Is there any role for the selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in the postoperative flexor tendon adhesion formation? A literature review
Keywords:
Flexor tendons, adhesion, NSAID, COX-2
Abstract
Tendon injuries are considered the second most frequent lesions of the hand (29%), whereas fractures are first (42%). Despite the progress in the surgical techniques and postoperative rehabilitation protocols for preventing adhesions, still several pharmacological agents are being studied in order to inhibit the excessive inflammatory response and the production of growth factors that follow tendon injuries and repair.
A large number of studies has targeted the inflammatory cascade, and in particular COX enzyme isoforms in an effort to inhibit adhesion formation and promote tendon healing and although results have been promising regarding adhesion formation, non-steroidal anti-inflammatory drugs (NSAIDs) have repeatedly shown concomitant losses in the strength of repair, a concerning outcome for tissues that experience high loads such as the flexor tendons.
In conclusion, selective and non-selective NSAIDs seem to have a significant effect in limiting adhesion formation. Nonetheless, the questions that arise about their role on tendon healing, and their potential detrimental effect, are primarily to be addressed by larger animal studies that will provide a better viewpoint for statistical implementation and will check the safety of these drugs for side effects and the danger of tendon re-rupture.
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References
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2. deJong J, Nguyen JT, Sonnema A et al. The Incidence of Acute Traumatic Tendon Injuries in the Hand and Wrist: A 10-Year Population-based Study. Clin Orthop Surg. 2014; 6(2):196-202
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7. Ferguson MW, O’Kane S. Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond B Biol Sci. 2004; 29:839-850
8. Khanna A, Gougoulias N, Maffulli N. Prevention of adhesions in surgery of the flexor tendons of the hand: what is the evidence? Br Med Bull. 2009; 90:85-109
9. Kulick MI, Smith S, Hadler K. Oral ibuprofen: evaluation of its effect on peritendinous adhesions and the breaking strength of a tenorrhaphy. J Hand Surg Am. 1986; 11(1):110-120
10. Akasaka T, Nishida J, Araki S, Shimamura T, Amadio PC, An KN. Hyaluronic acid diminishes the resistance to excursion after flexor tendon repair: an in vitro biomechanical study. J Biomech. 2005; 38(3):503-507
11. Chang J, Thunder R, Most D, Longaker MT, Lineaweaver WC. Studies in flexor tendon wound healing: neutralizing antibody to TGF-beta1 increases postoperative range of motion. Plast Reconstr Surg. 2000; 105(1):148-155
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30. Beck A, Krischak G, Sorg T et al. Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing. Arch Orthop Trauma Surg 2003; 123,327–332
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35. Allen HL, Wase A, Bear WT. Indomethacin and aspirin: Effect of nonsteroidal anti-inflammatory agents on the rate of fracture repair in the rat. Acta Orthop 1980; 51:595–600
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37. Gerstenfeld LC, Thiede M, Seibert K et al. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res 2003; 21:670–675
38. Brown KM, Saunders MM, Kirsch T et al. Effect of COX-2-specific inhibition on fracture-healing in the rat femur. J Bone Joint Surg Am 2004; 86:116-123
39. Barry S. Non-steroidal anti-inflammatory drugs inhibit bone healing: A review. Vet Comp Orthop Traumatol 2010; 23:385-92
40. Goodman S, Ma T, Trindade M et al. COX-2 selective NSAID decreases bone ingrowth in vivo. J Orthop Res 2002; 20:1164–1169
41. Leonelli SM, Goldberg BA, Safanda J et al. Effects of a cyclooxygenase-2 inhibitor (rofecoxib) on bone healing. Am J Orthop 2006; 35:79–84
42. Simon AM, O’Connor JP. Dose and time-dependent effects of cyclooxygenase-2 inhibition on fracture healing. J Bone Joint Surg Am 2007; 89:500–511
43. Singh A, Saraf SK, Garbyal RS et al. Effect of etoricoxib on fracture healing – An experimental study. Biomedical Research 2011; 22(1):52-56,
44. Simon AM, Manigrasso MB, O’Connor JP et al. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 2002; 17:963–976
45. Gerstenfeld LC, Einhorn TA. COX inhibitors and their effects on bone healing. Expert Opin Drug Saf 2004; 3:131–136
46. Adolphson P, Abbaszadegan H, Jonsson U et al. No effects of piroxicam on osteopenia and recovery after Colle’s fracture. Arch Orthop Trauma Surg 1993; 112:127–130
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52. Verdan CE. Practical considerations for primary and secondary repair in flexor tendon injuries. Surg Clin North Am. 1964; 44:951-970
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54. Kessler I, Nissim F. Primary repair without immobilization of flexor tendon division within the digital sheath: an experimental and clinical study. Acta Orthop Scand. 1969; 40:587-601
55. Tang JB, Clinical outcomes associated with flexor tendon repair. Hand Clin. 2005; 21(2):199-210
56. Beredjiklian Pedro K. Biologic Aspects of Flexor Tendon Laceration and Repair. J Bone Joint Surg Am. 2003; 85-A(3):539-550.
57. Amadio PC. Friction of the gliding surface. Implications for tendon surgery and rehabilitation. J Hand Ther. 2005; 18(2):112-119
58. Murphy PG, Loitz BJ, Frank CB, Hart DA. Influence of exogenous growth factors on the synthesis and secretion of collagen types I and III by explants of normal and healing rabbit ligaments. Biochem Cell Biol. 1994; 72:403-9
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61. Hooley CJ, Cohen RE. A model for the creep behaviour of tendon. Int J Biol Macromol. 1979; 1:123-32
62. Gelberman RH, Manske PR. Factors influencing flexor tendon adhesions. Hand Clinics 1985; 1:35-42
63. Kvist M, Jozsa L, Jarvinen M, Kvist H. Fine structural alterations in chronic Achilles paratenonitis in athletes. Pathol Res Pract. 1985; 180:416-23
64. Kulick MI, Brazlow R, Smith S, Hentz VR. Injectable ibuprofen: preliminary evaluation of its ability to decrease peritendinous adhesions. Ann Plast Surg 1984; 13, 459–467
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66. Vogel HC. Mechanical and chemical properties of various connective tissue organs in rats as influenced by nonsteroidal antirheumatic drugs. Conn Tissue Res 1977; 5:91-5.
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2. deJong J, Nguyen JT, Sonnema A et al. The Incidence of Acute Traumatic Tendon Injuries in the Hand and Wrist: A 10-Year Population-based Study. Clin Orthop Surg. 2014; 6(2):196-202
3. Thomopoulos S, Parks WC, Rifkin D, Derwin K. Mechanism of tendon injury and repair. J Orthop Res. 2015; 33(6):832-839
4. Dy CJ, Hernandez-Soria A, Ma Y, Roberts TR, Daluiski A. Complications after flexor tendon repair: a systematic review and metaanalysis. J Hand Surg Am. 2012; 37(3)
5. Skouteris D, Magnissalis E, Papalois A et al. An experimental model on the biomechanical behavior of the flexor tendons in New Zealand rabbits. J Hand Surg Asian Pacific. 2017; 22(3):320-328
6. Moran SL, Ryan CK, Orlando GS, Pratt CE, Michalko KB. Effects of 5-fluorouracil on flexor tendon repair. J Hand Surg Am. 2000; 25(2):242-51
7. Ferguson MW, O’Kane S. Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond B Biol Sci. 2004; 29:839-850
8. Khanna A, Gougoulias N, Maffulli N. Prevention of adhesions in surgery of the flexor tendons of the hand: what is the evidence? Br Med Bull. 2009; 90:85-109
9. Kulick MI, Smith S, Hadler K. Oral ibuprofen: evaluation of its effect on peritendinous adhesions and the breaking strength of a tenorrhaphy. J Hand Surg Am. 1986; 11(1):110-120
10. Akasaka T, Nishida J, Araki S, Shimamura T, Amadio PC, An KN. Hyaluronic acid diminishes the resistance to excursion after flexor tendon repair: an in vitro biomechanical study. J Biomech. 2005; 38(3):503-507
11. Chang J, Thunder R, Most D, Longaker MT, Lineaweaver WC. Studies in flexor tendon wound healing: neutralizing antibody to TGF-beta1 increases postoperative range of motion. Plast Reconstr Surg. 2000; 105(1):148-155
12. Zhao C, Sun Y L, Amadio PC, Tanaka T, Ettema AM, An KN. Surface treatment of flexor tendon autografts with carbodiimide derivatized hyaluronic acid. An in vivo canine model. J Bone Joint Surg. 2006; 88(10):2181-2191
13. Xia C, Zuo J, Wang C, Wang Y. Tendon healing in vivo: effect of mannose-6-phosphate on flexor tendon adhesion formation. Orthopedics. 2012; 35(7):1056-1060
14. Zhao H, Guan H, Gu J, Luo Z, Zhang W, Chen B, Gu Q, Yang H, Shi Q. Collagen membrane alleviates peritendinous adhesion in the rat Achilles tendon injury model. Chin Med J. 2013; 126(4):729-733
15. Bates J, Morrow E, Zhang A, Pham H, Longaker MT, Chang J. Mannose-6-Phosphate, an Inhibitor of Transforming Growth Factor-β , Improves Range of Motion After Flexor Tendon Repair. J Bone Joint Surg. 2006; 88(11):2465-2472
16. Brevet D, Hocine O, Delalande A et al. Improved gene transfer with histidine-functionalized mesoporous silica nanoparticles. Int J Pharm. 2014; 471(1–2):197–205
17. Tang JB, Zhou YL, Wu YF et al. Gene therapy strategies to improve strength and quality of flexor tendon healing. Expert Opinion on Biological Therapy. 2016; 16(3):291-301
18. Mohale DS, Tripathi AS, Wahane JB. A Pharmacological Review on Cyclooxygenase Enzyme, Indian Journal of Pharmacy and Pharmacology 2014; 1(1):46-58
19. Rainford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem 2007; 42:3-27,
20. Rainsford KD. Fifty years since the discovery of ibuprofen. Inflammopharmacol 2011; 19:293-297
21. Evans D, Williamson WRN. Chemistry of clinically active anti-inflammatory compounds. In: Anti- Inflammatory Compounds. New York & Basel: Marcel Dekker, 1987; 193–302
22. Simmons DL, Levy DB, Yannoni Y et al. Identification of a phorbol ester-repressible v-src-inducible gene. Proc Natl Acad Sci USA 1989; 86:1178-1182
23. Warden SJ. Cyclo-oxygenase-2 inhibitors. Beneficial or detrimental for athletes with acute musculoskeletal injuries? Sports Med 2005; 35(4):271-283
24. Boursinos LA, Karachalios T, Poultsides L. Do steroids, conventional non-steroidal anti-inflammatory drugs and selective Cox-2 inhibitors adversely affect fracture healing? J Musculoskelt Neuronal Interact 2009; 9(1):44-52
25. Ro J, Sudmann E, Marton PF. Effect of indomethacin on fracture healing in rats. Acta Orthop Scand 1976; 47:588–599
26. O’Connor JP, Capo JT, Tan V et al. A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing. Acta Orthop 2009; 80:597–605
27. Cottrell J, O’Connor PJ. Effect of non-steroidal anti-inflammatory drugs on bone healing. Pharmaceuticals 2010; 3:1668-1693
28. Karachalios T, Boursinos L, Poultsides L et al. The effects of the short-term administration of low therapeutic doses of anti-COX-2 agents on the healing of fractures. An experimental study in rabbits. J Bone Joint Surg Br 2007; 789:1253–1260
29. Engesaeter LB, Sudmann B, Sudmann E. Fracture healing in rats inhibited by locally administered indomethacin. Acta Orthop. Scand 1992; 63:330–333
30. Beck A, Krischak G, Sorg T et al. Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing. Arch Orthop Trauma Surg 2003; 123,327–332
31. Krischak GD, Augat P, Blakytny R et al. The nonsteroidal anti-inflammatory drug diclofenac reduces appearance of osteoblasts in bone defect healing in rats. Arch Orthop Trauma Surg 2007; 127:453–458
32. Dimmen S, Nordsletten L, Madsen JE. Parecoxib and indomethacin delay early fracture healing: A study in rats. Clin Orthop Relat Res 2009; 467:1992–1999
33. Sudmann E, Dregelid E, Bessesen A et al. Inhibition of fracture healing by indomethacin in rats. Eur J Clin Invest 1979; 9:333–339
34. Giannoudis PV, Hak D, Sanders D et al. Inflammation, bone healing and anti-inflammatory drugs: an update. J Orthop Trauma 2015; 29:6-9
35. Allen HL, Wase A, Bear WT. Indomethacin and aspirin: Effect of nonsteroidal anti-inflammatory agents on the rate of fracture repair in the rat. Acta Orthop 1980; 51:595–600
36. Long J, Lewis S, Kuklo T et al. The effect of cyclooxygenase-2 inhibitors on spinal fusion. J Bone Joint Surg Am 2002; 84A:1763–1768
37. Gerstenfeld LC, Thiede M, Seibert K et al. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res 2003; 21:670–675
38. Brown KM, Saunders MM, Kirsch T et al. Effect of COX-2-specific inhibition on fracture-healing in the rat femur. J Bone Joint Surg Am 2004; 86:116-123
39. Barry S. Non-steroidal anti-inflammatory drugs inhibit bone healing: A review. Vet Comp Orthop Traumatol 2010; 23:385-92
40. Goodman S, Ma T, Trindade M et al. COX-2 selective NSAID decreases bone ingrowth in vivo. J Orthop Res 2002; 20:1164–1169
41. Leonelli SM, Goldberg BA, Safanda J et al. Effects of a cyclooxygenase-2 inhibitor (rofecoxib) on bone healing. Am J Orthop 2006; 35:79–84
42. Simon AM, O’Connor JP. Dose and time-dependent effects of cyclooxygenase-2 inhibition on fracture healing. J Bone Joint Surg Am 2007; 89:500–511
43. Singh A, Saraf SK, Garbyal RS et al. Effect of etoricoxib on fracture healing – An experimental study. Biomedical Research 2011; 22(1):52-56,
44. Simon AM, Manigrasso MB, O’Connor JP et al. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 2002; 17:963–976
45. Gerstenfeld LC, Einhorn TA. COX inhibitors and their effects on bone healing. Expert Opin Drug Saf 2004; 3:131–136
46. Adolphson P, Abbaszadegan H, Jonsson U et al. No effects of piroxicam on osteopenia and recovery after Colle’s fracture. Arch Orthop Trauma Surg 1993; 112:127–130
47. Burd TA, Hughes MS, Anglen JO. Heterotopic ossification prophylaxis with indomethacin increases the risk of long bone nonunion. J Bone Joint Surg Br 2003; 85-B:700–705,
48. Glassman SD, Rose SM, Dimar JR. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine 1998; 23:834–838,
49. Giannoudis PV, MacDonald DA, Matthews SJ et al. Nonunion of the femoral diaphysis: The influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br 2000; 82B:655–658,
50. Pradhan BB, Tatsumi RL, Gallina J et al. Ketorolac and spinal fusion: Does the perioperative use of ketorolac really inhibit spinal fusion? Spine 2008; 33:2079–2082
51. Strickland J W MD. The scientific basis for advances in flexor tendon surgery. J Hand Ther. 2005; 18(2):94-110.
52. Verdan CE. Practical considerations for primary and secondary repair in flexor tendon injuries. Surg Clin North Am. 1964; 44:951-970
53. Kleinert HE, Kutz JE, Ashbell TS, Martinez E. Primary repair of lacerated flexor tendons in ‘‘no man’s land’’. J Bone Joint Surg Am. 1967; 49:577
54. Kessler I, Nissim F. Primary repair without immobilization of flexor tendon division within the digital sheath: an experimental and clinical study. Acta Orthop Scand. 1969; 40:587-601
55. Tang JB, Clinical outcomes associated with flexor tendon repair. Hand Clin. 2005; 21(2):199-210
56. Beredjiklian Pedro K. Biologic Aspects of Flexor Tendon Laceration and Repair. J Bone Joint Surg Am. 2003; 85-A(3):539-550.
57. Amadio PC. Friction of the gliding surface. Implications for tendon surgery and rehabilitation. J Hand Ther. 2005; 18(2):112-119
58. Murphy PG, Loitz BJ, Frank CB, Hart DA. Influence of exogenous growth factors on the synthesis and secretion of collagen types I and III by explants of normal and healing rabbit ligaments. Biochem Cell Biol. 1994; 72:403-9
59. Oakes BW. Tissue healing and repair: tendons and ligaments. In: Frontera WR, editor. Rehabilitation of sports injuries: scientific basis. Boston: Blackwell Science; 2003. p 56-98
60. Sharma P, Maffuli N. Tendon Injury and Tendinopathy: Healing and Repair. J Bone Joint Surg Am 2005; 87:187-202
61. Hooley CJ, Cohen RE. A model for the creep behaviour of tendon. Int J Biol Macromol. 1979; 1:123-32
62. Gelberman RH, Manske PR. Factors influencing flexor tendon adhesions. Hand Clinics 1985; 1:35-42
63. Kvist M, Jozsa L, Jarvinen M, Kvist H. Fine structural alterations in chronic Achilles paratenonitis in athletes. Pathol Res Pract. 1985; 180:416-23
64. Kulick MI, Brazlow R, Smith S, Hentz VR. Injectable ibuprofen: preliminary evaluation of its ability to decrease peritendinous adhesions. Ann Plast Surg 1984; 13, 459–467
65. Szabo RM, Younger E. Effects of indomethacin on adhesion formation after repair of zone II tendon lacerations in the rabbit. J Hand Surg Am 1990; 15A:480–483
66. Vogel HC. Mechanical and chemical properties of various connective tissue organs in rats as influenced by nonsteroidal antirheumatic drugs. Conn Tissue Res 1977; 5:91-5.
67. Carlstedt CA, Madsen K, Wredmark T. The influence of indomethacin on biomechanical and biochemical properties of the plantaris longus tendon in the rabbit. Arch Orthop Trauma Surg 1987; 106:157-60.
68. Almekinders LC, Baynes AJ, Bracey LW. An in vitro investigation into the effects of repetitive motion and nonsteroidal anti-inflammatory medication on human tendon fibroblasts. Am J Sports Med 1995; 23:119–123
69. Tsai WC, Hsu CC, Chen CP et al. Ibuprofen inhibition of tendon cell migration and down-regulation of paxillin expression. J Orthop Res 2006; 24:551–558
70. Rouhani A, Tabrizi A, Ghavidel E. Effects of non-steroidal anti-inflammatory drugs on flexor tendon rehabilitation after repair. Arch Bone Joint Surg 2013, 1(1):28-30
71. Dimmen S. Effects of cox inhibitors on bone and tendon healing. Experimental studies of fracture healing, tendon healing and tendon-to-bone healing in the rat. Acta Orthopaedica 2011; 82(342):1-22
72. Forslund C, Bylander B, Aspenberg P. Indomethacin and celecoxib improve tendon healing in rats. Acta Orthop Scand 2003; 74-4:465-9
73. Tan V, Nourbakhsh A, Capo J et al. Effects of nonsteroidal anti-inflammatory drugs on flexor tendon adhesion. J Hand Surg 2010, 35A:941-947
74. Virchenko O, Skoglund B, Aspenberg P. Parecoxib impairs early tendon repair but improves later remodeling. Am J Sports Med 2004; 32(7):1743-7
75. Blomgran P, Blomgran R, Ernerudh J et al. COX-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing. Muscles, Ligaments and Tendons Journal 2017; 7(2)223-229
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Published
2020-12-11
Section
Review
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