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Published in: Clinical Orthopaedics and Related Research® 8/2014

01-08-2014 | Symposium: Surgery and Science of the Rotator Cuff

The Detrimental Effects of Systemic Ibuprofen Delivery on Tendon Healing Are Time-Dependent

Authors: Brianne K. Connizzo, BS, Sarah M. Yannascoli, MD, Jennica J. Tucker, BS, Adam C. Caro, DVM, Corinne N. Riggin, BS, Robert L. Mauck, PhD, Louis J. Soslowsky, PhD, David R. Steinberg, MD, Joseph Bernstein, MD

Published in: Clinical Orthopaedics and Related Research® | Issue 8/2014

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Abstract

Background

Current clinical treatment after tendon repairs often includes prescribing NSAIDs to limit pain and inflammation. The negative influence of NSAIDs on bone repair is well documented, but their effects on tendon healing are less clear. While NSAIDs may be detrimental to early tendon healing, some evidence suggests that they may improve healing if administered later in the repair process.

Questions/purposes

We asked whether the biomechanical and histologic effects of systemic ibuprofen administration on tendon healing are influenced by either immediate or delayed drug administration.

Methods

After bilateral supraspinatus detachment and repair surgeries, rats were divided into groups and given ibuprofen orally for either Days 0 to 7 (early) or Days 8 to 14 (delayed) after surgery; a control group did not receive ibuprofen. Healing was evaluated at 1, 2, and 4 weeks postsurgery through biomechanical testing and histologic assessment.

Results

Biomechanical evaluation resulted in decreased stiffness and modulus at 4 weeks postsurgery for early ibuprofen delivery (mean ± SD [95% CI]: 10.8 ± 6.4 N/mm [6.7–14.8] and 8.9 ± 5.9 MPa [5.4–12.3]) when compared to control repair (20.4 ± 8.6 N/mm [16.3–24.5] and 15.7 ± 7.5 MPa [12.3–19.2]) (p = 0.003 and 0.013); however, there were no differences between the delayed ibuprofen group (18.1 ± 7.4 N/mm [14.2–22.1] and 11.5 ± 5.6 MPa [8.2–14.9]) and the control group. Histology confirmed mechanical results with reduced fiber reorganization over time in the early ibuprofen group.

Conclusions

Early administration of ibuprofen in the postoperative period was detrimental to tendon healing, while delayed administration did not affect tendon healing.

Clinical Relevance

Historically, clinicians have often prescribed ibuprofen after tendon repair, but this study suggests that the timing of ibuprofen administration is critical to adequate tendon healing. This research necessitates future clinical studies investigating the use of ibuprofen for pain control after rotator cuff repair and other tendon injuries.
Literature
1.
go back to reference Almekinders LC, Baynes AJ, Bracey LW. An in vitro investigation into the effects of repetitive motion and nonsteroidal antiinflammatory medication on human tendon fibroblasts. Am J Sports Med. 1995;23:119–123.PubMedCrossRef Almekinders LC, Baynes AJ, Bracey LW. An in vitro investigation into the effects of repetitive motion and nonsteroidal antiinflammatory medication on human tendon fibroblasts. Am J Sports Med. 1995;23:119–123.PubMedCrossRef
2.
go back to reference Altman RD, Latta LL, Keer R, Renfree K, Hornicek FJ, Banovac K. Effect of nonsteroidal antiinflammatory drugs on fracture healing: a laboratory study in rats. J Orthop Trauma. 1995;9:392–400.PubMedCrossRef Altman RD, Latta LL, Keer R, Renfree K, Hornicek FJ, Banovac K. Effect of nonsteroidal antiinflammatory drugs on fracture healing: a laboratory study in rats. J Orthop Trauma. 1995;9:392–400.PubMedCrossRef
3.
go back to reference Beason DP, Connizzo BK, Dourte LM, Mauck RL, Soslowsky LJ, Steinberg DR, Bernstein J. Fiber-aligned polymer scaffolds for rotator cuff repair in a rat model. J Shoulder Elbow Surg. 2012;21:245–250.PubMedCrossRef Beason DP, Connizzo BK, Dourte LM, Mauck RL, Soslowsky LJ, Steinberg DR, Bernstein J. Fiber-aligned polymer scaffolds for rotator cuff repair in a rat model. J Shoulder Elbow Surg. 2012;21:245–250.PubMedCrossRef
4.
go back to reference Cohen DB, Kawamura S, Ehteshami JR, Rodeo SA. Indomethacin and celecoxib impair rotator cuff tendon-to-bone healing. Am J Sports Med. 2006;34:362–369.PubMedCrossRef Cohen DB, Kawamura S, Ehteshami JR, Rodeo SA. Indomethacin and celecoxib impair rotator cuff tendon-to-bone healing. Am J Sports Med. 2006;34:362–369.PubMedCrossRef
5.
go back to reference Dimmen S, Engebretsen L, Nordsletten L, Madsen JE. Negative effects of parecoxib and indomethacin on tendon healing: an experimental study in rats. Knee Surg Sports Traumatol Arthrosc. 2009;17:835–839.PubMedCrossRef Dimmen S, Engebretsen L, Nordsletten L, Madsen JE. Negative effects of parecoxib and indomethacin on tendon healing: an experimental study in rats. Knee Surg Sports Traumatol Arthrosc. 2009;17:835–839.PubMedCrossRef
6.
go back to reference Dimmen S, Nordsletten L, Engebretsen L, Steen H, Madsen JE. The effect of parecoxib and indometacin on tendon-to-bone healing in a bone tunnel: an experimental study in rats. J Bone Joint Surg Br. 2009;91:259–263.PubMedCrossRef Dimmen S, Nordsletten L, Engebretsen L, Steen H, Madsen JE. The effect of parecoxib and indometacin on tendon-to-bone healing in a bone tunnel: an experimental study in rats. J Bone Joint Surg Br. 2009;91:259–263.PubMedCrossRef
7.
go back to reference Edelstein L, Thomas SJ, Soslowsky LJ. Rotator cuff tears: what have we learned from animal models? J Musculoskelet Neuronal Interact. 2011;11:150–162.PubMed Edelstein L, Thomas SJ, Soslowsky LJ. Rotator cuff tears: what have we learned from animal models? J Musculoskelet Neuronal Interact. 2011;11:150–162.PubMed
8.
go back to reference Ferry ST, Dahners LE, Afshari HM, Weinhold PS. The effects of common anti-inflammatory drugs on the healing rat patellar tendon. Am J Sports Med. 2007;35:1326–1333.PubMedCrossRef Ferry ST, Dahners LE, Afshari HM, Weinhold PS. The effects of common anti-inflammatory drugs on the healing rat patellar tendon. Am J Sports Med. 2007;35:1326–1333.PubMedCrossRef
9.
go back to reference Feucht CL, Patel DR. Analgesics and anti-inflammatory medications in sports: use and abuse. Pediatr Clin North Am. 2010;57:751–774.PubMedCrossRef Feucht CL, Patel DR. Analgesics and anti-inflammatory medications in sports: use and abuse. Pediatr Clin North Am. 2010;57:751–774.PubMedCrossRef
10.
go back to reference Gerstenfeld LC, Al-Ghawas M, Alkhiary YM, Cullinane DM, Krall EA, Fitch JL, Webb EG, Thiede MA, Einhorn TA. Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing: reversibility of effects after short-term treatment. J Bone Joint Surg Am. 2007;89:114–125.PubMedCrossRef Gerstenfeld LC, Al-Ghawas M, Alkhiary YM, Cullinane DM, Krall EA, Fitch JL, Webb EG, Thiede MA, Einhorn TA. Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing: reversibility of effects after short-term treatment. J Bone Joint Surg Am. 2007;89:114–125.PubMedCrossRef
11.
go back to reference Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res. 2003;21:670–675.PubMedCrossRef Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res. 2003;21:670–675.PubMedCrossRef
12.
go back to reference Gimbel JA, Van Kleunen JP, Lake SP, Williams GR, Soslowsky LJ. The role of repair tension on tendon to bone healing in an animal model of chronic rotator cuff tears. J Biomech. 2007;40:561–568.PubMedCrossRef Gimbel JA, Van Kleunen JP, Lake SP, Williams GR, Soslowsky LJ. The role of repair tension on tendon to bone healing in an animal model of chronic rotator cuff tears. J Biomech. 2007;40:561–568.PubMedCrossRef
13.
go back to reference Gimbel JA, Van Kleunen JP, Mehta S, Perry SM, Williams GR, Soslowsky LJ. Supraspinatus tendon organizational and mechanical properties in a chronic rotator cuff tear animal model. J Biomech. 2004;37:739–749.PubMedCrossRef Gimbel JA, Van Kleunen JP, Mehta S, Perry SM, Williams GR, Soslowsky LJ. Supraspinatus tendon organizational and mechanical properties in a chronic rotator cuff tear animal model. J Biomech. 2004;37:739–749.PubMedCrossRef
14.
go back to reference Gimbel JA, Van Kleunen JP, Williams GR, Thomopoulos S, Soslowsky LJ. Long durations of immobilization in the rat result in enhanced mechanical properties of the healing supraspinatus tendon insertion site. J Biomech Eng. 2007;129:400–404.PubMedCrossRef Gimbel JA, Van Kleunen JP, Williams GR, Thomopoulos S, Soslowsky LJ. Long durations of immobilization in the rat result in enhanced mechanical properties of the healing supraspinatus tendon insertion site. J Biomech Eng. 2007;129:400–404.PubMedCrossRef
15.
go back to reference Holmes N, Cronholm PF, Duffy AJ 3rd, Webner D. Nonsteroidal anti-inflammatory drug use in collegiate football players. Clin J Sport Med. 2013;23:283–286.PubMedCrossRef Holmes N, Cronholm PF, Duffy AJ 3rd, Webner D. Nonsteroidal anti-inflammatory drug use in collegiate football players. Clin J Sport Med. 2013;23:283–286.PubMedCrossRef
16.
go back to reference Hsu JE, Reuther KE, Sarver JJ, Lee CS, Thomas SJ, Glaser DL, Soslowsky LJ. Restoration of anterior-posterior rotator cuff force balance improves shoulder function in a rat model of chronic massive tears. J Orthop Res. 2011;29:1028–1033.PubMedCentralPubMedCrossRef Hsu JE, Reuther KE, Sarver JJ, Lee CS, Thomas SJ, Glaser DL, Soslowsky LJ. Restoration of anterior-posterior rotator cuff force balance improves shoulder function in a rat model of chronic massive tears. J Orthop Res. 2011;29:1028–1033.PubMedCentralPubMedCrossRef
17.
go back to reference 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;11:110–120.PubMedCrossRef 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;11:110–120.PubMedCrossRef
18.
go back to reference Lin TW, Cardenas L, Soslowsky LJ. Biomechanics of tendon injury and repair. J Biomech. 2004;37:865–877.PubMedCrossRef Lin TW, Cardenas L, Soslowsky LJ. Biomechanics of tendon injury and repair. J Biomech. 2004;37:865–877.PubMedCrossRef
19.
go back to reference Lindholm TS, Törnkvist H. Inhibitory effect on bone formation and calcification exerted by the anti-inflammatory drug ibuprofen: an experimental study on adult rat with fracture. Scand J Rheumatol. 1981;10:38–42.PubMedCrossRef Lindholm TS, Törnkvist H. Inhibitory effect on bone formation and calcification exerted by the anti-inflammatory drug ibuprofen: an experimental study on adult rat with fracture. Scand J Rheumatol. 1981;10:38–42.PubMedCrossRef
20.
go back to reference Pedowitz RA, Yamaguchi K, Ahmad CS, Burks RT, Flatow EL, Green A, Iannotti JP, Miller BS, Tashjian RZ, Watters WC 3rd, Weber K, Turkelson CM, Wies JL, Anderson S, St Andre J, Boyer K, Raymond L, Sluka P, McGowan R. Optimizing the management of rotator cuff problems. J Am Acad Orthop Surg. 2011;19:368–379.PubMed Pedowitz RA, Yamaguchi K, Ahmad CS, Burks RT, Flatow EL, Green A, Iannotti JP, Miller BS, Tashjian RZ, Watters WC 3rd, Weber K, Turkelson CM, Wies JL, Anderson S, St Andre J, Boyer K, Raymond L, Sluka P, McGowan R. Optimizing the management of rotator cuff problems. J Am Acad Orthop Surg. 2011;19:368–379.PubMed
21.
go back to reference Peltz CD, Dourte LM, Kuntz AF, Sarver JJ, Kim SY, Williams GR, Soslowsky LJ. The effect of postoperative passive motion on rotator cuff healing in a rat model. J Bone Joint Surg Am. 2009;91:2421–2429.PubMedCentralPubMedCrossRef Peltz CD, Dourte LM, Kuntz AF, Sarver JJ, Kim SY, Williams GR, Soslowsky LJ. The effect of postoperative passive motion on rotator cuff healing in a rat model. J Bone Joint Surg Am. 2009;91:2421–2429.PubMedCentralPubMedCrossRef
22.
go back to reference Rainsford KD. Ibuprofen: A Critical Bibliographic Review. London, UK: Taylor & Francis; 2003. Rainsford KD. Ibuprofen: A Critical Bibliographic Review. London, UK: Taylor & Francis; 2003.
23.
go back to reference Reddy GK, Stehno-Bittel L, Enwemeka CS. Matrix remodeling in healing rabbit Achilles tendon. Wound Repair Regen. 1999;7:518–527.PubMedCrossRef Reddy GK, Stehno-Bittel L, Enwemeka CS. Matrix remodeling in healing rabbit Achilles tendon. Wound Repair Regen. 1999;7:518–527.PubMedCrossRef
24.
go back to reference Shah A, Jung D. Dose-dependent pharmacokinetics of ibuprofen in the rat. Drug Metab Dispos. 1987;15:151–154.PubMed Shah A, Jung D. Dose-dependent pharmacokinetics of ibuprofen in the rat. Drug Metab Dispos. 1987;15:151–154.PubMed
25.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
26.
go back to reference Tan V, Nourbakhsh A, Capo J, Cottrell JA, Meyenhofer M, O’Connor JP. Effects of nonsteroidal anti-inflammatory drugs on flexor tendon adhesion. J Hand Surg Am. 2010;35:941–947.PubMedCrossRef Tan V, Nourbakhsh A, Capo J, Cottrell JA, Meyenhofer M, O’Connor JP. Effects of nonsteroidal anti-inflammatory drugs on flexor tendon adhesion. J Hand Surg Am. 2010;35:941–947.PubMedCrossRef
27.
go back to reference Thomopoulos S, Hattersley G, Rosen V, Mertens M, Galatz LM, Williams GR, Soslowsky LJ. The localized expression of extracellular matrix components in healing tendon insertion sites: an in situ hybridization study. J Orthop Res. 2002;20:454–463.PubMedCrossRef Thomopoulos S, Hattersley G, Rosen V, Mertens M, Galatz LM, Williams GR, Soslowsky LJ. The localized expression of extracellular matrix components in healing tendon insertion sites: an in situ hybridization study. J Orthop Res. 2002;20:454–463.PubMedCrossRef
28.
go back to reference Thomopoulos S, Williams GR, Gimbel JA, Favata M, Soslowsky LJ. Variation of biomechanical, structural, and compositional properties along the tendon to bone insertion site. J Orthop Res. 2003;21:413–419.PubMedCrossRef Thomopoulos S, Williams GR, Gimbel JA, Favata M, Soslowsky LJ. Variation of biomechanical, structural, and compositional properties along the tendon to bone insertion site. J Orthop Res. 2003;21:413–419.PubMedCrossRef
29.
go back to reference Thomopoulos S, Williams GR, Soslowsky LJ. Tendon to bone healing: differences in biomechanical, structural, and compositional properties due to a range of activity levels. J Biomech Eng. 2003;125:106–113.PubMedCrossRef Thomopoulos S, Williams GR, Soslowsky LJ. Tendon to bone healing: differences in biomechanical, structural, and compositional properties due to a range of activity levels. J Biomech Eng. 2003;125:106–113.PubMedCrossRef
30.
go back to reference Tsai WC, Hsu CC, Chang HN, Lin YC, Lin MS, Pang JH. Ibuprofen upregulates expressions of matrix metalloproteinase-1, -8, -9, and -13 without affecting expressions of Types I and III collagen in tendon cells. J Orthop Res. 2010;28:487–491.PubMed Tsai WC, Hsu CC, Chang HN, Lin YC, Lin MS, Pang JH. Ibuprofen upregulates expressions of matrix metalloproteinase-1, -8, -9, and -13 without affecting expressions of Types I and III collagen in tendon cells. J Orthop Res. 2010;28:487–491.PubMed
31.
go back to reference Tsai WC, Hsu CC, Chen CP, Chen MJ, Lin MS, Pang JH. Ibuprofen inhibition of tendon cell migration and down-regulation of paxillin expression. J Orthop Res. 2006;24:551–558.PubMedCrossRef Tsai WC, Hsu CC, Chen CP, Chen MJ, Lin MS, Pang JH. Ibuprofen inhibition of tendon cell migration and down-regulation of paxillin expression. J Orthop Res. 2006;24:551–558.PubMedCrossRef
32.
go back to reference Tsai WC, Hsu CC, Chou SW, Chung CY, Chen J, Pang JH. Effects of celecoxib on migration, proliferation and collagen expression of tendon cells. Connect Tissue Res. 2007;48:46–51.PubMedCrossRef Tsai WC, Hsu CC, Chou SW, Chung CY, Chen J, Pang JH. Effects of celecoxib on migration, proliferation and collagen expression of tendon cells. Connect Tissue Res. 2007;48:46–51.PubMedCrossRef
33.
go back to reference Virchenko O, Skoglund B, Aspenberg P. Parecoxib impairs early tendon repair but improves later remodeling. Am J Sports Med. 2004;32:1743–1747.PubMedCrossRef Virchenko O, Skoglund B, Aspenberg P. Parecoxib impairs early tendon repair but improves later remodeling. Am J Sports Med. 2004;32:1743–1747.PubMedCrossRef
34.
go back to reference Woo SL, Debski RE, Zeminski J, Abramowitch SD, Saw SS, Fenwick JA. Injury and repair of ligaments and tendons. Annu Rev Biomed Eng. 2000;2:83–118.PubMedCrossRef Woo SL, Debski RE, Zeminski J, Abramowitch SD, Saw SS, Fenwick JA. Injury and repair of ligaments and tendons. Annu Rev Biomed Eng. 2000;2:83–118.PubMedCrossRef
Metadata
Title
The Detrimental Effects of Systemic Ibuprofen Delivery on Tendon Healing Are Time-Dependent
Authors
Brianne K. Connizzo, BS
Sarah M. Yannascoli, MD
Jennica J. Tucker, BS
Adam C. Caro, DVM
Corinne N. Riggin, BS
Robert L. Mauck, PhD
Louis J. Soslowsky, PhD
David R. Steinberg, MD
Joseph Bernstein, MD
Publication date
01-08-2014
Publisher
Springer US
Published in
Clinical Orthopaedics and Related Research® / Issue 8/2014
Print ISSN: 0009-921X
Electronic ISSN: 1528-1132
DOI
https://doi.org/10.1007/s11999-013-3258-2

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