Do Selective COX-2 Inhibitors Affect

Pain Control and Healing After

Arthroscopic Rotator Cuff Repair?
A Preliminary Study
Joo Han Oh,* MD, PhD, Hyuk Jun Seo,y MD, PhD, Ye-Hyun Lee,z MD,
Hye-Yeon Choi,§ MD, Ho Yun Joung,|| MD, and Sae Hoon Kim,{# MD, PhD
Investigation performed at Seoul National University Bundang Hospital,
Seongnam, Republic of Korea

Background: Selective cyclooxygenase (COX)–2 inhibitors are commonly used analgesics that provide similar analgesia as that of
other analgesics but with fewer adverse effects. However, few prospective studies have performed comparative analyses in this
regard.
Purpose: To evaluate the efficacy of a selective COX-2 inhibitor in early postoperative pain control, satisfaction with pain man-
agement, and incidence of systemic adverse effects in patients undergoing arthroscopic rotator cuff repair.
Study Design: Randomized controlled trial; Level of evidence, 1.
Methods: This study included 180 patients who underwent arthroscopic rotator cuff repair between September 2011 and August
2012. The patients were randomly assigned to receive celecoxib, ibuprofen, or tramadol (n = 60 each). Visual analog scale (VAS) scores
for pain intensity and satisfaction with medication, incidence of adverse effects, and use of rescue medication were recorded and com-
pared between the 3 groups at 3 days and 2 weeks after surgery. Magnetic resonance and ultrasonography images of 82 patients
were retrospectively reviewed at least 24 months after surgery, along with the range of motion and pain VAS and functional scores.
Results: There were no significant differences among the 3 groups in terms of pain intensity, incidence of adverse effects, or
dosage of rescue medication at 3 days or 2 weeks after surgery. Pain VAS and functional scores at the final follow-up were
also comparable among the 3 groups. However, the retear rate in the celecoxib group (11/30 [37%]) was significantly higher
than those in the ibuprofen (2/27 [7%]) and tramadol (1/25 [4%]) groups (P = .009).
Conclusion: Despite having similar postoperative analgesic effects as other nonsteroidal anti-inflammatory drugs and opioids,
selective COX-2 inhibitors should not be used for postoperative analgesia because they might negatively affect tendon-to-
bone healing after surgical repair.
Registration: NCT02850211 (ClinicalTrials.gov identifier)
Keywords: arthroscopic rotator cuff repair; cyclooxygenase (COX)–2 inhibitor; pain; postoperative analgesia

Injury to rotator cuff tendons is one of the more common
causes of pain and functional limitation in the shoulder
joint. Arthroscopic repair of symptomatic rotator cuff tears
typically provides satisfactory results, including decreased
shoulder pain and improved shoulder motion.14,18,35,40
Although the long-term result of arthroscopic rotator cuff
repair is satisfactory, patients suffer from severe immediate
postoperative pain because of extensive bursectomy, acro-
mioplasty, and soft tissue swelling caused by infiltration of
The American Journal of Sports Medicine
1–8
DOI: 10.1177/0363546517744219
! 2017 The Author(s)
a large amount of perfusate, particularly within the first
48 hours after surgery. Pain experienced after rotator cuff
repair is reported to be as severe as that after gastrectomy
or thoracic surgery.26,31 If postoperative pain is not effec-
tively controlled during the early postoperative period, it
may lead to delayed rehabilitation, which might result in
decreased shoulder function and postponement of return
to normal life. Therefore, achieving optimal pain control
after arthroscopic surgery is important.
Various methods of pain control have been introduced,
including regional nerve block, intravenous patient-
controlled analgesia, and cryotherapy. Nonsteroidal anti-
inflammatory drugs (NSAIDs) and opioids are among the
more commonly used oral medications.15,31 However, in
addition to pain relief, oral medications often cause adverse

1
2 Oh et al The American Journal of Sports Medicine

side effects. For instance, traditional nonselective NSAIDs
inhibit cyclooxygenase (COX)–1 and thus disturb normal
platelet function, leading to gastrointestinal toxicity and
bleeding.2,20 On the other hand, opioid drugs cause adverse
side effects, such as nausea, vomiting, constipation, respira-
tory depression, and sedation. In recent times, selective
COX-2 inhibitors have received much attention since they
are thought to provide similar analgesia as that of nonselec-
tive NSAIDs and opioid drugs but with fewer adverse
effects.16
Despite advances in surgical techniques, significant
complications, such as incomplete healing and recurrence
of tears, occur after rotator cuff repair. Studies aimed at
improving tendon-to-bone healing currently pursue sys-
temic approaches, such as stopping smoking and control-
ling hypercholesterolemia and diabetes.1,3-6,8,17 Several
studies have reported an association between the use of
selective COX-2 inhibitors and impaired muscle regenera-
tion and weakened tendon-to-bone healing.11,13,21,28 There-
fore, understanding the pharmacodynamics of selective
COX-2 inhibitors during rotator cuff tendon healing is of
great clinical relevance.
To the authors’ knowledge, few studies have compara-
tively evaluated the effects of selective COX-2 inhibitors,
nonselective NSAIDs, and opioid analgesics after arthro-
scopic rotator cuff repair in terms of postoperative pain
and tendon-to-bone healing. This prospective, randomized
comparative study evaluated the efficacy of a selective
COX-2 inhibitor in early postoperative pain control, patient
satisfaction regarding pain management, and incidence of
systemic adverse effects in patients undergoing arthroscopic
rotator cuff repair. The hypothesis of this study was that
pain intensity, patient satisfaction, incidence of adverse
effects, and tendon-to-bone healing rate would be compara-
ble among patients receiving a selective COX-2 inhibitor,
a nonselective NSAID, and an opioid drug.
METHODS
Patient Selection
The primary study was a single-center, double-blinded ran-
domized controlled trial, which was registered with the US
National Institutes of Health (clinicaltrials.gov) as trial num-
ber NCT02850211. After obtaining institutional review board
approval and written informed consent from the patients, we
prospectively enrolled 180 patients who were scheduled to
undergo arthroscopic rotator cuff repair between September
2011 and August 2012. Patients with rotator cuff tear
arthropathy, severe osteoarthritis (Samilson-Prieto grade 2
or higher), rheumatoid arthritis, chronic renal failure (ie, at
high risk for use of NSAIDs or opioid drugs), liver failure,
myocardial infarction or chronic heart failure, cerebral vascu-
lar disease, active gastric ulcer or bleeding, allergies to
NSAIDs or opioid drugs, or previous surgery on the same
side were excluded, as were pregnant or breast-feeding
patients and those unwilling to participate in the trial.
A priori statistical power analysis was performed to calcu-
late the number of subjects required. A difference of 1.4 points
(SD, 1.8) in visual analog scale (VAS) scores was defined as
the minimal clinically relevant difference.24,36,37 With a power
of 80% and an alpha value of .05, the results of power analysis
revealed that a sample size of 51 patients per group would be
needed. Assuming a dropout rate of 20%, the required sample
size was determined to be 60 patients per group. Patients
were randomly allocated in equal numbers to receive a selec-
tive COX-2 inhibitor (celecoxib, Celebrex 200 mg twice a day;
Pfizer), a traditional NSAID (ibuprofen, Carol-F 385 mg
3 times a day; Ildong), or an opioid drug (tramadol, Tridol
50 mg twice a day; Yuhan) for 2 weeks from the first day after
surgery. Group allocation was achieved through computer-
aided block randomization.
Analgesic medication was not prescribed before surgery.
All patients received subacromial patient-controlled analge-
sia (Automed 3200; Ace Medical) for the first 48 hours after
surgery. A 20-gauge multi-orifice epidural catheter was
inserted by a surgeon through an arthroscopic lateral portal
in the subacromial space at the end of surgery. The catheter
was filled with 10 mL of 0.75% ropivacaine and was then con-
nected through a bacterial filter to an infusion pump contain-
ing 150 mL of 0.5% ropivacaine. Ropivacaine was infused at
2 mL/h, and a bolus (2 mL) of ropivacaine was administered
by the patient with a lockout time of 30 minutes. Intravenous
cefazolin was administered as a postoperative antibiotic for 1
day. If the patients could not tolerate pain with the regular
postoperative medication, oxycodone (IR codon 5 mg;
Unimed) was administered as rescue medication for 2 weeks
after surgery; the maximum dosage was limited to 20 mg/d in
accordance with the standard postoperative pain control pro-
cedures of the institution. After 2 weeks of the primary study,
postoperative pain was controlled solely with oxycodone, fol-
lowing the same regimen.
In addition, upon conclusion of the primary study of this
prospective randomized trial, some differences in tendon-
to-bone healing rate were observed among the 3 groups
during routine follow-up evaluation. Until 6 months after
surgery, 8 patients from the celecoxib group, 1 patient
from the ibuprofen group, and 1 patient from the tramadol
group showed retear of the rotator cuff. Therefore, patients

#
Address correspondence to Sae Hoon Kim, MD, PhD, Department of Orthopedic Surgery, College of Medicine, Seoul National University Hospital,
Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea (email: drjacobkim@gmail.com).
*Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic
of Korea.
y
Department of Orthopaedic Surgery, Daegu Chamtntn Hospital, Daegu, Republic of Korea.
z
Department of Orthopaedic Surgery, National Police Hospital, Seoul, Republic of Korea.
§
Department of Orthopaedic Surgery, Seoul Medical Center, Seoul, Republic of Korea.
||
Department of Orthopaedic Surgery, Wonkwang University School of Medicine, Wonkwang University Sanbon Hospital, Gunpo, Republic of Korea.
{
Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
The authors declared that they have no conflicts of interest in the authorship and publication of this contribution.
AJSM Vol. XX, No. X, XXXX Selective COX-2 Inhibitors Affect Healing After ARCR 3

TABLE 1
Classification of Postoperative Rotator Cuff Integrity by Sugaya et al34

Type No. of Cuffs Definition of Type

I 31 Sufficient thickness compared with that of the normal cuff and homogeneously low intensity
II 21 Sufficient thickness compared with that of the normal cuff and partial high intensity
III 5 Insufficient thickness (less than half the thickness of the normal cuff) but no discontinuity, suggesting
a partial-thickness delaminated tear
IV 5 Presence of a minor discontinuity in 1-2 slices on both oblique coronal and sagittal images, suggesting
a small full-thickness tear
V 8 Presence of a major discontinuity in more than 2 slices on both oblique coronal and sagittal images, suggesting
a medium or large full-thickness tear

available for evaluation of healing at 24 months after sur-
gery were examined to further investigate these differen-
ces. As the secondary objective of this prospective
randomized control trial, tendon-to-bone healing of rotator
cuff tears, as well as pain VAS scores, range of motion
(ROM), and functional outcomes, was compared among
the 3 patient groups.
Clinical and Radiological Assessment
Of the 180 patients, 162 were followed up for at least 2
weeks after surgery. Patients rated the severity of pain
and satisfaction with medication before and at 3 days and
2 weeks after surgery, using a VAS of 0 (no pain/no satisfac-
tion) to 10 (unbearable pain/extreme satisfaction) points.
The best score for satisfaction on the VAS is 10 points. A
specially designed VAS ruler was used to evaluate satisfac-
tion with the medication. Patients were allowed to place the
indicator along a 10-cm interval. The VAS was scaled 0 to
10, with 10 indicating the highest satisfaction. Administra-
tion of rescue medication and incidence of side effects were
also recorded. Side effects were categorized into 5 catego-
ries: nausea/vomiting, somnolence/dizziness, gastrointesti-
nal complications (constipation, diarrhea, and abdominal
discomfort), pruritus, and bruising. Instances of respiratory
difficulties, renal and heart failure, and seizure were also
evaluated.
Of the 180 patients, 82 were available for follow-up and
repeat clinical evaluation at least 24 months after surgery.
Shoulder functional scores were recorded on the basis of
ROM, which was assessed by an independent observer by
means of a goniometer, pain VAS, Constant scores, Amer-
ican Shoulder and Elbow Surgeons scores, and Korean
shoulder scores. Muscle strength was also measured by
a clinical researcher using an electronic isometric dyna-
mometer. Anatomic integrity of the repaired rotator cuff
was assessed by magnetic resonance imaging (MRI) in 70
patients (celecoxib group, 25; ibuprofen group, 23; trama-
dol group, 22) and by actual dynamic ultrasonography
(USG) in the remaining 12 patients (celecoxib group, 5;
ibuprofen group, 4; tramadol group, 3) who refused MRI
for financial reasons. The MRI and USG data were ana-
lyzed by an expert musculoskeletal radiologist with 15
years of experience who was blinded to the study design.
Postoperative rotator cuff integrity assessed by MRI was
categorized as types I to V in accordance with the
classification system developed by Sugaya et al34 (Table
1). Incomplete healing and retear after surgery were cate-
gorized as Sugaya type IV or V findings.
The deltoid muscle, subacromial/subdeltoid bursa, long
head of the biceps tendon, and entire rotator cuff were
examined by USG, with special emphasis on the integrity
of the rotator cuff tendon. The tendons were scanned along
their long and short axes. The criteria for diagnosis of full-
thickness rotator cuff tears by USG were as follows25: rota-
tor cuff could not be visualized because of complete avulsion
and retraction under the acromion, the presence of focal
defects, or retraction of the torn cuff by variable degrees
from the surgical trough. Partial-thickness tears were diag-
nosed when distinct hypoechoic or mixed hyperechoic and
hypoechoic defects were visualized on the deep articular
side of the rotator cuff (articular-side partial-thickness
tears) in both the longitudinal and transverse planes. A
thinned cuff or a cuff with a subtle concave contour was con-
sidered to be intact in the absence of focal defects. Incom-
plete healing and retear after surgery were defined as
full- or partial-thickness rotator cuff tears.
Surgical Procedure and Postoperative Care
All surgical procedures were performed arthroscopically by
the senior author through the anterior, lateral, and posterior
portals. In patients with a stiff shoulder, manipulation was
performed with capsular release. Synovectomy, biceps proce-
dures, and debridement for partially torn rotator cuff tendons
were performed at the glenohumeral joint. After glenohum-
eral procedures, subacromial decompression was performed
to remove inflamed bursal tissue. In almost all patients,
except in those with an extremely thin acromion, acromio-
plasty was performed using a motorized bur to obtain a flat
acromion undersurface and ensure adequate working space
for the repair. Distal clavicle resection was performed in
selected patients. The anteroposterior and retraction sizes
of the tear were measured with a calibrated probe, and foot-
print preparation was achieved with a ring curette, rasp, and
shaver to expose the bleeding bony surface. After insertion of
anchors in accordance with the selected repair technique,
loaded sutures were passed through the tendon using
a suture passer (Expressew Flexible Suture Passer; Depuy
Mitek or Spectrum Suture Passer; Linvatec). Sutures were
secured with the Samsung Medical Center knot. Suture
bridge, single-row, or modified Masson-Allen repair was
4 Oh et al The American Journal of Sports Medicine

TABLE 2
Patient Demographic and Baseline Clinical Characteristicsa

Celecoxib (n = 60) Ibuprofen (n = 60) Tramadol (n = 60) P Value

Age, y 61.5 6 8.4 61.2 6 9.5 59.6 6 9.2 .469

Sex, male/female 17/43 22/38 24/36 .386
Diabetes mellitus 9 5 6 .481
Hypertension 20 21 21 .976
Smoking habit 3 11 7 .075
History of trauma 24 19 25 .481
Dominant hand, right/left 41/19 39/19 48/11 .226
Symptom duration, mo 45.3 6 83.8 42.7 6 66.5 32.1 6 93.6 .649
Symptom aggravation, mo 10.3 6 23.5 9.6 6 11.6 8.8 6 11.7 .881
Rotator cuff tear
Retraction, mm 18.3 6 10.5 17.6 6 9.0 16.1 6 8.2 .437
Anteroposterior dimension, mm 17.0 6 9.5 16.5 6 7.6 15.9 6 8.2 .772
Capsular release, yes:no 6:54 5:55 12:48 .117
Biceps procedure, no:tenotomy:tenodesis 19:19:22 17:18:25 25:14:21 .573
Acromioplasty, yes:no 58:2 59:1 57:3 .596
Distal clavicle resection, yes:no 12:48 10:50 15:45 .493
Repair methods, modified Masson-Allen:single row:suture bridge 8:20:32 4:16:40 6:17:37 .605

a
Values are expressed as mean 6 SD or number.

performed in accordance with the tear configuration and RESULTS

mobilization of the retracted tendon. After completion of sub-
acromial procedures, the surgeon always returned to the gle-
nohumeral joint for irrigation and for identifying medial
anchor pullout, overlooked foreign materials, or biceps incor-
porated into the repaired rotator cuff.9,10,22,23
All patients followed the same rehabilitation protocol.
They wore an abduction brace for 5 weeks after surgery.
Patients with limited motion before surgery started practic-
ing tolerable, controlled passive motion from the first day
after surgery. Shrugging of the shoulder and active motion
of the elbow (flexion and extension), forearm (supination
and pronation), wrist, and hand were encouraged immedi-
ately after surgery. After brace weaning, the patients per-
formed active assisted ROM exercise in accordance with
a preestablished protocol for 6 weeks. Once they achieved
full ROM, muscle-strengthening exercises were started,
usually at 3 months after surgery. Sports activities of all
types were permitted by 6 months after surgery. All physi-
cal therapy protocols were practiced with the cooperation
and supervision of a rehabilitation physician.
Statistical Analysis
Statistical analysis was performed using SPSS software
(version 18.0E; SPSS, Inc). Frequencies and descriptive
statistics were calculated for evaluation of baseline charac-
teristics. The t test, chi-square test, analysis of variance,
and Mann-Whitney test were used for comparison among
the 3 groups. In the comparison of the 3 groups, analysis
of variance was performed for parametric variables, and
the Kruskal-Wallis test was used for nonparametric varia-
bles. Tukey’s post hoc and Bonferroni tests were used to
identify the groups with differences in parameters. Statis-
tical significance was set at P \ .05.
The mean age of the 180 patients (63 men, 117 women) was
60.8 6 9.1 years. There were no significant differences
among the 3 groups in terms of age, underlying disease,
symptom duration, size of the rotator cuff tear, repair
method, or any of the additional procedures (Table 2). Of
the 180 patients, 162 (celecoxib group, 53; ibuprofen group,
55; tramadol group, 54) were followed up for at least 2
weeks after surgery. A total of 18 patients dropped out of
the study, including 7 in the celecoxib group (medication
missing, 3; refusal to participate, 1; loss to follow-up, 3);
5 in the ibuprofen group (medication missing, 1; complica-
tions from infection, 1; loss to follow-up, 3); and 6 in the
tramadol group (all 6 lost to follow-up) (Figure 1).
Table 3 presents the pain VAS scores. In all 3 groups, the
mean pain VAS scores had decreased by 3 days after surgery
and had decreased even further by 2 weeks after surgery;
however, the intergroup differences were not significant.
There were also no statistically significant intergroup differ-
ences in mean satisfaction VAS scores for pain management
at 3 days or 2 weeks after surgery (Table 3).
The proportions of patients who required rescue medica-
tion in the celecoxib, ibuprofen, and tramadol groups were
51% (27/53), 55% (30/55), and 67% (36/54), respectively (P =
.225), which indicated no significant intergroup differences.
There were also no statistically significant intergroup differ-
ences in the mean dose of rescue medication at 3 days or 2
weeks after surgery (Table 4). Two weeks after surgery, the
rescue medication was administered to 15, 17, and 21 patients
in the celecoxib, ibuprofen, and tramadol groups, respectively.
There were also no significant differences among the 3
groups in terms of incidence of adverse effects (Table 5).
Of the 180 patients, 82 (celecoxib group, 30/53; ibupro-
fen group, 27/55; tramadol group, 25/54) were available
for follow-up and repeat clinical evaluation at least 24
months after surgery (mean, 24 6 2 months). There were
AJSM Vol. XX, No. X, XXXX Selective COX-2 Inhibitors Affect Healing After ARCR 5

Figure 1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram.

TABLE 3
Pain and Medication Satisfaction Scoresa

Celecoxib (n = 53) Ibuprofen (n = 55) Tramadol (n = 54) P Value

Preoperative pain VAS score 6.4 6 2.2 6.9 6 2.4 6.1 6 2.4 .229
Pain VAS score at 3 days after surgery 3.4 6 1.6 3.9 6 1.9 4.1 6 1.7 .165
Pain VAS score at 2 weeks after surgery 2.8 6 2.1 3.2 6 1.9 3.2 6 1.9 .411
Medication satisfaction VAS score at 3 days after surgery 7.0 6 1.6 7.1 6 1.4 6.8 6 1.8 .605
Medication satisfaction VAS score at 2 weeks after surgery 7.4 6 2.1 7.5 6 1.8 7.2 6 2.1 .727

a
Values are expressed as mean 6 SD. VAS, visual analog scale.

3天 D
TABLE 4
Dosage of Rescue Medication After Surgerya

Celecoxib (n = 53) Ibuprofen (n = 55) Tramadol (n = 54) P Value

Rescue medication during 3 days after surgery (no. of tablets) 0.5 6 1.2 0.6 6 1.3 0.7 6 1.1 .653
Rescue medication during 2 weeks after surgery (no. of tablets) 2.5 6 3.4 2.8 6 3.5 3.4 6 3.6 .342

a
Values are expressed as mean 6 SD.

no significant differences among the 3 groups in terms of DISCUSSION

the size of rotator cuff tear or preoperative stiffness (Table
6).
The mean pain VAS and ROM outcomes are shown in
Table 7. Although there were no statistically significant
differences in pain VAS, ROM, or functional scores among
the 3 groups, the retear rate in the celecoxib group was sig-
nificantly higher than those in the ibuprofen and tramadol
groups (P = .009) (Table 7).
According to the present prospective and retrospective
results, the performance of celecoxib (a selective COX-2
inhibitor) in terms of postoperative analgesia and adverse
effects was comparable with those of ibuprofen (a nonselec-
tive NSAID) and tramadol (an opioid drug). However, cel-
ecoxib had a negative effect on tendon-to-bone healing
after arthroscopic rotator cuff repair.
6 Oh et al The American Journal of Sports Medicine

TABLE 5 TABLE 6
Incidence of Adverse Effectsa Preoperative Stiffness and Tear Size
at 24 Months After Surgerya
Celecoxib Ibuprofen Tramadol
(n = 53) (n = 55) (n = 54) P Value Celecoxib Ibuprofen Tramadol
3 days after surgery (n = 30) (n = 27) (n = 25) P Value
Nausea 1 1 1 ..999
Somnolence 2 4 6 .367 Stiffness 2 2 6 .112
Gastrointestinal 3 1 7 .073 Rotator cuff tear
disorders Retraction, mm 20.6 6 9.3 18.0 6 14.3 17.8 6 9.2 .587
Pruritus 1 1 0 .595 Anteroposterior 19.1 6 8.4 16.9 6 9.8 18.6 6 10.2 .641
Bruising 0 0 0 dimension, mm
2 weeks after surgery
Nausea 3 1 5 .228 a
Data were collected only among patients who were available
Somnolence 4 1 6 .143
for follow-up evaluation at 24 months after surgery. Values are
Gastrointestinal 6 5 7 .795
expressed as mean 6 SD or number.
disorders
Pruritus 0 1 3 .161
Bruising 0 0 0

a
Values are expressed as number.
Although pain experienced after arthroscopic surgery
appears to be less intense than that after open surgery,38 it
is still of clinical significance. A range of analgesics are com-
monly used for postoperative pain control. White et al39
reported that celecoxib and ibuprofen exhibited similar
effects in terms of recovery quality and patient satisfaction
with pain management after outpatient surgery. In the Cel-
ecoxib Long-term Arthritis Safety Study,30 which involved
7968 patients with osteoarthritis and rheumatoid arthritis,
celecoxib showed pain control similar to that of ibuprofen
and diclofenac but with a lower incidence of combined upper
gastrointestinal complications. In the Successive Celecoxib
Efficacy and Safety Study–1,32 which involved 13,274
patients with osteoarthritis, celecoxib again showed similar
pain control and a lower incidence of upper gastrointestinal
complications relative to naproxen and diclofenac. Roberts
et al27 reported that selective COX-2 inhibitors and opioids
are both effective for providing analgesia with minimal side
effects during the extended period after orthopaedic surgery.
Similarly, in the present prospective study, celecoxib, ibupro-
fen, and tramadol exhibited comparable performances in
terms of postoperative pain scores and use of rescue medica-
tion at 3 days and 2 weeks after surgery.
In terms of systemic adverse effects, celecoxib is known
to produce fewer gastrointestinal adverse effects than do
traditional NSAIDs and fewer adverse effects, such as nau-
sea, vomiting, and somnolence, than do opioid drugs in
general.30,32 In a meta-analysis of 22 studies, Marret
et al19 concluded that increased use of NSAIDs signifi-
cantly decreases postoperative nausea and vomiting—2
common side effects of opioid drugs. In a study by Gimbel
et al,16 hydrocodone/acetaminophen (89%) caused more
side effects than did celecoxib (39%); however, some
patients in the celecoxib and ibuprofen groups also showed
adverse effects, such as nausea/vomiting and dizziness/
somnolence. It is possible that opioid analgesics were
used as a rescue medication. However, in the present
study, there were no significant differences in the inci-
dence of adverse effects among the 3 groups. This study
employed fentanyl as an anesthetic agent, per routine,
which might explain the similarity in incidence of adverse
effects among the 3 groups.
Traditional NSAIDs are believed to have a negative
effect on bone and tendon healing. Shen et al28 reported
that the COX-2 pathway plays an important role in muscle
healing. Prostaglandins are key mediators of the COX-2
pathway. Hence, patients who use NSAIDs for treatment
of acute or chronic pain due to muscle injury are at an
increased risk of impaired functional healing or prolonged
rehabilitation. Chen and Dragoo7 reported that COX-2
inhibition results in reduced prostaglandin synthesis
and, consequently, inhibition of osteoblast function in the
early phase of bone formation. Cohen et al11 reported
that traditional and COX-2-specific NSAIDs significantly
inhibited enthesis formation after rotator cuff repair in
a rat model. Ferry et al13 also reported that therapeutic
dosages of COX-2 inhibitors administered in the early post-
operative period had a detrimental effect on healing
strength and collagen production after rat patellar tendon
injury at the osteotendinous junction; the authors also
reported similar changes with nonselective COX inhibi-
tors. Both previous studies reported higher rates of healing
failure with COX-2 inhibitors than with nonselective COX
inhibitors. The present retrospective data, too, demon-
strated that the tendon-to-bone retear rate was signifi-
cantly higher in the selective COX-2 inhibitor group than
in the other 2 groups. Recently, Dolkart et al12 addressed
the importance of the pro-inflammatory COX-2/prostaglan-
din E2 (PGE-2) pathway in stimulating tenocyte prolifera-
tion, adhesion, and migration during the early stage of
healing. They advocated a significant beneficial effect of
atorvastatin in promoting rotator cuff tendon healing
through stimulation of the COX-2/PGE-2 pathway in
a rat model. Thus, it appears that selective COX-2 inhibi-
tors block the acute inflammatory phase that occurs imme-
diately after tendon injury, which is consistent with the
present data. To the authors’ knowledge, there have been
few human studies on comparison of retear rate after
arthroscopic rotator cuff repair between COX-2 inhibitors
and traditional NSAIDs. The mechanism of action of
NSAIDs on tendon-to-bone healing is not yet known. How-
ever, since tendon-to-bone healing requires bone growth, it
is possible that the healing process is associated with bone
AJSM Vol. XX, No. X, XXXX Selective COX-2 Inhibitors Affect Healing After ARCR 7

TABLE 7
Pain Scores, ROM, Functional Scores, and Retear Rates at the Final Follow-up Visita

Celecoxib (n = 30) Ibuprofen (n = 27) Tramadol (n = 25) P Value

Pain VAS score 0.9 6 1.9 0.6 6 1.1 0.8 6 1.5 .773
Forward flexion, deg 169 6 12.0 172 6 7.6 168 6 19.2 .509
External rotation, deg 71 6 16.2 76 6 14.3 74 6 17.7 .613
Constant score 82.9 6 10.6 86.8 6 8.9 81.0 6 11.0 .115
ASES score 87.6 6 11.4 93.0 6 6.6 87.0 6 11.5 .063
KSS 92.4 6 8.2 95.1 6 4.5 90.6 6 10.1 .122
Retear rate 37% (11/30) 7% (2/27) 4% (1/25) .009b

a
Values are expressed as mean 6 SD or percentage (number). ASES, American Shoulder and Elbow Surgeons; KSS, Korean shoulder
score; ROM, range of motion; VAS, visual analog scale.
b
Significant difference.

healing. Su et al33 reported that celecoxib significantly
inhibits fracture healing, while nonselective NSAID ther-
apy delays, rather than stops, fracture healing. Therefore,
the COX-2 pathway, as well as the dosage of COX-2 inhib-
itors, might be related to bone healing.
The present study has several limitations that require
consideration. First, while the primary study was designed
as a prospective randomized trial for comparison of postop-
erative pain management outcomes among 3 drugs, the
secondary study was performed retrospectively for compar-
ison of postoperative rotator cuff healing among the drugs.
After the primary study, a relatively high incidence of re-
tear was noticed in the celecoxib group during routine
follow-up. This finding, although interesting, was not the
original focus of this study; however, it was subsequently
added as another objective of the study. Given this prelim-
inary result indicating a relatively high retear rate in the
celecoxib group, a similar prospective study would have
been unethical; therefore, the authors considered it neces-
sary to report this result here. It was also officially
reported as an investigator-initiated research serious
adverse event to the pharmaceutical company (Pfizer). Sec-
ond, the proportion of patients lost to follow-up was rela-
tively high. Although only a small number of patients
had dropped out from the primary prospective study at 2
weeks after surgery, more than half of the enrolled
patients did not present for the 24-month follow-up. Never-
theless, there were significant differences in retear rate
among the 3 groups, although there were no such differen-
ces in tear size or stiffness before repair. Third, the hetero-
geneity of imaging tools for detection of tendon healing
might raise some concern in terms of detection bias.
Although it would have been ideal to have all patients
undergo MRI, the second part of this study was not part
of the original study design. Therefore, we could not
enforce MRI for all patients, particularly for those who
refused for financial reasons. Nonetheless, the majority
of patients were evaluated by MRI; moreover, USG is
also a reliable imaging tool for confirming rotator cuff heal-
ing. Therefore, the present results are meaningful. Fourth,
the number of patients using a rescue medication was rel-
atively small. Approximately half of the patients used nar-
cotics as a rescue medication until 2 weeks after surgery.
The first reason is that ropivacaine as a subacromial
pain pump was administered for almost all patients, so
severe pain was managed until 48 hours after surgery.
The second reason might be the cultural difference regard-
ing pain perception and pain management using narcotics.
Fifth, Constant score and all other functional scores were
close to perfection. When a patient visits outpatient clinics
in the authors’ hospital, all functional scores including
muscle power and ROM are measured by a clinical
researcher who is blind to all clinical studies, and the
scores in this study are based on actual measured scores.
Functional scores, including Constant scores in this study,
are similar to those reported in the authors’ previously
published studies.29
CONCLUSION
Although they provide comparable postoperative analgesic
effects to those of other NSAIDs and opioids, selective
COX-2 inhibitors should not be used for postoperative
analgesia because they might negatively affect tendon-to-
bone healing after surgical repair.
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