh Z, Albrecht DS, Bergan C. , et al. In-vivo imaging of neuroinflammation in veterans with Gulf War illness. Brain Behav Immun 2020 ; February 4 (Epub ahead of print)
  • 81 Rodríguez-Muñoz M, Sánchez-Blázquez P, Herrero-Labrador R. , et al. The σ1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control. Antioxid Redox Signal 2015; 22 (10) 799-818
  • 82 Pan B, Guo Y, Kwok WM, Hogan Q, Wu HE. Sigma-1 receptor antagonism restores injury-induced decrease of voltage-gated Ca2+ current in sensory neurons. J Pharmacol Exp Ther 2014; 350 (02) 290-300
  • 83 Nieto FR, Cendán CM, Cañizares FJ. , et al. Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice. Mol Pain 2014; 10: 11
  • 84 Gris G, Merlos M, Vela JM, Zamanillo D, Portillo-Salido E. S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund's adjuvant models in mice. Behav Pharmacol 2014; 25 (03) 226-235
  • 85 Gris G, Portillo-Salido E, Aubel B. , et al. The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats. Sci Rep 2016; 6: 24591
  • 86 Tejada MA, Montilla-García A, Sánchez-Fernández C. , et al. Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors. Psychopharmacology (Berl) 2014; 231 (19) 3855-3869
  • 87 Bruna J, Videla S, Argyriou AA. , et al. Efficacy of a novel sigma-1 receptor antagonist for oxaliplatin-induced neuropathy: a randomized, double-blind, placebo-controlled phase IIa clinical trial. Neurotherapeutics 2018; 15 (01) 178-18
  • 88 Cendán CM, Pujalte JM, Portillo-Salido E, Montoliu L, Baeyens JM. Formalin-induced pain is reduced in sigma(1) receptor knockout mice. Eur J Pharmacol 2005; 511 (01) 73-74
  • 89 de la Puente B, Nadal X, Portillo-Salido E. , et al. Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain 2009; 145 (03) 294-303
  • 90 Entrena JM, Cobos EJ, Nieto FR. , et al. Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice. Pain 2009; 143 (03) 252-261
  • 91 Nieto FR, Cendán CM, Sánchez-Fernández C. , et al. Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice. J Pain 2012; 13 (11) 1107-1121