Current Rheumatology Reports

, Volume 14, Issue 6, pp 583–588 | Cite as

Control of Arthritis Pain with Anti–Nerve-Growth Factor: Risk and Benefit

  • Matthias F. SeidelEmail author
  • Nancy E. Lane


Arthritis is characterized by pain and inflammation. Recently, attention has been focused on nerve-growth factor (NGF), a neurotrophin that is a key regulator of peripheral nociception because it mediates overexpression of proinflammatory neuron-derived molecules such as substance P, serotonin, and calcitonin gene-related peptide. Antibodies have been generated for NGF and its receptor that are effective in reducing pain in preclinical pain models, and clinical trials in patients with advanced knee and hip osteoarthritis and low-back pain. Results show pain reduction is rapid and sustained. Adverse events with anti-NGF included transient paraesthesia and edema, rapidly progressive OA, and, in a small number of patients treated with both anti-NGF and nonsteroidal anti-inflammatory drugs, osteonecrosis. Inhibition of the NGF-stimulated nociceptive pathway seems to be effective; however, the adverse effects require further investigation.


Neurogenic inflammation Nerve-growth factor NGF Receptor antagonists Rheumatic diseases Arthritis Pain Risk Benefit Antagonists 



Dr Seidel has served on a board for Pfizer. Dr Lane has served as a consultant for, and had travel expenses covered/reimbursed by, Pfizer.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Riedel W, Neeck G. Nociception, pain, and antinociception: current concepts. Z Rheumatol. 2001;60(6):404–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Seidel M, Tsalik J, Vetter H, Müller W. Substance P in rheumatic diseases. Curr Rheum Rev. 2007;3:17–30.CrossRefGoogle Scholar
  3. 3.
    Regoli D, Boudon A, Fauchere J. Receptors and antagonists for substance P and related peptides. Pharmacol Rev. 1994;46(4):551–99.PubMedGoogle Scholar
  4. 4.
    Hartung HP, Toyka KV. Activation of macrophages by substance P: induction of oxidative burst and thromboxane release. Eur J Pharmacol. 1983;89(3–4):301–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Hafström I, Gyllenhammar H, Palmblad J, Ringertz B. Substance P activates and modulates neutrophil oxidative metabolism and aggregation. J Rheumatol. 1989;16(8):1033–7.PubMedGoogle Scholar
  6. 6.
    Nakagawa N, Sano H, Iwamoto I. Substance P induces the expression of intercellular adhesion molecule-1 on vascular endothelial cells and enhances neutrophil ransendothelial migration. Peptides. 1995;16(4):721–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Payan DG, Brewster DR, Goetzl EJ. Specific stimulation of human T lymphocytes by substance P. J Immunol. 1983;131(4):1613–5.PubMedGoogle Scholar
  8. 8.
    Reinhardt RR, Laub JB, Fricke JR, et al. Comparison of neurokinin-1 antagonist, L-745,030, to placebo, acetominophen and ibuprofen in the dental pain model. Clin Pharmacol Ther. 1998;63(2):168.Google Scholar
  9. 9.
    Kushnir-Sukhov NM, Brown JM, Wu Y, et al. Human mast cells are capable of serotonin synthesis and release. J Allergy Clin Immunol. 2007;119(2):498–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Tominaga K, Alstergren P, Kurita H, Kopp S. Serotonin in an antigen-induced arthritis of the rabbit temporomandibular joint. Arch Oral Biol. 1999;44:595–601.PubMedCrossRefGoogle Scholar
  11. 11.
    Harbuz MS, Perveen-Gill Z, Lalies MD, et al. The role of endogenous serotonin in adjuvant-induced arthritis in the rat. Br J Rheumatol. 1996;35(2):112–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Seidel MF, Müller W. Differential pharmacotherapy for subgroups of fibromyalgia patients with specific consideration of 5-HT3 receptor antagonists. Exp Opin Pharm. 2011;12(9):1381–91.CrossRefGoogle Scholar
  13. 13.
    Seidel MF. Local injections of serotonin type-3 receptor antagonists as a therapeutic option in rheumatology. Fut Med Chem. 2012;4(6):705–7.CrossRefGoogle Scholar
  14. 14.
    Liu L, Shenoy M, Pasricha PJ. Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve-growth factor. JOP. 2011;12(4):389–94.PubMedGoogle Scholar
  15. 15.
    Horigome K, Pryor JC, Bullock ED, Johnson Jr EM. Mediator release from mast cells by nerve-growth factor, neurotrophin specificity and receptor mediation. J Biol Chem. 1993;268(20):14881–7.PubMedGoogle Scholar
  16. 16.
    Gerber RK, Nie H, Arendt-Nielsen L, et al. Local pain and spreading hyperalgesia induced by intramuscular injection of nerve-growth factor are not reduced by local anesthesia of the muscle. Clin J Pain. 2011;27(3):240–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Levi-Montalcini R, Hamburger V. Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J Exp Zool. 1951;116(2):321–61.PubMedCrossRefGoogle Scholar
  18. 18.
    Barbacid M. Structural and functional properties of the TRK family of neurotrophin receptors. Ann N Y Acad Sci. 1995;7(766):442–58.CrossRefGoogle Scholar
  19. 19.
    Gruss HJ, Dower SK. The TNF ligand superfamily and its relevance for human diseases. Cytokines Mol Ther. 1995;1(2):75–105.PubMedGoogle Scholar
  20. 20.
    •• Seidel MF, Herguijuela M, Forkert R, Otten U. Nerve-growth factor in rheumatic diseases. Sem Arthr Rheum. 2009;40(2):109–26. This article summarizes the background and most important studies on NGF in rheumatic diseases.CrossRefGoogle Scholar
  21. 21.
    Otten U, Ehrhard P, Peck R. Nerve-growth factor induces growth and differentiation of human B lymphocytes. Proc Natl Acad Sci USA. 1989;86:10059–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Nassenstein C, Möhring UH, Luttmann W, et al. Differential expression of the neurotrophin receptors p75NTR, TrkA, TrkB and TrkC in human peripheral blood mononuclear cells. Exp Toxicol Pathol. 2006;57 Suppl 2:55–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Bischoff SC, Dahinden CA. Effect of nerve-growth factor on the release of inflammatory mediators by mature human basophils. Blood. 1992;79(10):2662–9.PubMedGoogle Scholar
  24. 24.
    Takafuji S, Bischoff SC, De Weck AL, Dahinden CA. Opposing effects of tumor necrosis factor-α and nerve-growth factor upon leukotriene C4 production by human eosinophils triggered with N-formyl-methionyl-leucyl-phenylalanine. Eur J Immunol. 1992;22(4):969–74.PubMedCrossRefGoogle Scholar
  25. 25.
    Gee AP, Boyle MD, Munger KL, et al. Nerve-growth factor: stimulation of polymorphonuclear leukocyte chemotaxis in vitro. Proc Natl Acad Sci USA. 1983;80(23):7215–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Cirulli F, Alleva E. The NGF saga: from animal models of psychosocial stress to stress-related psychopathology. Front Neuroendocrinol. 2009;30(3):379–95.PubMedCrossRefGoogle Scholar
  27. 27.
    Cirulli F, Francia N, Branchi I, et al. Changes in plasma levels of BDNF and NGF reveal a gender-selective vulnerability to early adversity in rhesus macaques. Psychoneuroendocrin. 2009;34:172–80.CrossRefGoogle Scholar
  28. 28.
    Aloe L, Alleva E, Böhm A, Levi-Montalcini R. Aggressive behaviour induces release of nerve-growth factor from mouse salivary gland into the bloodstream. Proc Natl Acad Sci USA. 1986;83(16):6184–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Aloe L, Bracci-Laudiero L, Alleva E, et al. Emotional stress induced by parachute jumping enhances blood nerve-growth factor levels and the distribution of nerve-growth factor receptors in lymphocytes. Proc Natl Acad Sci USA. 1994;91:10440–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Aloe L, Tuveri M, Guerra G, et al. Changes in human plasma nerve-growth factor level after chronic alcohol consumption and withdrawal. Alcohol Clin Exp Res. 1996;20(3):462–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci. 2006;27(2):85–91.PubMedCrossRefGoogle Scholar
  32. 32.
    •• Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363(16):1521–31. This study shows the efficacy of NGF antagonists on osteoarthritic pain.PubMedCrossRefGoogle Scholar
  33. 33.
    • Katz N, Borenstein DG, Birbara C, et al. Efficacy and safety of tanezumab in the treatment of chronic low-back pain. Pain. 2011;152(10):2248–58. This study shows the efficacy of NGF antagonists on low-back pain.PubMedCrossRefGoogle Scholar
  34. 34.
    Schnitzer TJ, Lane NE, Birbara C, et al. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthr Cart. 2011;19(6):639–46.CrossRefGoogle Scholar
  35. 35.
    Nagashima H, Suzuki M, Araki S, Tanezumab Investigators. Preliminary assessment of the safety and efficacy of tanezumab in Japanese patients with moderate to severe osteoarthritis of the knee: a randomized, double-blind, dose-escalation, placebo-controlled study. Osteoarthr Cart. 2011;19(12):1405–12.CrossRefGoogle Scholar
  36. 36.
    Tiseo P, Kivitz AJ, Ervin JE, et al. REGN475/SAR164877, a nerve growth factor inhibitor, in osteoarthritis patients with moderate to severe knee pain: results of a phase 2, randomized, double-blind, placebo-controlled study. Arthr Rheum. 2010;62 Suppl 10:710.Google Scholar
  37. 37.
    Feist E, Balanescu A, Wolfram G, et al. Efficacy and safety of tanezumab added on to diclofenac in patients with knee or hip osteoarthritis (NCT00864097). Arthr Rheum. 2011;63 Suppl 10:1096.Google Scholar
  38. 38.
    Yazici Y, Ekman EF, Greenberg HS, et al. Efficacy of tanezumab compared with non-steroidal anti-inflammatory drugs in patients with knee or hip osteoarthritis (NCT00809354). Arthr Rheum. 2011;63 Suppl 10:828.Google Scholar
  39. 39.
    Apfel SC, Arezzo JC, Brownlee M, et al. Nerve-growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res. 1994;634(1):7–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Ding J, Cheng Y, Gao S, Chen J. Effects of nerve-growth factor and Noggin-modified bone marrow stromal cells on stroke in rats. J Neurosci Res. 2011;89(2):222–30.PubMedCrossRefGoogle Scholar
  41. 41.
    Lecht S, Arien-Zakay H, Marcinkiewicz C, et al. Nerve-growth factor-induced protection of brain capillary endothelial cells exposed to oxygen-glucose deprivation involves attenuation of Erk phosphorylation. J Mol Neurosci. 2010;41(1):183–92.PubMedCrossRefGoogle Scholar
  42. 42.
    Liberini P, Cuello AC. Effects of nerve-growth factor in primate models of neurodegeneration: potential relevance in clinical neurology. Rev Neurosci. 1994;5(2):89–104.PubMedGoogle Scholar
  43. 43.
    Scott SA, Crutcher KA. Nerve-growth factor and Alzheimer’s disease. Rev Neurosci. 1994;5(3):179–211.PubMedGoogle Scholar
  44. 44.
    Colafrancesco V, Villoslada P. Targeting NGF pathway for developing neuroprotective therapies for multiple sclerosis and other neurological diseases. Arch Ital Biol. 2011;149(2):183–92.PubMedGoogle Scholar
  45. 45.
    Ghilardi JR, Freeman KT, Jimenez-Andrade JM et al. Neuroplasticity of sensory and sympathetic nerve fibers in the painful arthritic joint. Arthr Rheum 2012; in press.Google Scholar
  46. 46.
    Pincelli C, Sevignani C, Manfredini R, et al. Expression and function of nerve-growth factor and nerve-growth factor receptor on cultured keratinocytes. J Invest Dermatol. 1994;103(1):13–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Lambiase A, Rama P, Bonini S, et al. Topical treatment with nerve-growth factor for corneal neurotrophic ulcers. N Engl J Med. 1998;338(17):1174–80.PubMedCrossRefGoogle Scholar
  48. 48.
    Lambiase A, Bonini S, Micera A, et al. Expression of nerve-growth factor receptors on the ocular surface in healthy subjects and during manifestation of inflammatory diseases. Invest Ophthalmol Vis Sci. 1998;39(7):1272–5.PubMedGoogle Scholar
  49. 49.
    Tuveri MA, Generini S, Matucci-Cerinic M, Aloe L. NGF, a useful tool in the treatment of chronic vasculitic ulcers in rheumatoid arthritis. Lancet. 2000;356:1739–40.PubMedCrossRefGoogle Scholar
  50. 50.
    Aloe L. Nerve-growth factor, human skin ulcers and vascularization. Our experience. Prog Brain Res. 2004;146:515–22.PubMedCrossRefGoogle Scholar
  51. 51.
    Sensebe L, Deschaseaux M, Li J, et al. The broad spectrum of cytokine gene expression by myoid cells from the human marrow microenvironment. Stem Cells. 1997;15(2):133–43.PubMedCrossRefGoogle Scholar
  52. 52.
    Labouyrie E, Dubus P, Groppi A, et al. Expression of neurotrophins and their receptors in human bone marrow. Am J Pathol. 1999;154(2):405–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Aiga A, Asaumi K, Lee YJ, et al. Expression of neurotrophins and their receptors tropomyosin-related kinases (Trk) under tension-stress during distraction osteogenesis. Acta Med Okayama. 2006;60(5):267–77.PubMedGoogle Scholar
  54. 54.
    Yan XZ, Ge SH, Sun QF, et al. A pilot study evaluating the effect of recombinant human bone morphogenetic protein-2 and recombinant human beta-nerve-growth factor on the healing of class III furcation defects in dogs. J Periodontol. 2010;81(9):1289–98.PubMedCrossRefGoogle Scholar
  55. 55.
    Letic-Gavrilovic A, Piattelli A, Abe K. Nerve-growth factor beta (NGF beta) delivery via a collagen/hydroxyapatite (Col/HAp) composite and its effects on new bone ingrowth. J Mater Sci Mater Med. 2003;14(2):95–102.PubMedCrossRefGoogle Scholar
  56. 56.
    Mammoto T, Seerattan RA, Paulson KD, et al. Nerve-growth factor improves ligament healing. J Orthop Res. 2008;26(7):957–64.PubMedCrossRefGoogle Scholar
  57. 57.
    Koewler NJ, Freeman KT, Buus RJ, et al. Effects of a monoclonal antibody raised against nerve-growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur. J Bone Miner Res. 2007;22(11):1732–42.PubMedCrossRefGoogle Scholar
  58. 58.
    Gašperšic R, Kovacic U, Glisovic S, et al. Anti-NGF treatment reduces bone resorption in periodontitis. J Dent Res. 2010;89(5):515–20.PubMedCrossRefGoogle Scholar
  59. 59.
    Della Torre P, Picuti G, Di Filippo P. Rapidly progressive osteoarthritis of the hip. Ital J Orthop Traumatol. 1987;13(2):187–200.PubMedGoogle Scholar
  60. 60.
    Scuri M, Samsell L, Piedimonte G. The role of neurotrophins in inflammation and allergy. Inflamm Allergy Drug Targets. 2010;9(3):173–80.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhu ZW, Friess H, Wang L, et al. Nerve-growth factor exerts differential effects on the growth of human pancreatic cancer cells. Clin Cancer Res. 2001;7(1):105–12.PubMedGoogle Scholar
  62. 62.
    Jin H, Pan Y, Zhao L, et al. p75 neurotrophin receptor suppresses the proliferation of human gastric cancer cells. Neoplasia. 2007;9(6):471–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Goda M, Atagi S, Amitani K, et al. Nerve-growth factor suppresses prostate tumor growth. J Pharmacol Sci. 2010;112(4):463–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Section of RheumatologyMedizinische Klinik und Poliklinik III, University HospitalBonnGermany
  2. 2.Department of MedicineUniversity of California Davis School of MedicineSacramentoUSA

Personalised recommendations