
Towards a mechanism-based approach to pain management in osteoarthritis
- Select a language for the TTS:
- UK English Female
- UK English Male
- US English Female
- US English Male
- Australian Female
- Australian Male
- Language selected: (auto detect) - EN
Play all audios:
KEY POINTS * Current evidence supports the idea that osteoarthritis (OA) pain is generated and maintained through continuous nociceptive input from the joint * Chronic OA pain is associated
with changes in the central nervous system (CNS); these changes are reversible, reflecting the plasticity of the CNS and the requirement for continuous input from the periphery * Antibodies
to nerve growth factor, which do not cross the blood–brain barrier and therefore act entirely through effects in the periphery, are effective at relieving OA pain * OA pain pathways can also
respond to modulation centrally, as exemplified by data from OA pain trials with duloxetine, thus offering opportunity for the identification of new targets for pain relief * Heterogeneity
in the clinical presentation of OA pain and in the response to analgesic therapies suggests that, in the future, distinct mechanism-based therapeutic approaches could be tailored to specific
subsets of patients ABSTRACT Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and
are associated with serious health risks when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous
system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence
of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover,
studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic
OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might
become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management. Access through your institution Buy or subscribe
This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access
$209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are
calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE
CAUSAL ROLE OF BRAIN CIRCUITS IN OSTEOARTHRITIS PAIN Article 31 March 2025 NOCICEPTIVE MECHANISMS DRIVING PAIN IN A POST-TRAUMATIC OSTEOARTHRITIS MOUSE MODEL Article Open access 17
September 2020 OSTEOARTHRITIS: PATHOGENIC SIGNALING PATHWAYS AND THERAPEUTIC TARGETS Article Open access 03 February 2023 REFERENCES * Hing, E., Cherry, D. K. & Woodwell, D. A. National
Ambulatory Medical Care Survey: 2004 summary. _Advance Data_ 374, 1–33 (2006). Google Scholar * Hawker, G. A. _ et al_. Differences between men and women in the rate of use of hip and knee
arthroplasty. _N. Engl. J. Med._ 342, 1016–1022 (2000). Article CAS PubMed Google Scholar * Zhang, W. _ et al_. OARSI recommendations for the management of hip and knee osteoarthritis:
part III: Changes in evidence following systematic cumulative update of research published through January 2009. _Osteoarthritis Cartilage_ 18, 476–499 (2010). Article CAS PubMed Google
Scholar * Doherty, M. & Dieppe, P. The “placebo” response in osteoarthritis and its implications for clinical practice. _Osteoarthritis Cartilage_ 17, 1255–1262 (2009). Article CAS
PubMed Google Scholar * Wolfe, M. M., Lichtenstein, D. R. & Singh, G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. _N. Engl. J. Med._ 340, 1888–1899 (1999).
Article CAS PubMed Google Scholar * Kearney, P. M. _ et al_. Do selective cyclooxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of
atherothrombosis? Meta-analysis of randomised trials. _BMJ_ 332, 1302–1308 (2006). Article CAS PubMed PubMed Central Google Scholar * Furlan, A. D., Sandoval, J. A., Mailis-Gagnon, A.
& Tunks, E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. _CMAJ_ 174, 1589–1594 (2006). Article PubMed PubMed Central Google Scholar * Le
Graverand-Gastineau, M. Disease modifying osteoarthritis drugs: facing development challenges and choosing molecular targets. _Curr. Drug Targets_ 11, 528–535 (2010). Article CAS PubMed
Google Scholar * Stahl, S. M., Grady, M. M., Moret, C. & Briley, M. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants.
_CNS Spectr._ 10, 732–747 (2005). Article PubMed Google Scholar * Lane, N. E. _ et al_. Tanezumab for the treatment of pain from osteoarthritis of the knee. _N. Engl. J. Med._ 363,
1521–1531 (2010). Article CAS PubMed PubMed Central Google Scholar * Felson, D. T. Developments in the clinical understanding of osteoarthritis. _Arthritis Res. Ther._ 11, 203 (2009).
Article PubMed PubMed Central Google Scholar * Hawker, G. A. _ et al_. Understanding the pain experience in hip and knee osteoarthritis—an OARSI/OMERACT initiative. _Osteoarthritis
Cartilage_ 16, 415–422 (2008). Article CAS PubMed Google Scholar * Hochman, J. R., French, M. R., Bermingham, S. L. & Hawker, G. A. The nerve of osteoarthritis pain. _Arthritis Care
Res._ 62, 1019–1023 (2010). Article Google Scholar * Hochman, J. R., Gagliese, L., Davis, A. M. & Hawker, G. A. Neuropathic pain symptoms in a community knee OA cohort. _Osteoarthritis
Cartilage_ 19, 647–654 (2011). Article CAS PubMed Google Scholar * Hawker, G. A. Experiencing painful osteoarthritis: what have we learned from listening? _Curr. Opin. Rheumatol._ 21,
507–512 (2009). Article PubMed Google Scholar * Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. _Pain_ 152, S2–S15 (2011). Article PubMed
Google Scholar * Suokas, A. K. _ et al_. Quantitative sensory testing in painful osteoarthritis: a systematic review and meta-analysis. _Osteoarthritis Cartilage_ 20, 1075–1085 (2012).
Article CAS PubMed Google Scholar * Sharma, L. Proprioceptive impairment in knee osteoarthritis. _Rheum. Dis. Clin. North Am._ 25, 299–314 (1999). Article CAS PubMed Google Scholar *
Felson, D. T. _ et al_. The effects of impaired joint position sense on the development and progression of pain and structural damage in knee osteoarthritis. _Arthritis Rheum._ 61,
1070–1076 (2009). Article PubMed PubMed Central Google Scholar * Shakoor, N., Agrawal, A. & Block, J. A. Reduced lower extremity vibratory perception in osteoarthritis of the knee.
_Arthritis Rheum._ 59, 117–121 (2008). Article PubMed PubMed Central Google Scholar * Shakoor, N., Lee, K. J., Fogg, L. F. & Block, J. A. Generalized vibratory deficits in
osteoarthritis of the hip. _Arthritis Rheum._ 59, 1237–1240 (2008). Article PubMed PubMed Central Google Scholar * International Association for the Study of Pain. _IASP_ [online]. *
Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. _Cell_ 139, 267–284 (2009). Article CAS PubMed PubMed Central Google Scholar *
McDougall, J. J. Arthritis and pain. Neurogenic origin of joint pain. _Arthritis Res. Ther._ 8, 220 (2006). Article PubMed PubMed Central CAS Google Scholar * Hines, A. E., Birn, H.,
Teglbjaerg, P. S. & Sinkjaer, T. Fiber type composition of articular branches of the tibial nerve at the knee joint in man. _Anat. Rec._ 246, 573–578 (1996). Article CAS PubMed Google
Scholar * Freeman, M. A. & Wyke, B. The innervation of the knee joint. An anatomical and histological study in the cat. _J. Anat._ 101, 505–532 (1967). CAS PubMed PubMed Central
Google Scholar * Hukkanen, M. _ et al_. Innervation of bone from healthy and arthritic rats by substance P and calcitonin gene related peptide containing sensory fibers. _J. Rheum._ 19,
1252–1259 (1992). CAS PubMed Google Scholar * Nixon, A. J. & Cummings, J. F. Substance P immunohistochemical study of the sensory innervation of normal subchondral bone in the equine
metacarpophalangeal joint. _Am. J. Vet. Res._ 55, 28–33 (1994). CAS PubMed Google Scholar * McDougall, J. J., Bray, R. C. & Sharkey, K. A. Morphological and immunohistochemical
examination of nerves in normal and injured collateral ligaments of rat, rabbit, and human knee joints. _Anat. Rec._ 248, 29–39 (1997). Article CAS PubMed Google Scholar * Creamer, P.,
Hunt, M. & Dieppe, P. Pain mechanisms in osteoarthritis of the knee: effect of intraarticular anesthetic. _J. Rheum._ 23, 1031–1036 (1996). CAS PubMed Google Scholar * Dye, S. F.,
Vaupel, G. L. & Dye, C. C. Conscious neurosensory mapping of the internal structures of the human knee without intraarticular anesthesia. _Am. J. Sports Med._ 26, 773–777 (1998). Article
CAS PubMed Google Scholar * Hannan, M. T., Felson, D. T. & Pincus, T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. _J.
Rheum._ 27, 1513–1517 (2000). CAS PubMed Google Scholar * Bedson, J. & Croft, P. R. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and
summary of the literature. _BMC Musculoskelet. Disord._ 9, 116 (2008). Article PubMed PubMed Central Google Scholar * Dieppe, P. A. & Lohmander, L. S. Pathogenesis and management of
pain in osteoarthritis. _Lancet_ 365, 965–973 (2005). Article CAS PubMed Google Scholar * Duncan, R. _ et al_. Symptoms and radiographic osteoarthritis: not as discordant as they are
made out to be? _Ann. Rheum. Dis._ 66, 86–91 (2007). Article CAS PubMed Google Scholar * Neogi, T. _ et al_. Association between radiographic features of knee osteoarthritis and pain:
results from two cohort studies. _BMJ_ 339, b2844 (2009). Article PubMed PubMed Central Google Scholar * Eckstein, F. _ et al_. Greater rates of cartilage loss in painful knees than in
pain-free knees after adjustment for radiographic disease stage: data from the osteoarthritis initiative. _Arthritis Rheum._ 63, 2257–2267 (2011). Article PubMed PubMed Central Google
Scholar * Felson, D. T. Imaging abnormalities that correlate with joint pain. _Br. J. Sports Med._ 45, 289–291 (2011). Article PubMed Google Scholar * Yusuf, E., Kortekaas, M. C., Watt,
I., Huizinga, T. W. & Kloppenburg, M. Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review. _Ann. Rheum. Dis._ 70, 60–67 (2011). Article
PubMed Google Scholar * Zhang, Y. _ et al_. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. _Arthritis Rheum._ 63,
691–699 (2011). Article PubMed Google Scholar * Laslett, L. L. _ et al_. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. _Ann. Rheum.
Dis._ 71, 1322–1328 (2012). Article CAS PubMed Google Scholar * Scanzello, C. R. _ et al_. Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular
characterization and relationship to symptoms. _Arthritis Rheum._ 63, 391–400 (2011). Article PubMed PubMed Central Google Scholar * Loeser, R. F., Goldring, S. R., Scanzello, C. R.
& Goldring, M. B. Osteoarthritis: a disease of the joint as an organ. _Arthritis Rheum._ 64, 1697–1707 (2012). Article PubMed PubMed Central Google Scholar * Heppelmann, B. &
McDougall, J. J. Inhibitory effect of amiloride and gadolinium on fine afferent nerves in the rat knee: evidence of mechanogated ion channels in joints. _Exp. Brain Res._ 167, 114–118
(2005). Article CAS PubMed Google Scholar * Little, C. B. & Zaki, S. What constitutes an “animal model of osteoarthritis”—the need for consensus? _Osteoarthritis Cartilage_ 20,
261–267 (2012). Article CAS PubMed Google Scholar * Schuelert, N. & McDougall, J. J. Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent
model of osteoarthritis. _Arthritis Res. Ther._ 14, R5 (2012). Article CAS PubMed PubMed Central Google Scholar * Akopian, A. N., Sivilotti, L. & Wood, J. N. A
tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. _Nature_ 379, 257–262 (1996). Article CAS PubMed Google Scholar * Raouf, R. _ et al_. Sodium channels
and mammalian sensory mechanotransduction. _Mol. Pain_ 8, 21 (2012). Article CAS PubMed PubMed Central Google Scholar * Amaya, F. _ et al_. Diversity of expression of the sensory
neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2. _Mol. Cell. Neurosci._ 15, 331–342 (2000). Article CAS PubMed Google Scholar * Strickland, I. T. _ et al_.
Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. _Eur. J.
Pain_ 12, 564–572 (2008). Article CAS PubMed Google Scholar * Miller, R. J., Jung, H., Bhangoo, S. K. & White, F. A. Cytokine and chemokine regulation of sensory neuron function.
_Handb. Exp. Pharmacol._ 194, 417–449 (2009). Article CAS Google Scholar * Coggeshall, R. E., Hong, K. A., Langford, L. A., Schaible, H. G. & Schmidt, R. F. Discharge characteristics
of fine medial articular afferents at rest and during passive movements of inflamed knee joints. _Brain Res._ 272, 185–188 (1983). Article CAS PubMed Google Scholar * Schaible, H. G.
& Schmidt, R. F. Effects of an experimental arthritis on the sensory properties of fine articular afferent units. _J. Neurophysiol._ 54, 1109–1122 (1985). Article CAS PubMed Google
Scholar * Richter, F. _ et al_. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. _Arthritis Rheum._ 62, 3806–3814 (2010). Article
CAS PubMed Google Scholar * Brenn, D., Richter, F. & Schaible, H. G. Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin6 in the rat:
an inflammatory mechanism of joint pain. _Arthritis Rheum._ 56, 351–359 (2007). Article CAS PubMed Google Scholar * Schaible, H. G. _ et al_. The role of proinflammatory cytokines in the
generation and maintenance of joint pain. _Ann. NY Acad. Sci._ 1193, 60–69 (2010). Article CAS PubMed Google Scholar * Richter, F. _ et al_. Interleukin17 sensitizes joint nociceptors
to mechanical stimuli and contributes to arthritic pain through neuronal interleukin17 receptors in rodents. _Arthritis Rheum._ 64, 4125–4134 (2012). Article CAS PubMed Google Scholar *
Woolf, C. J., Safieh-Garabedian, B., Ma, Q. P., Crilly, P. & Winter, J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. _Neuroscience_ 62,
327–331 (1994). Article CAS PubMed Google Scholar * Svensson, P., Cairns, B. E., Wang, K. & Arendt-Nielsen, L. Injection of nerve growth factor into human masseter muscle evokes
long-lasting mechanical allodynia and hyperalgesia. _Pain_ 104, 241–247 (2003). Article CAS PubMed Google Scholar * Chuang, H. H. _ et al_. Bradykinin and nerve growth factor release the
capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. _Nature_ 411, 957–962 (2001). Article CAS PubMed Google Scholar * Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J.
& Julius, D. A capsaicin-receptor homologue with a high threshold for noxious heat. _Nature_ 398, 436–441 (1999). Article CAS PubMed Google Scholar * Huang, J., Zhang, X. &
McNaughton, P. A. Inflammatory pain: the cellular basis of heat hyperalgesia. _Curr. Neuropharmacol._ 4, 197–206 (2006). Article CAS PubMed PubMed Central Google Scholar * Ji, R. R.,
Samad, T. A., Jin, S. X., Schmoll, R. & Woolf, C. J. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia.
_Neuron_ 36, 57–68 (2002). Article CAS PubMed Google Scholar * Chao, M. V. Neurotrophins and their receptors: a convergence point for many signalling pathways. _Nat. Rev. Neurosci._ 4,
299–309 (2003). Article CAS PubMed Google Scholar * Bullock, E. D. & Johnson, E. M. Jr. Nerve growth factor induces the expression of certain cytokine genes and bcl2 in mast cells.
Potential role in survival promotion. _J. Biol. Chem._ 271, 27500–27508 (1996). Article CAS PubMed Google Scholar * Gigante, A. _ et al_. Expression of NGF, Trka and p75 in human
cartilage. _Eur. J. Histochem._ 47, 339–344 (2003). Article CAS PubMed Google Scholar * Iannone, F. _ et al_. Increased expression of nerve growth factor (NGF) and high affinity NGF
receptor (p140 TrkA) in human osteoarthritic chondrocytes. _Rheumatology_ 41, 1413–1418 (2002). Article CAS PubMed Google Scholar * Barthel, C. _ et al_. Nerve growth factor and receptor
expression in rheumatoid arthritis and spondyloarthritis. _Arthritis Res. Ther._ 11, R82 (2009). Article PubMed PubMed Central CAS Google Scholar * Halliday, D. A., Zettler, C., Rush,
R. A., Scicchitano, R. & McNeil, J. D. Elevated nerve growth factor levels in the synovial fluid of patients with inflammatory joint disease. _Neurochem. Res._ 23, 919–922 (1998).
Article CAS PubMed Google Scholar * Glasson, S. S., Blanchet, T. J. & Morris, E. A. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv
mouse. _Osteoarthritis Cartilage_ 15, 1061–1069 (2007). Article CAS PubMed Google Scholar * McNamee, K. E. _ et al_. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role
for nerve growth factor in non-inflammatory joint pain. _Pain_ 149, 386–392 (2010). Article CAS PubMed Google Scholar * Shelton, D. L., Zeller, J., Ho, W. H., Pons, J. & Rosenthal,
A. Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis. _Pain_ 116, 8–16 (2005). Article CAS PubMed Google Scholar * Mapp, P. I. & Walsh, D. A. Mechanisms
and targets of angiogenesis and nerve growth in osteoarthritis. _Nat. Rev. Rheumatol._ 8, 390–398 (2012). Article CAS PubMed Google Scholar * Suri, S. & Walsh, D. A. Osteochondral
alterations in osteoarthritis. _Bone_ 51, 204–211 (2012). Article PubMed Google Scholar * Suri, S. _ et al_. Neurovascular invasion at the osteochondral junction and in osteophytes in
osteoarthritis. _Ann. Rheum. Dis._ 66, 1423–1428 (2007). Article PubMed PubMed Central Google Scholar * Ashraf, S. _ et al_. Increased vascular penetration and nerve growth in the
meniscus: a potential source of pain in osteoarthritis. _Ann. Rheum. Dis._ 70, 523–529 (2011). Article PubMed Google Scholar * Acosta, C. & Davies, A. Bacterial lipopolysaccharide
regulates nociceptin expression in sensory neurons. _J. Neurosci. Res._ 86, 1077–1086 (2008). Article CAS PubMed Google Scholar * Kim, D., You, B., Lim, H. & Lee, S. J. Toll-like
receptor 2 contributes to chemokine gene expression and macrophage infiltration in the dorsal root ganglia after peripheral nerve injury. _Mol. Pain_ 7, 74 (2011). CAS PubMed PubMed
Central Google Scholar * Liu, T., Gao, Y. J. & Ji, R. R. Emerging role of Toll-like receptors in the control of pain and itch. _Neurosci. Bull._ 28, 131–144 (2012). Article CAS
PubMed PubMed Central Google Scholar * Scanzello, C. R., Plaas, A. & Crow, M. K. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? _Curr. Opin.
Rheumatol._ 20, 565–572 (2008). Article CAS PubMed Google Scholar * Sokolove, J. & Lepus, C. M. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and
interpretations. _Ther. Adv. Musculoskelet. Dis._ 5, 77–94 (2013). Article CAS PubMed PubMed Central Google Scholar * Ren, K. & Dubner, R. Interactions between the immune and
nervous systems in pain. _Nat. Med._ 16, 1267–1276 (2010). Article CAS PubMed PubMed Central Google Scholar * Miller, R. E. _ et al_. CCR2 chemokine receptor signaling mediates pain in
experimental osteoarthritis. _Proc. Natl Acad. Sci. USA_ 109, 20602–20607 (2012). Article CAS PubMed PubMed Central Google Scholar * Segond von Banchet, G. _ et al_. Experimental
arthritis causes tumor necrosis factor-α-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior. _Pain_ 145, 151–159 (2009). Article
CAS PubMed Google Scholar * Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. _J. Pain_ 10, 895–926 (2009).
Article PubMed PubMed Central Google Scholar * Milligan, E. D. & Watkins, L. R. Pathological and protective roles of glia in chronic pain. _Nat. Rev. Neurosci._ 10, 23–36 (2009).
Article CAS PubMed PubMed Central Google Scholar * O'Driscoll, S. L. & Jayson, M. I. Proceedings: Pain threshold (PT) analysis in patients with osteoarthritis of the hip. _Ann.
Rheum. Dis._ 34, 195–196 (1975). Article CAS PubMed PubMed Central Google Scholar * Bajaj, P., Graven-Nielsen, T. & Arendt-Nielsen, L. Osteoarthritis and its association with
muscle hyperalgesia: an experimental controlled study. _Pain_ 93, 107–114 (2001). Article CAS PubMed Google Scholar * Kosek, E. & Ordeberg, G. Abnormalities of somatosensory
perception in patients with painful osteoarthritis normalize following successful treatment. _Eur. J. Pain_ 4, 229–238 (2000). Article CAS PubMed Google Scholar * Finan, P. H. _ et al_.
Quantitative sensory tests of central sensitization are associated with discordance between pain and radiographic severity in knee osteoarthritis. _Arthritis Rheum._ 65, 363–372 (2013).
Article PubMed Google Scholar * Graven-Nielsen, T., Wodehouse, T., Langford, R. M., Arendt-Nielsen, L. & Kidd, B. L. Normalization of widespread hyperesthesia and facilitated spatial
summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. _Arthritis Rheum._ 64, 2907–2916 (2012). Article CAS PubMed Google Scholar * Apkarian, A. V.,
Baliki, M. N. & Geha, P. Y. Towards a theory of chronic pain. _Prog. Neurobiol._ 87, 81–97 (2009). Article PubMed Google Scholar * Parks, E. L. _ et al_. Brain activity for chronic
knee osteoarthritis: dissociating evoked pain from spontaneous pain. _Eur. J. Pain_ 15, 843 (2011). PubMed PubMed Central Google Scholar * Kulkarni, B. _ et al_. Arthritic pain is
processed in brain areas concerned with emotions and fear. _Arthritis Rheum._ 56, 1345–1354 (2007). Article CAS PubMed Google Scholar * Apkarian, A. V. Cortical pathophysiology of
chronic pain. _Novartis Found. Symp._ 261, 239–245 (2004). PubMed Google Scholar * Gwilym, S. E., Filippini, N., Douaud, G., Carr, A. J. & Tracey, I. Thalamic atrophy associated with
painful osteoarthritis of the hip is reversible after arthroplasty: a longitudinal voxel-based morphometric study. _Arthritis Rheum._ 62, 2930–2940 (2010). Article PubMed Google Scholar *
Farmer, M. A., Baliki, M. N. & Apkarian, A. V. A dynamic network perspective of chronic pain. _Neurosci. Lett._ 520, 197–203 (2012). Article CAS PubMed PubMed Central Google Scholar
* Apkarian, A. V. The brain in chronic pain: clinical implications. _Pain Management_ 1, 577–586 (2011). Article PubMed Google Scholar * Baliki, M. N. _ et al_. Corticostriatal
functional connectivity predicts transition to chronic back pain. _Nat. Neurosci._ 15, 1117–1119 (2012). Article CAS PubMed PubMed Central Google Scholar * Millan, M. J. Descending
control of pain. _Prog. Neurobiol._ 66, 355–474 (2002). Article CAS PubMed Google Scholar * Ossipov, M. H., Dussor, G. O. & Porreca, F. Central modulation of pain. _J. Clin. Invest._
120, 3779–3787 (2010). Article CAS PubMed PubMed Central Google Scholar * Davis, M. P. in _Research and Development of Opioid-Related Ligands_ Ch. 3 (eds Ko, M.-C. & Husbands, S.
M.) 9–38 (ACS, 2013). Book Google Scholar * Kosek, E. & Ordeberg, G. Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful
osteoarthritis before, but not following, surgical pain relief. _Pain_ 88, 69–78 (2000). Article CAS PubMed Google Scholar * Arendt-Nielsen, L. _ et al_. Sensitization in patients with
painful knee osteoarthritis. _Pain_ 149, 573–581 (2010). Article PubMed Google Scholar * Hochberg, M. C. _ et al_. American College of Rheumatology 2012 recommendations for the use of
nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. _Arthritis Care Res._ 64, 465–474 (2012). Article CAS Google Scholar * Pharmacological
management of persistent pain in older persons. _J. Am. Geriatr. Soc._ 57, 1331–1346 (2009). * Jordan, K. M. _ et al_. EULAR Recommendations 2003: an evidence based approach to the
management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). _Ann. Rheum. Dis._ 62,
1145–1155 (2003). Article CAS PubMed PubMed Central Google Scholar * Zhang, W. _ et al_. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task
force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). _Ann. Rheum. Dis._ 64, 669–681 (2005). Article CAS PubMed Google Scholar * The
National Collaborating Centre for Chronic Conditions. Osteoarthritis: national clinical guideline for care and management in adults. _NICE_ [online], (2008). * Richmond, J. _ et al_.
American Academy of Orthopaedic Surgeons clinical practice guideline on the treatment of osteoarthritis (OA) of the knee. _J. Bone Joint Surg. Am._ 92, 990–993 (2010). Article PubMed
Google Scholar * Towheed, T., Shea, B., Wells, G. & Hochberg, M. Analgesia and non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the hip. _Cochrane Database Syst.
Rev._ CD000517 (2000). * Watson, M. C., Brookes, S. T., Kirwan, J. R. & Faulkner, A. Non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the knee. _Cochrane
Database Syst. Rev._ CD000142 (2000). * McQuay, H. J. & Moore, R. A. Dose-response in direct comparisons of different doses of aspirin, ibuprofen and paracetamol (acetaminophen) in
analgesic studies. _Br. J. Clin. Pharmacol._ 63, 271–278 (2007). Article CAS PubMed Google Scholar * Pham, T. _ et al_. OMERACT-OARSI initiative: Osteoarthritis Research Society
International set of responder criteria for osteoarthritis clinical trials revisited. _Osteoarthritis Cartilage_ 12, 389–399 (2004). Article CAS PubMed Google Scholar * Dworkin, R. H. _
et al_. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. _J. Pain_ 9, 105–121 (2008). Article PubMed Google Scholar *
Dworkin, R. H. _ et al_. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. _Pain_ 146, 238–244 (2009). Article PubMed
Google Scholar * Osiri, M., Suarez-Almazor, M. E., Wells, G. A., Robinson, V. & Tugwell, P. Number needed to treat (NNT): implication in rheumatology clinical practice. _Ann. Rheum.
Dis._ 62, 316–321 (2003). Article CAS PubMed PubMed Central Google Scholar * Rostom, A. _ et al_. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of
traditional NSAIDs with gastroprotection and COX2 inhibitors. _Drug Healthc. Patient Saf._ 1, 47–71 (2009). Article CAS PubMed PubMed Central Google Scholar * Strand, V. Are COX2
inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin? _Lancet_ 370, 2138–2151 (2007). Article
CAS PubMed Google Scholar * Catella-Lawson, F. _ et al_. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. _N. Engl. J. Med._ 345, 1809–1817 (2001). Article CAS PubMed
Google Scholar * Hohlfeld, T., Saxena, A. & Schror, K. High on treatment platelet reactivity against aspirin by non-steroidal anti-inflammatory drugs—pharmacological mechanisms and
clinical relevance. _Thromb. Haemost._ 109, 825–833 (2013). Article CAS PubMed Google Scholar * US Food and Drug Administration. Information for healthcare professionals: concomitant use
of ibuprofen and aspirin. _FDA_ [online]. * Moncada, S. & Vane, J. R. Mode of action of aspirin-like drugs. _Adv. Intern. Med._ 24, 1–22 (1979). CAS PubMed Google Scholar * Momin, A.
& McNaughton, P. A. Regulation of firing frequency in nociceptive neurons by pro-inflammatory mediators. _Exp. Brain Res._ 196, 45–52 (2009). Article CAS PubMed Google Scholar *
Adatia, A., Rainsford, K. D. & Kean, W. F. Osteoarthritis of the knee and hip. Part I: aetiology and pathogenesis as a basis for pharmacotherapy. _J. Pharm. Pharmacol._ 64, 617–625
(2012). Article CAS PubMed Google Scholar * Vardeh, D. _ et al_. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice. _J. Clin. Invest._ 119, 287–294
(2009). CAS PubMed PubMed Central Google Scholar * Gupta, S., Nihalani, N. & Masand, P. Duloxetine: review of its pharmacology, and therapeutic use in depression and other
psychiatric disorders. _Ann. Clin. Psychiatry_ 19, 125–132 (2007). Article PubMed Google Scholar * Sultan, A., Gaskell, H., Derry, S. & Moore, R. A. Duloxetine for painful diabetic
neuropathy and fibromyalgia pain: systematic review of randomised trials. _BMC Neurol._ 8, 29 (2008). Article PubMed PubMed Central CAS Google Scholar * Lunn, M. P., Hughes, R. A. &
Wiffen, P. J. Duloxetine for treating painful neuropathy or chronic pain. _Cochrane Database Syst. Rev._ CD007115 (2009). * Chappell, A. S. _ et al_. Duloxetine, a centrally acting
analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial. _Pain_ 146, 253–260 (2009). Article CAS PubMed Google Scholar *
Skljarevski, V. _ et al_. Efficacy and safety of duloxetine in patients with chronic low back pain. _Spine_ 35, E578–E585 (2010). Article PubMed Google Scholar * Chappell, A. S. _ et al_.
A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee. _Pain Pract._ 11, 33–41
(2011). Article PubMed Google Scholar * Hochberg, M. C., Wohlreich, M., Gaynor, P., Hanna, S. & Risser, R. Clinically relevant outcomes based on analysis of pooled data from 2 trials
of duloxetine in patients with knee osteoarthritis. _J. Rheum._ 39, 352–358 (2012). Article CAS PubMed Google Scholar * Lee, Y. C. & Chen, P. P. A review of SSRIs and SNRIs in
neuropathic pain. _Expert Opin. Pharmacother._ 11, 2813–2825 (2010). Article CAS PubMed Google Scholar * Derry, S., Gill, D., Phillips, T. & Moore, R. A. Milnacipran for neuropathic
pain and fibromyalgia in adults. _Cochrane Database Syst. Rev._ 3, CD008244 (2012). Google Scholar * Lane, N. E. _ et al_. RN624 (anti-NGF) improves pain and function in subjects with
moderate knee osteoarthritis: a phase I study. _Arthritis Rheum._ 52, S461 (2005). Article Google Scholar * Brown, M. T. _ et al_. Tanezumab reduces osteoarthritic knee pain: results of a
randomized, double-blind, placebo-controlled phase III trial. _J. Pain_ 13, 790–798 (2012). Article CAS PubMed Google Scholar * Balanescu, A. R. _ et al_. Efficacy and safety of
tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical
trial. _Ann. Rheum. Dis._ http://dx.doi.org/10.1136/annrheumdis-2012-203164. * Brown, M. T. _ et al_. Tanezumab reduces osteoarthritic hip pain: results of a randomized, double-blind,
placebo-controlled phase III trial. _Arthritis Rheum._ 65, 1795–1803 (2013). Article CAS PubMed Google Scholar * Spierings, E. L. _ et al_. A phase III placebo- and oxycodone-controlled
study of tanezumab in adults with osteoarthritis pain of the hip or knee. _Pain_ http://dx.doi.org/10.1016/j.pain.2013.04.035. * FDA Center For Drug Evaluation And Research. Arthritis
Advisory Committee Meeting: March 12, 2012. _FDA_ [online]. * Hefti, F. F. _ et al_. Novel class of pain drugs based on antagonism of NGF. _Trends Pharmacol. Sci._ 27, 85–91 (2006). Article
CAS PubMed Google Scholar * Pezet, S. & McMahon, S. B. Neurotrophins: mediators and modulators of pain. _Annu. Rev. Neurosci._ 29, 507–538 (2006). Article CAS Google Scholar *
Bonnin, M. P., Basiglini, L. & Archbold, H. A. What are the factors of residual pain after uncomplicated TKA? _Knee Surg. Sports Traumatol. Arthrosc._ 19, 1411–1417 (2011). Article
PubMed Google Scholar * Hofmann, S., Seitlinger, G., Djahani, O. & Pietsch, M. The painful knee after TKA: a diagnostic algorithm for failure analysis. _Knee Surg. Sports Traumatol.
Arthrosc._ 19, 1442–1452 (2011). Article CAS PubMed Google Scholar * Fortin, P. R. _ et al_. Outcomes of total hip and knee replacement: preoperative functional status predicts outcomes
at six months after surgery. _Arthritis Rheum._ 42, 1722–1728 (1999). Article CAS PubMed Google Scholar * Lingard, E. A., Katz, J. N., Wright, E. A. & Sledge, C. B. Predicting the
outcome of total knee arthroplasty. _J. Bone Joint Surg. Am._ 86A, 2179–2186 (2004). Article Google Scholar * Valdes, A. M. _ et al_. Inverse relationship between preoperative radiographic
severity and postoperative pain in patients with osteoarthritis who have undergone total joint arthroplasty. _Semin. Arthritis Rheum._ 41, 568–575 (2012). Article PubMed Google Scholar *
Diatchenko, L., Nackley, A. G., Tchivileva, I. E., Shabalina, S. A. & Maixner, W. Genetic architecture of human pain perception. _Trends Genet._ 23, 605–613 (2007). Article CAS PubMed
Google Scholar * Valdes, A. M. _ et al_. The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis. _Ann. Rheum. Dis._ 70, 1556–1561 (2011). Article PubMed Google
Scholar * Malfait, A. M. _ et al_. A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype. _Ann. Rheum. Dis._ 71, 1042–1048 (2012).
Article CAS PubMed Google Scholar * Sorge, R. E. _ et al_. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. _Nat. Med._ 18, 595–599
(2012). Article CAS PubMed PubMed Central Google Scholar * van Meurs, J. B. _ et al_. A functional polymorphism in the catechol-O-methyltransferase gene is associated with
osteoarthritis-related pain. _Arthritis Rheum._ 60, 628–629 (2009). Article PubMed Google Scholar * Reimann, F. _ et al_. Pain perception is altered by a nucleotide polymorphism in
_SCN9A_. _Proc. Natl Acad. Sci. USA_ 107, 5148–5153 (2010). Article CAS PubMed PubMed Central Google Scholar * Valdes, A. M. _ et al_. Role of the Nav1.7 R1150W amino acid change in
susceptibility to symptomatic knee osteoarthritis and multiple regional pain. _Arthritis Care Res._ 63, 1440–1444 (2011). Article CAS Google Scholar Download references ACKNOWLEDGEMENTS
A.-M. Malfait acknowledges funding from the US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060364 and R01AR064251) and from the
Arthritis Foundation. The funding sources had no role in the preparation of this publication. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine, and Department of
Biochemistry, Section of Rheumatology, Rush University Medical Center, 1611 W. Harrison Street, Chicago, 60612, IL, USA Anne-Marie Malfait * Department of Physical Medicine and
Rehabilitation and Department of Internal Medicine, Northwestern University Feinberg School of Medicine, 710 N. Lake Shore Drive, Chicago, 60611, IL, USA Thomas J. Schnitzer Authors *
Anne-Marie Malfait View author publications You can also search for this author inPubMed Google Scholar * Thomas J. Schnitzer View author publications You can also search for this author
inPubMed Google Scholar CONTRIBUTIONS Both authors contributed substantially to all aspects of the preparation of this manuscript. CORRESPONDING AUTHOR Correspondence to Thomas J. Schnitzer.
ETHICS DECLARATIONS COMPETING INTERESTS A. M. Malfait declares that she has acted as a consultant for Allergan. T. J. Schnitzer declares that he has acted as a consultant for Pfizer,
Janssen and Regeneron, and has received research funding from Pfizer and Lilly. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR TABLE 1 RIGHTS AND PERMISSIONS Reprints and
permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Malfait, AM., Schnitzer, T. Towards a mechanism-based approach to pain management in osteoarthritis. _Nat Rev Rheumatol_ 9, 654–664 (2013).
https://doi.org/10.1038/nrrheum.2013.138 Download citation * Published: 17 September 2013 * Issue Date: November 2013 * DOI: https://doi.org/10.1038/nrrheum.2013.138 SHARE THIS ARTICLE
Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided
by the Springer Nature SharedIt content-sharing initiative