Skip to main content

Advertisement

SpringerLink
Log in

A Mechanism-Based Approach to the Management of Osteoarthritis Pain

  • Bone and Joint Pain (PW Mantyh and TJ Schnitzer, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Pain from osteoarthritis (OA) affects millions of people worldwide, yet treatments are limited to acetaminophen, NSAIDs, physical therapy, and ultimately, surgery when there is significant disability. In recent years, our understanding of pain pathways in OA has developed considerably. Though joint damage and inflammation play a significant role in pain generation, it is now understood that both central and peripheral nervous system mechanisms exacerbate symptoms. Evolving management strategies for OA address central factors (e.g., sleep difficulties, catastrophizing, and depression) with treatments such as cognitive behavioral therapy and exercise. In addition, emerging data suggest that antibodies against peripheral signaling neuropeptides, such as nerve growth factor-1 (NGF-1), may significantly alleviate pain. However, concerns regarding potential adverse effects, such as rapidly progressive OA, still remain. A nuanced understanding is essential if we are to make headway in developing more effective treatments for OA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15–25.

    Article  PubMed  Google Scholar 

  2. Leigh JP, Seavey W, Leistikow B. Estimating the costs of job related arthritis. J Rheumatol. 2001;28:1647–54.

    CAS  PubMed  Google Scholar 

  3. White AG, Birnbaum HG, Janagap C, Buteau S, Schein J. Direct and indirect costs of pain therapy for osteoarthritis in an insured population in the United States. J Occup Environ Med. 2008;50:998–1005.

    Article  PubMed  Google Scholar 

  4. Gabriel SE, Crowson CS, Campion ME, O’Fallon WM. Indirect and nonmedical costs among people with rheumatoid arthritis and osteoarthritis compared with nonarthritic controls. J Rheumatol. 1997;24:43–8.

    CAS  PubMed  Google Scholar 

  5. Elliott AM, Smith BH, Penny KI, Smith WC, Chambers WA. The epidemiology of chronic pain in the community. Lancet. 1999;354:1248–52.

    Article  CAS  PubMed  Google Scholar 

  6. Neogi T, Felson D, Niu J, Nevitt M, Lewis CE, Aliabadi P, et al. Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ. 2009;339:b2844.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Torres L, Dunlop DD, Peterfy C, Guermazi A, Prasad P, Hayes KW, et al. The relationship between specific tissue lesions and pain severity in persons with knee osteoarthritis. Osteoarthr Cartil. 2006;14:1033–40.

    Article  CAS  PubMed  Google Scholar 

  8. Stoppiello LA, Mapp PI, Wilson D, Hill R, Scammell BE, Walsh DA. Structural associations of symptomatic knee osteoarthritis. Arthritis Rheumatol (Hoboken, NJ). 2014;66:3018–27.

    Article  Google Scholar 

  9. McKelvey L, Shorten GD, O’Keeffe GW. Nerve growth factor-mediated regulation of pain signalling and proposed new intervention strategies in clinical pain management. J Neurochem. 2013;124:276–89.

    Article  CAS  PubMed  Google Scholar 

  10. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999;282:2131–5.

    Article  CAS  PubMed  Google Scholar 

  11. Isola M, Ferrari V, Miolo A, Stabile F, Bernardini D, Carnier P, et al. Nerve growth factor concentrations in the synovial fluid from healthy dogs and dogs with secondary osteoarthritis. Vet Comp Orthop Traumatol. 2011;24:279–84.

    Article  CAS  PubMed  Google Scholar 

  12. Pecchi E, Priam S, Gosset M, Pigenet A, Sudre L, Laiguillon M-C, et al. Induction of nerve growth factor expression and release by mechanical and inflammatory stimuli in chondrocytes: possible involvement in osteoarthritis pain. Arthritis Res Ther. 2014;16:R16.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Walsh DA, Mcwilliams DF, Turley MJ, Dixon MR, Fransès RE, Mapp PI, et al. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology. 2010;49:1852–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Svensson P, Cairns BE, Wang K, Arendt-Nielsen L. Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia. Pain. 2003;104:241–7.

    Article  CAS  PubMed  Google Scholar 

  15. König C, Zharsky M, Möller C, Schaible HG, Ebersberger A. Involvement of peripheral and spinal tumor necrosis factor α in spinal cord hyperexcitability during knee joint inflammation in rats. Arthritis Rheum. 2014;66:599–609.

    Article  Google Scholar 

  16. Stannus OP, Jones G, Blizzard L, Cicuttini FM, Ding C. Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study. Ann Rheum Dis. 2013;72:535–40.

    Article  CAS  PubMed  Google Scholar 

  17. Takeshita M, Nakamura J, Ohtori S, Inoue G, Orita S, Miyagi M, et al. Sensory innervation and inflammatory cytokines in hypertrophic synovia associated with pain transmission in osteoarthritis of the hip: a case-control study. Rheumatology (Oxford). 2012;51:1790–5.

    Article  CAS  Google Scholar 

  18. Lee YC, Lu B, Bathon JM, Haythornthwaite JA, Smith MT, Page GG, et al. Pain sensitivity and pain reactivity in osteoarthritis. Arthritis Care Res. 2011;63:320–7.

    Google Scholar 

  19. Graven-Nielsen T, Wodehouse T, Langford RM, Arendt-Nielsen L, Kidd BL. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum. 2012;64:2907–16.

    Article  CAS  PubMed  Google Scholar 

  20. Malfait A-M, Schnitzer TJ. Towards a mechanism-based approach to pain management in osteoarthritis. Nat Rev Rheumatol. 2013;9:654–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, et al. Sensitization in patients with painful knee osteoarthritis. Pain. 2010;149:573–81.

    Article  PubMed  Google Scholar 

  22. Petersen KK, Arendt-Nielsen L, Simonsen O, Wilder-Smith O, Laursen MB. Presurgical assessment of temporal summation of pain predicts the development of chronic postoperative pain 12 months after total knee replacement. Pain. 2015;156:55–61. Petersen et al. studied patients undergoing total knee replacement and found a significant association between pre-operative measures of central sensitization and post-operative pain intensity. This knowledge may ultimately be useful to predict which patients with OA are suitable candidates for total knee replacement surgery.

  23. Baliki M, Petre B, Torbey S. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci. 2012;15:1117–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. 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. 2000;88:69–78.

    Article  CAS  PubMed  Google Scholar 

  25. Kulkarni B, Bentley DE, Elliott R, Julyan PJ, Boger E, Watson A, et al. Arthritic pain is processed in brain areas concerned with emotions and fear. Arthritis Rheum. 2007;56:1345–54.

    Article  CAS  PubMed  Google Scholar 

  26. Monfort J, Pujol J, Lopez-Ruiz M, Llorente-Onaindia J, Martinez-Vilavella G, Macia D, et al. Functional magnetic resonance imaging evaluation of pain central sensitization phenomena in subjects with knee osteoarthritis. Osteoarthr Cartil. 2015; 23:A60.

  27. Smith MT, Quartana PJ, Okonkwo RM, Nasir A. Mechanisms by which sleep disturbance contributes to osteoarthritis pain: a conceptual model. Curr Pain Headache Rep. 2009;13:447–54.

    Article  PubMed  Google Scholar 

  28. Vitiello MV, McCurry SM, Shortreed SM, Baker LD, Rybarczyk BD, Keefe FJ, et al. Short-term improvement in insomnia symptoms predicts long-term improvements in sleep, pain, and fatigue in older adults with comorbid osteoarthritis and insomnia. Pain. 2014;155:1547–54.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Petrov M, Goodin B, Cruz-Almeida Y. Disrupted sleep is associated with altered pain processing by sex and ethnicity in knee osteoarthritis. J Pain. 2015;16:478–90.

    Article  PubMed  Google Scholar 

  30. Smith MT, Edwards RR, McCann UD, Haythornthwaite JA. The effects of sleep deprivation on pain inhibition and spontaneous pain in women. Sleep. 2007;30:494–505.

    PubMed  Google Scholar 

  31. Haack M, Sanchez E, Mullington JM. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep. 2007;30:1145–52.

    PubMed Central  PubMed  Google Scholar 

  32. Egsgaard L, Eskehave T, Bay-Jensen AC, Hoeck HC, Arendt-Nielsen L. Identifying specific profiles in patients with different degrees of painful knee osteoarthritis based on serological biochemical and mechanistic pain biomarkers: a diagnostic approach based on cluster analysis. Pain. 2015;156:96–107. This paper provides an example of how biochemical, physical and psychological factors can be integrated to characterize OA patients into distinct pain profiles that reflect underlying pain mechanisms.

  33. Campbell C, Buenaver L, Finan P, Bounds SC, Redding M, McCauley L, et al. Sleep, pain catastrophizing and central sensitization in knee osteoarthritis patients with and without insomnia. Arthritis Care Res (Hoboken). 2015;67(10):1387–96.

  34. Cruz‐Almeida Y, King C. Psychological profiles and pain characteristics of older adults with knee osteoarthritis. Arthritis Care Res (Hoboken). 2013;65:1786–94.

    Article  Google Scholar 

  35. Finan P, Quartana P, Smith M. Positive and negative affect dimensions in chronic knee osteoarthritis: effects on clinical and laboratory pain. Psychosom Med. 2013;75:463–70.

    Article  CAS  PubMed  Google Scholar 

  36. Hochberg MC 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 (Hoboken). 2012;64(4):465–74.

    Article  CAS  Google Scholar 

  37. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. New Engl J Med. 1991;325:87–91.

  38. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006;1:CD004257.

  39. Anderson BJ. Paracetamol (acetaminophen): mechanisms of action. Paediatr Anaesth. 2008;18:915–21.

    Article  PubMed  Google Scholar 

  40. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006;12:250–75.

    Article  CAS  PubMed  Google Scholar 

  41. Bjordal JM, Ljunggren AE, Klovning A, Slørdal L. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ. 2004;329:1317.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Chou R, McDonagh M, Nakamoto E, Griffin J. Analgesics for osteoarthritis: an update of the 2006 comparative effectiveness review. Comp Eff Rev. 2011;38:1–113.

  43. Baigent C, Bhala N, Emberson J, Merhi A, Abramson S, Arber N, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769–79.

    Article  CAS  PubMed  Google Scholar 

  44. Altman RD, Barthel HR. Topical therapies for osteoarthritis. Drugs. 2011;71:1259–79.

    Article  CAS  PubMed  Google Scholar 

  45. Kienzler J-L, Gold M, Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J Clin Pharmacol. 2010;50:50–61.

    Article  CAS  PubMed  Google Scholar 

  46. Radermacher J, Jentsch D, Scholl MA, Lustinetz T, Frölich JC. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol. 1991;31:537–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Singh P, Roberts MS. Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application. J Pharmacol Exp Ther. 1994;268:144–51.

    CAS  PubMed  Google Scholar 

  48. Zacher J, Burger KF, Farber L. Topical diclofenac Emulgel versus oral ibuprofen in the treatment of active osteoarthritis of the finger joints (Heberden’s and/ or Bouchard’s nodes): double-blind, controlled, randomized study. Aktuelle Rheumatologie. 2001; 26:7–14.

  49. Simon LS, Grierson LM, Naseer Z, et al. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain 2009; 143:238–45.

  50. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (Pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31:2002–12.

  51. Sandelin J, Harilainen A, Crone H, et al. Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee: a double blind study comparing eltenac with oral diclofenac and placebo gel. Scand J Rheumatol. 1997;26:287–92.

  52. Dickson DJ. A double-blind evaluation of topical piroxicam gel with oral ibuprofen in osteoarthritis of the knee. Curr Ther Res Clin Exp. 1991;49:199–207.

  53. Rains C, Bryson HM. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging. 1995;7:317–28.

    Article  CAS  PubMed  Google Scholar 

  54. Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8 patch. Br J Anaesth. 2011;107:490–502.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Bode AM, Dong Z. The two faces of capsaicin. Cancer Res. 2011;71:2809–14.

    Article  CAS  PubMed  Google Scholar 

  56. McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol. 1992;19:604–7.

    CAS  PubMed  Google Scholar 

  57. Altman RD, Aven A, Holmburg CE, Pfeifer LM, Sack M, Young GT. Capsaicin cream 0.025% as monotherapy for osteoarthritis: a double-blind study. Semin Arthritis Rheum. 1994;23:25–33.

    Article  Google Scholar 

  58. Schnitzer TJ, Marks JA. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthr Cartil. 2015;23 Suppl 1:S8–S17.

    Article  PubMed  Google Scholar 

  59. Schnitzer TJ, Ekman EF, Spierings ELH, Greenberg HS, Smith MD, Brown MT, et al. Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain. Ann Rheum Dis. 2015;74:1202–11. Schnitzer et al. conducted a trial comparing tanezumab (an anti-NGF-1 antibody) monotherapy, with NSAID monotherapy and a combination of both tanezumab and NSAIDs. Both tanezumab monotherapy and tanezumab plus NSAID combination therapy produced statistically significant improvements in WOMAC scores, compared to NSAIDs alone. However, combination therapy was associated with the highest frequency of serious adverse events, including osteonecrosis and progressive OA.

  60. Chappell AS, Desaiah D, Liu-Seifert H, Zhang S, Skljarevski V, Belenkov Y, 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. 2011;11:33–41.

    Article  PubMed  Google Scholar 

  61. Abou-Raya S, Abou-Raya A, Helmii M. Duloxetine for the management of pain in older adults with knee osteoarthritis: randomised placebo-controlled trial. Age Ageing. 2012;41:646–52.

    Article  PubMed  Google Scholar 

  62. Chappell AS, Ossanna MJ, Liu-Seifert H, Iyengar S, Skljarevski V, Li LC, et al. Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial. Pain. 2009;146:253–60.

    Article  CAS  PubMed  Google Scholar 

  63. Brunton S, Wang F, Edwards SB, Crucitti AS, Ossanna MJ, Walker DJ, et al. Profile of adverse events with duloxetine treatment: a pooled analysis of placebo-controlled studies. Drug Saf. 2010;33:393–407.

    Article  CAS  PubMed  Google Scholar 

  64. Nijs J, Kosek E, Van Oosterwijck J, Meeus M. Dysfunctional endogenous analgesia during exercise in patients with chronic pain: to exercise or not to exercise? Pain Physician. 2012;15(3 Suppl):ES205–13.

    PubMed  Google Scholar 

  65. Uthman OA, van der Windt DA, Jordan JL, Dziedzic KS, Healey EL, Peat GM, et al. Exercise for lower limb osteoarthritis: systematic review incorporating trial sequential analysis and network meta-analysis. BMJ. 2013;347:f5555.

  66. Bosomworth NJ. Exercise and knee osteoarthritis: benefit or hazard? Can Fam Physician. 2009;55:871–8.

    PubMed Central  PubMed  Google Scholar 

  67. Smith MT, Finan PH, Buenaver LF, Robinson M, Haque U, Quain A, et al. Cognitive-behavioral therapy for insomnia in knee osteoarthritis: a randomized, double-blind, active placebo-controlled clinical trial. Arthritis Rheumatol (Hoboken, NJ). 2015;67:1221–33. This group conducted a randomized, double-blind, placebo-controlled trial of cognitive behavioral therapy for insomnia in knee OA. They found that this intervention decreased clinical pain but did not have any effect on conditioned pain modulation as measured by quantitative sensory testing.

    Article  Google Scholar 

  68. Hochberg M, Martel-Pelletier J, Monfort J, Moller I, Castillo JR, Arden N, et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis. 2015. doi:10.1136/annrheumdis-2014-206792.

  69. Yang S, Eaton C. Effects of glucosamine and chondroitin supplementation on knee osteoarthritis: an analysis with marginal structural models. Arthritis Rheum. 2015;67:714–23.

    Article  CAS  Google Scholar 

  70. Rutjes AWS, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012;157:180–91.

    Article  PubMed  Google Scholar 

  71. Arrich J, Piribauer F, Mad P, Schmid D, Klaushofer K, Müllner M. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. CMAJ. 2005;172:1039–43.

    Article  PubMed Central  PubMed  Google Scholar 

  72. Drengk A, Zapf A, Stürmer EK, Stürmer KM, Frosch KH. Influence of platelet-rich plasma on chondrogenic differentiation and proliferation of chondrocytes and mesenchymal stem cells. Cells Tissues Organs. 2009;189:317–26.

    Article  PubMed  Google Scholar 

  73. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013;41:356–64.

    Article  PubMed  Google Scholar 

  74. Pendleton A, Arden N, Dougados M, Doherty M, Bannwarth B, Bijlsma JW, et al. EULAR recommendations for 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. 2000;59:936–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Zhang W, Doherty M, Leeb BF, Alekseeva L, Arden NK, Bijlsma JW et al. EULAR evidence based recommendations for the management of hand osteaorthritis: report of a task force of the EULAR standing committee for international clinical studies including therapeutics (ESCISIT). Ann Rheum Dis. 2007;66:377–88.

  76. Zhang W, Doherty M, Arden N, Bannwarth B, Bijlsma J, Gunther K-P, 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. 2005;64:669–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Dr. Lee receives funding from the NIH-NIAMS (R01 AR064850). Dr. Lee reports grants from the Forest Research Institute, other from Merck, other from Novartis, other from Perrigo, and outside the submitted work.Dr. Cohen has nothing to disclose.

Human and Animal Rights and Informed Consent

All studies by Dr. Lee involving animal or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA

    Ezra Cohen

  2. Department of Rheumatology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA, 02115, USA

    Yvonne C. Lee

Authors
  1. Ezra Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yvonne C. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yvonne C. Lee.

Additional information

This article is part of the Topical Collection on Bone and Joint Pain

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cohen, E., Lee, Y.C. A Mechanism-Based Approach to the Management of Osteoarthritis Pain. Curr Osteoporos Rep 13, 399–406 (2015). https://doi.org/10.1007/s11914-015-0291-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-015-0291-y

Keywords

Search

Navigation