Review

Effects of Perioperative Nonsteroidal

Anti-inflammatory Drug Administration
on Soft Tissue Healing
A Systematic Review of Clinical Outcomes After
Sports Medicine Orthopaedic Surgery Procedures
David S. Constantinescu,*† BS, Michael P. Campbell,† MD, Gilbert Moatshe,‡ MD, PhD,
and Alexander R. Vap,† MD
Investigation performed at the Department of Orthopedic Surgery,
Virginia Commonwealth University, Richmond, Virginia, USA

Background: The effects of perioperative nonsteroidal anti-inflammatory drugs (NSAIDs) on soft tissue healing in humans have yet
to be established.
Purpose: To systematically review the literature addressing the effects of perioperative NSAID administration on soft tissue healing
and clinical patient outcomes.
Study Design: Systematic review; Level of evidence, 3.
Methods: This review study was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews
and Meta-Analyses) statement. A review of the literature regarding the existing evidence for clinical effects of NSAID use on soft
tissue healing was performed through use of the Cochrane Database of Systematic Reviews, the Cochrane Central Register of
Controlled Trials, PubMed (1980 to present), and MEDLINE. Inclusion criteria for articles were as follows: outcome studies after soft
tissue (ligament, meniscus, tendon, muscle) healing after surgical procedure with perioperative NSAID administration, at least 1
year of follow-up, English language, and human participants.
Results: A total of 466 studies were initially retrieved, with 4 studies satisfying all inclusion criteria. Among the surgical procedures
reported, 93% of the patients (4144/4451) underwent anterior cruciate ligament (ACL) reconstruction, 3% (120/4451) underwent
rotator cuff repair, 3% (155/4451) underwent Bankart shoulder repair, and 1% (32/4451) underwent meniscal repair. The reported
surgical failure rate among patients administered NSAIDs was 3.6% (157/4360). The reported surgical failure rate among control
participants not given NSAIDs was 3.7% (147/3996). NSAID use showed no statistically significant effect on need for reoperation in
meniscal repair (P ¼ .99), ACL reconstruction (P ¼ .8), and Bankart repair (P ¼ .8) compared with no NSAID administration. Celecoxib
administration had a significantly higher rate of retear (37%) after rotator cuff repair compared with ibuprofen (7%) (P ¼ .009).
Conclusion: Insufficient data are available to definitively state the effects of perioperative NSAIDs on soft tissue healing. Use
of NSAIDs should be considered on a case-by-case basis and may not affect healing rates following either meniscal, ACL,
rotator cuff, or Bankart repair. However, celecoxib (a selective COX-2 inhibitor) may inhibit tendon-to-bone healing in rotator
cuff repair. Further research through clinical trials is required to fully determine whether NSAIDs have an adverse effect on
soft tissue healing.
Keywords: sports medicine; soft tissue; NSAIDs; healing; ACL; meniscus; rotator cuff; Bankart

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used reduce prostaglandin production through the inhibition
to aid recovery by decreasing inflammation and pain after of cyclooxygenase (COX), an important enzyme for the for-
injury.1 This is attributed to the ability of NSAIDs to mation of prostaglandin, an inflammatory mediator, from
arachidonic acid.2 The subsequent reduction of prosta-
The Orthopaedic Journal of Sports Medicine, 7(4), 2325967119838873
glandin concentration alters the cell signaling cascade
DOI: 10.1177/2325967119838873 after musculoskeletal injury and diminishes the inflam-
ª The Author(s) 2019 matory response.

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licenses/by-nc-nd/4.0/), which permits the noncommercial use, distribution, and reproduction of the article in any medium, provided the original author and source are
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1
2 Constantinescu et al The Orthopaedic Journal of Sports Medicine

The inflammatory cascade is a natural response to injury included studies were reviewed to identify any other relevant
that entails the recruitment of macrophages and neutro- articles, and no additional articles were discovered.
phils that remove the resultant necrotic cell debris after The primary outcome measure of our study was to
an injury to provide an initial connective tissue frame- compile all existing studies examining clinical effects of
work.15 Interfering with the inflammatory process by using NSAIDs on soft tissue healing after sports medicine
NSAIDs has been theorized to affect bone and soft tissue orthopaedic surgery procedures in human patients. The
healing. The use of NSAIDs after orthopaedic surgery is a secondary outcomes of our study included identifying the
controversial topic with ongoing research. Conflicting procedures performed and their objective outcome scores
results have been found regarding whether NSAIDs inter- to assess soft tissue healing rates. The level of evidence
fere with bone healing after surgery.4,6,9,12,19 However, the for each article was reported according to Wright et al.28
effects of NSAIDs on soft tissue healing in humans have yet Of the 4 studies included, 3 studies3,22,24 were retrospec-
to be established. Numerous studies on animal models have tive reviews with matched cohorts, providing level 3 evi-
examined the effects of NSAIDs on soft tissue healing but dence. The remaining study21 was described as a level 1
have reported conflicting results.7,8,10,11,13 randomized controlled trial. However, the 24-month
NSAIDs are an effective means of controlling postopera- follow-up was 46% (82/180); therefore, we consider the
tive pain after orthopaedic surgical procedures. Given the level of evidence to be level 2 as a poor-quality random-
opioid crisis in the United States, it is relevant to look for ized controlled trial.
safe alternatives for pain control.29 Thus, the aim of our Risk of bias was analyzed for each of the studies
study was to examine all available clinical studies regard- included. The study by Oh et al21 was a randomized con-
ing the effect of perioperative NSAID administration on trolled trial and was therefore assessed by use of the
soft tissue (ligament, meniscal, tendon, muscle) healing Cochrane “risk of bias” tool.14 Risk-of-bias judgment was
and clinical patient outcomes after sports medicine ortho- deemed “low” across domains 1 through 5, and the study
paedic surgery procedures. We then analyzed differences in was therefore considered to have a low risk of bias. The
healing among varying sports medicine procedures to remaining 3 studies were retrospective cohort studies pro-
determine whether administering NSAIDs caused a detri- viding level 3 evidence and as such were analyzed by use of
the ROBINS-I (Risk Of Bias In Non-randomized Studies–of
mental effect. Our hypothesis was that perioperative
Interventions) assessment tool.25 All 3 retrospective cohort
NSAID administration does not affect soft tissue healing
studies were analyzed across domains 1 through 7 via the
after sports medicine surgical procedures.
ROBINS-I assessment tool and were assigned an overall
risk-of-bias judgment of “moderate.”
METHODS
This study was conducted in accordance with the PRISMA RESULTS
(Preferred Reporting Items for Systematic Reviews and
Study Selection
Meta-Analyses) statement. A systematic review of the
existing evidence for clinical effects of NSAID use on soft A total of 466 articles were initially retrieved. A PRISMA
tissue healing was performed through use of the Cochrane flowchart demonstrates the selection of articles based on
Database of Systematic Reviews, the Cochrane Central inclusion and exclusion criteria (Figure 1). Studies that did
Register of Controlled Trials, PubMed (1980 to present), not report the effects of NSAIDs on soft tissue healing were
and MEDLINE. Searches were performed using the fol- excluded based on title (n ¼ 403). Studies or case studies
lowing terms: nonsteroidal anti-inflammatory drug OR that were performed on animal models were excluded based
NSAID AND meniscus OR ligament OR tendon OR muscle on abstract review (n ¼ 50). Studies that did not report
OR soft tissue AND healing. The searches were performed clinical outcomes following NSAID administration with
in June 2018. no comparison with control groups were excluded upon
Inclusion criteria for articles were as follows: outcome stud- full-text analysis (n ¼ 9). Ultimately, we identified 4 studies
ies of soft tissue (ligament, meniscal, tendon, muscle) healing on the effects of perioperative NSAIDs on healing after
after surgical procedure with perioperative NSAID adminis- sports medicine procedures in humans.3,21,22,24
tration, at least 1 year of follow-up, English language, and
human patients. We excluded case reports, case series, and Patient Demographics
animal model studies. We reviewed titles, abstracts, and,
when necessary, the full text of all identified articles to assess The review included a total of 4451 patients (2523 male,
inclusion and exclusion criteria. All references from the 1928 female), mean age 29.5 years (range, 15.9-61 years),

*Address correspondence to David S. Constantinescu, BS, 1820 East Broad Street, #442, Richmond, VA 23223, USA (email: constantineds@[Link]).
†
Department of Orthopedic Surgery, Virginia Commonwealth University, Richmond, Virginia, USA.
‡
Oslo Sports Trauma Research Center, Oslo, Norway.
One or more of the authors has declared the following potential conflict of interest or source of funding: A.R.V. has received educational support from
DJO, Smith & Nephew, and Supreme Orthopedic Systems; research support from DJO; and hospitality payments from RTI Surgical. AOSSM checks author
disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or
responsibility relating thereto.
The Orthopaedic Journal of Sports Medicine Effects of Perioperative Nonsteroidal Anti-inflammatory Drugs 3

466 iden!fied by relevant journal database searching

Exclusion Criteria

466 studies analyzed by !tle

Studies that did not report NSAID

effects on so# !ssue healing
(n = 403)
63 studies analyzed by abstract review

Case studies or studies that

included animal models (n = 50)

13 studies analyzed by full-text review

Studies that did not report
clinical outcomes in NSAID and
control groups (n = 9)

4 studies selected for inclusion

Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram. Search and selection
criteria for systematic review of the literature addressing effects of perioperative nonsteroidal anti-inflammatory drug (NSAID)
administration on soft tissue healing and clinical patient outcomes.

i i
TABLE 1
Study Design, Patient Demographics. and Clinical Outcome Scales of Included Perioperative NSAID Effect Studiesa

Level of No. of Patients Administered Mean Patient

Study Evidence NSAID (Male/Female) Age, y Mean Follow-up Outcome Scales

Proffen et al22 3 32 (14/18) 15.9 5.5 y Need for reoperation

Soreide et al24 3 4144 (2404/1740) 28.9 2.8 y Graft survival; need for reoperation
Oh et al21 1 120 (39/81) 61 108/120 patients Retear of rotator cuff
assessed for 2 wk
57/120 patients had
2-y follow-up
Blomquist et al3 3 155 (66/89) 24 21 mo Recurrence of shoulder dislocation;
need for reoperation
a
NSAID, nonsteroidal anti-inflammatory drug.

who underwent soft tissue surgical repair and were admin- Bankart shoulder repair,3 and 1% (32/4451) underwent
istered NSAIDs perioperatively (Table 1). Weighted mean meniscal repair.22 The type of NSAID administered was
follow-up was 2.8 years (range, 21-66 months). Oh et al21 reported in 3 of 4 studies (Table 2). Proffen et al22 solely
reported that 108 of 120 patients were evaluated for 2 used ketorolac with a dosage adjusted to body weight and
weeks, but only 57 of 120 patients had a follow-up of 2 years did not specific the length of treatment. Soreide et al24
in order to assess retear rates. used diclofenac, ketorolac, celecoxib, or another NSAID for
a mean of 6.7 days but did not report the dosage. Oh et al21
Procedures Performed compared celecoxib (200 mg twice a day) versus ibupro-
fen (385 mg 3 times a day) administered for 14 days after
Among the studies included, 4 procedures were identified: treatment. Blomquist et al3 did not report the specific
93% (4144/4451) of patients underwent anterior cruciate NSAID used or the dosage but noted that the NSAID
ligament (ACL) reconstruction,24 3% (120/4451) under- was administered for an interval ranging from 1 to 7
went rotator cuff repair, 21 3% (155/4451) underwent days postoperatively.
4 Constantinescu et al The Orthopaedic Journal of Sports Medicine

TABLE 2
Surgical Procedure, NSAID Treatment Modality, and Clinical Failure Rates
of Included Perioperative NSAID Effect Studiesa

Study Tissue/Procedure Drug Dosage Length of Treatment Failure Rate P Value

Proffen et al22 Meniscal repair Ketorolac 7.5-60 mg (adjusted Perioperative NSAID: 34% (11/32) .99
to body weight) Control: 35% (26/75)
Soreide et al24 ACL reconstruction Diclofenac (91.5%) NR Mean, 6.7 days NSAID: 3% (127/4144) .794
Ketorolac (3.1%) Control: 3% (109/3678)
Celecoxib (2.4%)
Other NSAIDs (1%)
Oh et al21 Rotator cuff repair Celecoxib (50%) Celecoxib (200 mg, 14 days after surgery Celecoxib: 37% (11/30) .009
Ibuprofen (50%) 2 times per day) Ibuprofen: 7% (2/27)
Ibuprofen (385 mg,
3 times per day)
Blomquist et al3 Bankart repair NSAID NR 1-3 days (50%) NSAID: 5% (6/127) .8
4-7 days (41%) Control: 5% (12/243)
"7 days (9%)
a
ACL, anterior cruciate ligament; NR, not reported; NSAID, nonsteroidal anti-inflammatory drug.

Outcome Data tissue (meniscus, ligament, tendon) healing after sports

medicine surgical procedures. Of the 3 studies examining
In all 4 studies, healing rates were objectively measured by ACL, shoulder labrum/capsule, or meniscus tissue, no
the need for reoperation or revision after initial sur- difference in healing was found regardless of whether
gery.3,21,22,24 The reported surgical failure rate among all NSAIDs were administered. 3,22,24 For rotator cuff
patients administered NSAIDs was 3.6% (157/4360). The repairs, celecoxib had a significant adverse effect on
reported surgical failure rate among control participants who healing versus indomethacin.21
were not given NSAIDs was 3.7% (147/3996). Surgical failure A recent systematic review indicated that NSAIDs had
rates among patients administered NSAIDs for each proce- no effect on nonunion rates of bone healing after fracture or
dure were as follows: meniscal repair, 34% (11/32)22; ACL spinal fusion healing in clinical studies.4 Furthermore,
reconstruction, 3% (127/4144)24; rotator cuff repair, 23% (cel- another systematic review indicated that NSAID adminis-
ecoxib 11/30 and ibuprofen 2/27)21; and Bankart repair, 5% (6/ tration affected bone healing but not soft tissue healing;
127).3 NSAID use showed no statistically significant effect that review, conducted by Chen and Dragoo,6 was based
on need for reoperation after meniscal repair solely on 9 animal studies. Chen and Dragoo6 concluded
(P ¼ .99), ACL reconstruction (P ¼ .8), and Bankart that NSAIDs did not demonstrate a difference in soft tissue
repair (P ¼ .8) compared with no NSAID administra- healing according to markers such as tendon biomechan-
tion. Celecoxib had a significantly higher rate of retear ical strength and cross-sectional area measurements.
after rotator cuff repair compared with ibuprofen (P ¼ Our finding of no difference in the rate of reoperation
.009). Blomquist et al 3 reported a recurrence rate of after NSAID administration indicates that the observed
anterior shoulder dislocation after Bankart repair in findings in animal studies may correlate clinically.
12% (15/127) of patients administered NSAIDs versus The observed difference in effects of NSAIDs on bone
14% (34/243), with a P value of .56, indicating no sig- versus soft tissue healing may be due to the differences
nificant difference.
in pathways involved in healing. NSAIDs inhibit the
COX-2 enzyme, further inhibiting prostaglandins, which
Complications are required for osteoblast and osteoclast activation dur-
ing bone healing. However, soft tissue healing relies on
Proffen et al22 and Soreide et al24 reported that patients
many pathways and growth factors, including platelet-
had no complications, whereas Blomquist et al3 did not
derived growth factor, among others, that are not
report whether any patients had complications. Oh et al21
affected by NSAIDs blocking the inflammatory pathway.
reported side effects of nausea, somnolence, gastrointesti-
Furthermore, tendon-to-bone healing involves a third
nal disorders, and pruritis 3 days after surgery as well as
category, which relies on a combined healing model
nausea, somnolence, and gastrointestinal disorders 2
including both bone and soft tissue.5 NSAIDs were not
weeks after surgery, with no significant difference between
shown to affect soft tissue healing but did have a detri-
celecoxib and ibuprofen.
mental effect on tendon-to-bone healing in animal mod-
els. 6 NSAIDs have a direct effect on the mediators
DISCUSSION involved in tendon healing.26,27 However, successful sur-
gical reattachment of a failed tendon relies on the qual-
The most important finding of this study was that peri- ity of soft tissue as well as fixation on bone. Formation of
operative NSAID administration does not affect soft the subsequent enthesis relies on fibrous scar tissue and
The Orthopaedic Journal of Sports Medicine Effects of Perioperative Nonsteroidal Anti-inflammatory Drugs 5

bone healing, in which NSAIDs may interfere with the As with any systematic review, there is the possibility of
inflammatory process. noninclusion of relevant articles. However, our search
Further differentiation between NSAID classes may be strategy combined with searching the reference lists of all
made, specifically with selective COX-2 inhibitors. Oh relevant articles should have minimized this type of bias.
et al21 found that selective COX-2 inhibitors (celecoxib) sig-
nificantly lowered tendon-to-bone healing after surgical
repair of rotator cuff compared with nonselective indometh- CONCLUSION
acin. A similar finding was observed by Lu et al17 in a rabbit
model of rotator cuff healing. However, Cohen et al7 dem- We believe that our review of the available literature pro-
onstrated that both indomethacin and celecoxib impaired vides guidance regarding the use of NSAIDs following
rotator cuff healing in an animal model, with no difference sports medicine orthopaedic surgery procedures in terms
observed between indomethacin and celecoxib. Rotator cuff of healing rates and the need for reoperation. Insufficient
healing is modulated by multiple enzymes including COX-1 data are available to definitively state the effects of perio-
and COX-2.20 Although an interplay of growth mediators is perative NSAIDs on soft tissue healing. Use of NSAIDs
involved in rotator cuff healing, selectivity toward COX-2 should be considered on a case-by-case basis and may not
inhibition may be a factor leading to delayed healing. affect healing rates after meniscal, ACL, rotator cuff, or
Dose and duration of NSAID use varied among studies. Bankart repair. However, celecoxib (a selective COX-2
Blomquist et al3 and Soreide et al24 did not specify the inhibitor) may inhibit tendon-to-bone healing in rotator
dosing regimen used. All studies noted the length of NSAID cuff repair. Further research in clinical trials is required
treatment.3,21,22,24 Proffen et al22 delivered a dosage of to fully determine whether NSAIDs have a negligible effect
ketorolac that was adjusted to patients’ body weight, rang- on soft tissue healing.
ing from 7.5 to 60 mg, either intraoperatively or in the
postanesthesia care unit for patients undergoing meniscal
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