Meta-analyses

Pain Management Strategies After Anterior Cruciate

Ligament Reconstruction: A Systematic Review With
Network Meta-analysis
Martin S. Davey, M.B., B.Ch., M.Ch., M.R.C.S., Eoghan T. Hurley, M.B., B.Ch., M.Ch.,
Utkarsh Anil, M.D., Akini Moses, M.D., Kamali Thompson, B.S., Michael Alaia, M.D.,
Eric J. Strauss, M.D., and Kirk A. Campbell, M.D.

Purpose: To systematically review randomized controlled trials (RCTs) evaluating various pain control interventions after
anterior cruciate ligament reconstruction (ACLR) to determine the best-available evidence in managing postoperative pain
and to optimize patient outcomes. Methods: A systematic review of the literature was performed based on the PRISMA
(Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A study was included if it was an RCT
evaluating an intervention to reduce postoperative pain acutely after ACLR in one of the following areas: (1) nerve blocks,
(2) nerve block adjuncts, (3) intra-articular injections, (4) oral medications, (5) intravenous medications, (6) tranexamic
acid, and (7) compressive stockings and cryotherapy. Quantitative and qualitative statistics were carried out, and network
meta-analysis was performed where applicable. Results: Overall, 74 RCTs were included. Across 34 studies, nerve blocks
were found to significantly reduce postoperative pain and opioid use, but there was no significant difference among the
various nerve blocks in the network meta-analysis. Intra-articular injections consisting of bupivacaine and an adjunct
were found to reduce reported postoperative pain scores up to 12 hours after ACLR, with significantly lower postoperative
opioid use. Conclusions: Nerve blocks and regional anesthesia are the mainstay treatment of postoperative pain after
ACLR, with the commonly used nerve blocks being equally efficacious. Intra-articular injections consisting of bupivacaine
and an adjunct were found to reduce reported postoperative pain scores up to 12 hours after ACLR, with significantly
lower postoperative opioid use. There was promising evidence for the use of some oral and intravenous medications,
tranexamic acid, and nerve block adjuncts, as well as cryotherapy, to control pain and reduce postoperative opioid use.
Level of Evidence: Level II, systematic review and meta-analysis of RCTs.

A nterior cruciate ligament (ACL) ruptures are

common sporting injuries among athletes, for
which surgical reconstruction is the gold-standard
treatment option.1,2 Although it is widely accepted
that surgical management of these injuries with ACL
reconstruction (ACLR) results in satisfactory clinical
and functional outcomes, as well as high levels of re-
turn to play approaching 100%, postoperative pain is a
common complaint among patients after surgery.3,4
Effective analgesia is required after ACLR to control
postoperative pain levels and enable earlier rehabilita-
tion.5 Opioid medications have been a primary method
of pain management, but because of the increase in
reported addictions, alternative analgesics are becoming
more popular to treat pain postoperatively.6
The management of postoperative pain after ACLR is
often achieved using a variety of analgesic regimens,
which are often based on both surgeon- and
anesthesiologist-specific preferences.7 Therefore, decisions
regarding optimal analgesia require a multidisciplinary

From the Sports Medicine Division, Orthopaedic Surgery Department, NYU
Langone Health, New York, New York, U.S.A. (M.S.D., E.T.H., U.A., A.M.,
K.T., M.A, E.J.S., K.A.C.); and Royal College of Surgeons in Ireland, Dublin,
Ireland (M.S.D., E.T.H.).
The authors report the following potential conflicts of interest or sources of
funding: M.A. receives grant support from Arthrex and Concours, outside the
submitted work. E.J.S. receives grant support from Arthrex, Cartiheal, Fidia,
and Organogenesis and receives personal fees from Arthrex, Flexion Thera-
peutics, JRF, Organogenesis, Smith & Nephew, Subchondral Solutions, and
Vericel, outside the submitted work. K.A.C. receives personal fees from
Samumed, outside the submitted work. Full ICMJE author disclosure forms
are available for this article online, as supplementary material.
Received September 9, 2020; accepted January 5, 2021.
Address correspondence to Eoghan T. Hurley, M.B., B.Ch., M.Ch., Royal
College of Surgeons in Ireland, 123 St. Stephens Green, Dublin, Ireland.
E-mail: eoghanhurley@rcsi.ie
Ó 2021 by the Arthroscopy Association of North America
0749-8063/201523/$36.00
https://doi.org/10.1016/j.arthro.2021.01.023

1290 Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 37, No 4 (April), 2021: pp 1290-1300
 ACL PAIN: NETWORK META-ANALYSIS
approach with orthopaedic and anesthesiology input.
Perioperative consideration must be given to patient
comorbidities, associated side effects, and contraindica-
tions when prescribing not only opioids but all analgesic
medications.8,9 Additionally, many different pain control
treatments are used in the management of patients after
ACLR, including various permutations of nerve blocks,
nerve block adjuncts (NBAs), intra-articular injections,
intravenous (IV) and oral medications, and cryotherapy, as
well as compression stockings.10
Secrist et al.11 published a systematic review in 2016
evaluating the various methods of reducing postoperative
pain levels after ACLR. Despite this, no gold-standard
postoperative analgesia guideline has emerged, and
many randomized controlled trials (RCTs) on the topic
have been published in the interim. Therefore, the pur-
pose of this study was to systematically review RCTs
evaluating various pain control interventions after ACLR
to determine the best-available evidence in managing
postoperative pain and to optimize patient outcomes. Our
hypothesis was that there would be no superior nerve
block for pain but all nerve blocks would be shown to be
efficacious and that several medications and modalities
would be identified that are beneficial in reducing post-
operative pain.
Methods
Search Strategy and Study Selection
Two independent reviewers (M.S.D. and E.T.H.) per-
formed a literature search based on the Preferred
Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) guidelines.12 The MEDLINE,
Embase, and Cochrane Library databases were reviewed
in March 2020, with the reviewers using the following
search terms: (anterior cruciate ligament OR acl) AND
(analgesia OR ia OR intraarticular OR po OR oral
OR nsaids OR non-steroidal anti-inflammatory drugs OR
gabapentinoid OR gabapentin OR pregabalin OR im OR
intramuscular OR iv OR intravenous OR nb OR nerve
block OR adjuncts OR compression OR cryotherapy).
There was no time limit with respect to publication date.
All search results were reviewed independently and
compared, with a senior author (K.A.C.) arbitrating in
case of disagreement. After removal of duplicates, fol-
lowed by review of the abstracts of all search results by
both reviewers independently, full texts of potentially
eligible studies were evaluated. Both reviewers screened
the reference lists of the included studies and literature
reviews to obtain additional articles for inclusion.
Eligibility Criteria
Only RCTs evaluating an analgesic intervention used
to reduce postoperative pain levels after ACLR
were considered. The following interventions were
considered for inclusion: (1) nerve blocks, (2) NBAs,
1291
(3) intra-articular injections, (4) oral medications,
(5) IV medications, (6) tranexamic acid (TXA), and (7)
compressive stockings and cryotherapy. The exclusion
criteria included studies that (1) compared drug dosing
regimens, (2) compared more than 1 intervention, (3)
were not prospective RCTs, (4) included pain pumps,
(5) were not published in English, and (6) were not
published in peer-reviewed journals.
Data Extraction and Analysis
Two independent reviewers (M.S.D. and E.T.H.)
collected data in relation to study characteristics including
study design, level of evidence, methodologic quality of
evidence, patient population, and outcome measures
using a predetermined data sheet, with a senior author
arbitrating any discrepancies in opinion. Assessment of
each study’s level of evidence was based on the criteria
described by Wright et al.,13 and the methodologic quality
of evidence, as well as risk of bias, was evaluated using The
Cochrane Collaboration risk-of-bias tool. Primary
outcome measures evaluated were (1) postoperative pain
score and (2) postoperative opioid use. In the instance of
inconsistencies among various study results, meta-
analysis and quantitative pooling were performed.
Statistics
Network meta-analyses were performed using the R
program (R Foundation for Statistical Computing,
Vienna, Austria). A frequentist approach to network
meta-analysis with a random-effects model was per-
formed using the “netmeta” package (version 0.9-6) in
R.14 Heterogeneity was quantified using the I2 statis-
tic.15 To rank the treatments, we used the frequentist
analog to the surface under the cumulative ranking
curve (SUCRA) probabilities called the P-score.14,16
Studies were ranked according to their P-scores. P <
.05 was considered statistically significant. Additionally,
qualitative analysis was performed for each study.
Results
Literature Search
Our search found 5,341 studies (including 406 RCTs)
on pain control after ACLR that met our inclusion
criteria. The PRISMA study selection flow diagram is
illustrated in Fig 1. All of the included studies’ charac-
teristics are summarized in Appendix Table 1 (available
at www.arthroscopyjournal.org).
Nerve Blocks
Overall, 34 RCTs were found to evaluate the use of
nerve blocks for postoperative pain control after
ACLR.17-49 An adductor canal block (ACB) was chosen as
the control against which to compare.50 In the post-
anesthesia care unit (PACU), the modality with the
highest P-score for the visual analog scale (VAS) score was
1292
Identification
Records identified through Additional records identified
database searching through other sources
(n = 7985)
Records after duplicates removed
(n = 5341)
Screening
Records screened
(n = 5341)
Full-text articles
Eligibility
assessed for eligibility
(n = 409)
Studies included in
qualitative synthesis
(n = 74)
Included
Studies included in
quantitative synthesis
(n = 74)
a femoral sciatic nerve block (FSNB) (P-score, 0.9847). At
2 hours, the modality with the highest P-score for the VAS
score was a continuous femoral nerve block (FNB)
(P-score, 0.7110). At 3 to 4 hours, it was a single-shot FNB
(P-score, 0.8114). At 6 to 8 hours, it was a single-shot
FNB (P-score, 0.7724). At 12 hours, it was a single-shot
FNB (P-score, 0.7896). At 24 hours, it was a single-
shot FNB (P-score, 0.7824). At 48 hours, it was a
continuous FNB (P-score, 0.9506). In the PACU, the
modality with the highest P-score for opioid use was an
ACB (P-score, 0.7942). At 24 hours, the modality with the
highest P-score for opioid use was an FSNB (P-score,
0.7643). The P-scores are presented in Table 1, and the
forest plots of nerve blocks are shown in Appendix
Figure 1 (available at www.arthroscopyjournal.org).
Nerve Block Adjuncts
We found 3 RCTs evaluating the use of NBAs in the
management of postoperative pain after ACLR,51-53 all
of which used different NBA agents. Ekmekci et al.52
compared the use of magnesium sulfate as an NBA to
FNBs after ACLR versus an FNB alone (control). Their
study showed significant reductions in VAS scores at 4,
6, 12, and 24 hours postoperatively, with lower opioid
M. S. DAVEY ET AL.
(n = 4)
Records excluded
(n = 1595) Fig 1. PRISMA (Preferred
Reporting Items for Systematic
Reviews and Meta-analyses)
study selection flow diagram.
Full-text articles
excluded, with reasons
(n = 335)
analgesic requirements in the test group; however, the
time to first mobilization was delayed by a mean of 3
hours. Additionally, Ibrahim et al.51 compared the use
of dexamethasone as an NBA to ACB versus an ACB
alone (control). Their study showed significant re-
ductions in VAS scores at 6, 12, and 18 hours post-
operatively, with lower rescue analgesic requirements,
as well as significantly higher reported patient satis-
faction, in the test group. Finally, Couture et al.53
compared the use of clonidine as an NBA to an FSNB
after ACLR versus an FSNB alone (control). Their study
showed no significant differences in VAS scores in the
first 24 hours postoperatively, with no differences in the
time to first complaint of pain, patient satisfaction, and
time to discharge home.
Intra-articular Injections
Overall, 10 RCTs were found to evaluate the use of
intra-articular injections for postoperative pain control
after ACLR.46,54-62 Intra-articular morphine was chosen
as the control against which to compare.63 In the PACU,
the modality with the highest P-score for the VAS score
was intra-articular bupivacaine and tramadol (P-score,
0.6798). At 2 hours, it was intra-articular morphine and
 ACL PAIN: NETWORK META-ANALYSIS 1293

ACB, adductor canal block; FNB, femoral nerve block; FSNB, femoral sciatic nerve block; PACU, postanesthesia care unit; SSNB, subsartorial saphenous nerve block; VAS, visual analog scale.
Continuous FNB: 0.1362
bupivacaine (IAMB) (P-score, 0.9105). At 3 to 4 hours, it

Single-shot FNB: 0.7342

was IAMB (P-score, 0.8856). At 6 to 8 hours, it was

Opioid at 24 h
IAMB (P-score, 0.7895). At 12 hours, it was intra-

Control: 0.3137
articular ropivacaine, morphine, and ketorolac (P-score,

FSNB: 0.7643

SSNB: 0.4688
ACB: 0.5829
0.7486). At 24 hours, it was continuous ISB (P-score,
0.9713). At 24 hours, the modality with the highest
P-score for opioid use was IAMB (P-score, 0.8841). The
P-scores are presented in Table 2, and the forest plots of
intra-articular injections are shown in Appendix Figure 2
Continuous FNB: 0.4532
Single-shot FNB: 0.7824

(available at www.arthroscopyjournal.org).
VAS Score at 24 h

Control: 0.5266

Oral Medications
SSNB: 0.4474
ACB: 0.2904

Nonsteroidal Anti-inflammatory Drugs

Seven RCTs were found to evaluate the use of oral
nonsteroidal anti-inflammatory drugs in the manage-
ment of postoperative pain after ACLR.64-70 Barber and
Gladu66 found that the use of ketorolac led to superior
Single-shot FNB: 0.7898
VAS Score at 12 h

pain control compared with hydrocodone and acet-

aminophen in the immediate postoperative period up
Control: 0.1961

to 4 hours after ACLR. Boonriong et al.67 showed that

FSNB: 0.4741
ACB: 0.5401

the use of etoricoxib or celecoxib yielded similar results

in the immediate postoperative period up to 4 hours
after ACLR compared with a placebo control. Dahl
et al.64 found that the use of ibuprofen led to superior
Single-shot FNB: 0.7724

pain control compared with acetaminophen in the

VAS Score at 6-8 h

immediate postoperative period up to 24 hours after

ACLR. MacDonald et al.69 found that the use of
Control: 0.2258

ibuprofen or opioids resulted in significantly superior

FSNB: 0.2976
ACB: 0.7042

pain relief compared with acetaminophen in the im-

mediate postoperative period up to 24 hours after
ACLR. Mardani-Kivi et al.70 showed that the use of
celecoxib resulted in superior pain control compared
Single-shot FNB: 0.8114

with a placebo control in the immediate postoperative

VAS Score at 3-4 h

period up to 24 hours after ACLR. Onda et al.68 showed

that the use of celecoxib and loxoprofen resulted in
Control: 0.4789
SSNB: 0.1357

superior pain control compared with acetaminophen in

ACB: 0.5739

the immediate postoperative period up to 24 hours after

ACLR. Dahl et al.65 found that the use of a combination
of etoricoxib and dexamethasone resulted in superior
pain control compared with either agent used inde-
Continuous FNB: 0.7110
Single-shot FNB: 0.6562

pendently in the immediate postoperative period up to

VAS Score at 2 h

24 hours after ACLR.

Control: 0.1787

Gabapentinoids. Three RCTs evaluated the efficacy of

ACB: 0.4540

preoperative administration of gabapentinoids in pa-

tients undergoing ACLR.71-73 Ménigaux et al.71
Table 1. Nerve Block P-Scores

evaluated the use of oral gabapentin preoperatively,

showing a significant reduction in preoperative VAS
anxiety scores, as well as postoperative morphine
Continuous FNB: 0.7308

Single-shot FNB: 0.4886

consumption in the first 48 hours, when compared

VAS Score in PACU

with a placebo. Two studies evaluated the preoperative

Control: 0.1298

use of pregabalin versus a placebo control in patients

FSNB: 0.9847

SSNB: 0.1481
ACB: 0.5180

undergoing ACLR; however, there were no statistically

significant differences in reported subjective pain scores
or morphine consumption between the groups in the
first 24 hours postoperatively.72,73
1294 M. S. DAVEY ET AL.
Table 2. Intra-articular Injection P-Scores
VAS Score in PACU VAS Score at 2 h VAS Score at 3-4 h
IABT: 0.6798 IAMB: 0.8135 IAMB: 0.8856
IAMB: 0.6365 IABC: 0.5755 IABT: 0.6278
Control: 0.6308 IAB: 0.5048 IABC: 0.5528
IARM: 0.6016 IABT: 0.43803 IAB: 0.5229
IARMK: 0.6016 Control: 0.4135 IARM: 0.3956
IAM: 0.2782 IAM: 0.2547 IARMK: 0.3956
IAB: 0.0714 Control: 0.3582
IAM: 0.2615
IAB, intra-articular bupivacaine; IABC, intra-articular bupivacaine and clonidine; IABT, intra-articular bupivacaine and tramadol; IAM, intra-
articular morphine; IAMB, intra-articular morphine and bupivacaine; IAME, intra-articular methadone; IARM, intra-articular ropivacaine and
morphine; IARMK, intra-articular ropivacaine, morphine, and ketorolac; PACU, postanesthesia care unit; VAS, visual analog scale.
Non-benzodiazepine Medications. One RCT compared
the use of non-benzodiazepine medications in the
management of postoperative pain after ACLR:
Tompkins et al.74 evaluated the use of zolpidem to
augment postoperative analgesia versus a placebo
control. Their study showed that although the use of
zolpidem did not result in significant differences in
pain after ACLR, it did reduce the amount of rescue
narcotic required in the test group.
Tranexamic Acid
Three RCTs evaluated the use of TXA to reduce
postoperative hemarthrosis and pain after ACLR.75-77
Felli et al.75 evaluated the use of TXA versus no TXA
after ACLR and found no significant difference in VAS
scores after 1 day. However, the other 2 RCTs showed
significant differences in VAS scores 3 days post-
operatively when TXA was administered versus no TXA
administration intraoperatively.76,77 This difference was
sustained at up to 4 weeks in the included studies.
IVMedications
One RCT sought to assess the use of IV ketamine
perioperatively during ACLR versus a saline solution
control: Menigaux et al.78 showed that the use of
perioperative IV ketamine led to superior pain control
compared with a placebo control in the immediate
postoperative period up to 24 hours, as well as reduced
postoperative morphine consumption, after ACLR. One
RCT evaluated the use of IV ketorolac in the manage-
ment of postoperative pain after ACLR: Peng et al.37
compared an FNB, IV ketorolac, and a saline solution
control as analgesic regimens after ACLR and found
significant reductions in VAS scores up to 1 hour
postoperatively in both the FNB and IV ketorolac
groups compared with the control group.
Compression and Cryotherapy
Eleven RCTs were found to evaluate the use of
compression and cryotherapy in the management of
postoperative pain after ACLR.79-89 A total of 10 RCTs
compared cryotherapy versus no cryotherapy as a
VAS Score at 6-8 h VAS Score at 12 h VAS Score at 24 h Opioid at 24 h
IAMB: 0.7895 IAME: 0.8422 IARMK: 0.7486 IAMB: 0.8842
IABC: 0.6259 IABC: 0.6811 IAMB: 0.7312 IABC: 0.7753
IABT: 0.5719 IAMB: 0.6558 IABT: 0.5923 IABT: 0.6548
Control: 0.4878 IAB: 0.5969 IABC: 0.5449 IAME: 0.5083
IAB: 0.3828 IABT: 0.5146 IAB: 0.4611 IAB: 0.4251
IAM: 0.1423 IAM: 0.3787 Control: 0.3375 IAM: 0.2386
IARMK: 0.2926 IARM: 0.3246 Control: 0.0138
IARM: 0.2926 IAM: 0.2598
Control: 0.2455
control in the postoperative period after ACLR. Of these
studies, 3 found significant reductions in VAS scores
within the first 24 hours postoperatively whereas 1 re-
ported significantly improved VAS scores at 48 hours
postoperatively when compared with room-temperature
cryotherapy. Furthermore, Schröder and Pässler81 found
that cryotherapy and compression resulted in signifi-
cantly improved VAS scores at 6 days after ACLR when
compared with cryotherapy alone, whereas Waterman
et al.79 showed that compression and cryotherapy
resulted in significant improvements in VAS scores at 6
weeks postoperatively when compared with an ice
control. Two studies reported that cryotherapy resulted
in significant reductions in rescue opioid use within the
first 24 hours after ACLR when compared with controls.
Additionally, Ohkoshi et al.80 reported significant re-
ductions in rescue opioid consumption in patients who
received cryotherapy and compression within the first
48 hours postoperatively compared with those who
received cryotherapy alone.
Discussion
The most important finding in this study was that the
use of peripheral nerve blocks and regional anesthesia
remains the primary treatment of postoperative pain
after ACLR; however, the data did not identify a specific
nerve block as superior to the others. Intra-articular
injections of bupivacaine used in combination with
other agents were found to reduce reported post-
operative pain scores up to 12 hours after ACLR, with
limited evidence showing their benefit in reducing
postoperative opioid use. Additionally, there was
promising evidence of the use of some oral and IV
medications, TXA, and NBAs, as well as cryotherapy, to
control pain and reduce opioid use, with limited evi-
dence for NBAs based on the included RCTs in this
study.
Interest in the study of postoperative pain control has
risen in recent years owing to the opioid crisis in the
United States, with increasing legislation over the
regulation of opioid prescriptions in relation to the rise
 ACL PAIN: NETWORK META-ANALYSIS
in dependency.6 This problem is believed to be preva-
lent in orthopaedic surgery, given that orthopaedic
surgeons are thought to be the third largest prescribers
of opioids in the United States and are responsible for
approximately one-tenth of opioid prescriptions.90-92
After ACL injury, up to one-third of patients have
been shown to take opioids preoperatively, which is a
major risk factor for prolonged postoperative opioid use
and subsequent dependency.93-95 Additionally, one-
third of patients require repeated opioid prescriptions
up to 3 months after surgery. Thus, achieving adequate
perioperative and immediate postoperative pain control
is imperative because there can be severe pain after
ACLR owing to bone tunnel creation and donor-site
harvest if autografts are used.96
We performed a network meta-analysis in this study,
which is an ideal method of comparison given the
multiple different nerve blocks and intra-articular in-
jections being assessed. A network meta-analysis allows
for direct and indirect comparisons of treatments using
common comparators, with the P-score being used to
rank them. The P-score represents the probability that
the treatment option is the ideal method for an optimal
result in each outcome measure. The P-score does not
represent the magnitude of difference between the
treatment choices, and it does not signify clinically
significant differences. Thus, ensuring that statistical
significance must not be mistaken for clinical signifi-
cance, it is important to look at the odds ratio, mean
difference, and confidence interval between each study.
Overall, there was no clear superior nerve block for
postoperative pain control. The FSNB resulted in the
highest P-score for postoperative pain in the PACU, as
well as opioids required over the first 24 hours, but it was
not significantly better than the FNB or ACB. Similarly, at
all time points, although there may have been a slightly
higher-ranked nerve block by the P-score, no nerve block
was shown to be significantly better than the others. The
FNB and ACB are the 2 most common nerve blocks used,
with several recent meta-analyses directly comparing
them, showing no difference. However, the FNB and
FSNB may be detrimental to postoperative rehabilitation
because they can damage the motor branch of the femoral
nerve, with quadriceps strength deficits being shown at
up to 6 months postoperatively. This is important to
consider because patients with strength deficits on return-
to-play testing have been shown to have a higher risk of
graft rerupture. Thus, if there is no difference in post-
operative pain or opioid use, then the ACB may be a
superior approach because it only targets a sensory nerve,
the saphenous nerve.
Although at up to 24 hours, there was a decrease in
opioid use, the efficacy of nerve blocks started to decline
at this point, with the control treatment having a higher
P-score than all but the single-shot FNB, indicating a
rebound effect may be occurring. Therefore, NBAs may
1295
also have the potential to improve the quality and
longevity of nerve blocks, allowing for longer-lasting
pain relief, while the patient is in the acute post-
operative phase. In addition, intra-articular injections
had a minor effect on pain in the PACU, with morphine
or bupivacaine alone having a lower P-score than the
control treatment, but at up to 24 hours postoperatively,
they showed decreased opioid use and VAS scores.
Furthermore, combination injections comprising bupi-
vacaine and an adjunct proved to be the most beneficial,
with morphine alone showing a lack of efficacy.
Several oral medications have shown the potential to
reduce postoperative pain and opioid use. Non-opioid
oral medications are the first rung on the World
Health Organization pain ladder and are often under-
appreciated for their efficacy.11,97,98 The majority of this
literature is focused on nonsteroidal anti-inflammatory
drugs, and although these may be problematic because
of an increased risk of cardiovascular and gastrointes-
tinal issues in older patients, the majority of ACLR pa-
tients are young and may not be as prone to these
potential complications.99 However, it is worth noting
that they still carry risks to patients with renal impair-
ment, and this should be screened for before their use.
Additionally, several studies evaluated gabapentinoids,
which work on modulating nerve pain by dulling the
neural response.71-73 In contrast to other oral medica-
tions, these are often given preoperatively to pre-empt
the postoperative pain because they do require time
before the effects are shown.100 There was scant liter-
ature on the efficacy of gabapentinoids for patients
undergoing ACLR; however, throughout the ortho-
paedic surgery literature, there is evidence regarding its
efficacy in managing postoperative pain.
TXA has gained popularity throughout the ortho-
paedic surgery field in recent years for its ability to
control bleeding, with recent evidence suggesting it can
reduce hematoma formation with a subsequent effect
on pain. Thus, several RCTs have evaluated its use for
ACLR.75-77 Although they did not establish a pain effect
immediately postoperatively, this was shown to occur
over the first few postoperative days, with sustained
benefits at up to a month. The optimal administration
strategy is unclear, with both IV and intra-articular
methods being used, although there is a concern with
intra-articular administration that it may be harmful to
chondrocytes. Additionally, all of the included studies
used a postoperative drain, which has been shown to
increase postoperative blood loss owing to a suction
effect, and our RCT published in the interim101 suggests
that without a drain, TXA may not be ineffective in
reducing hemarthrosis and subsequent pain.75-77
The use of ice and cryotherapy remains popular in the
immediate postoperative period after ACLR.102 These
methods offer surgeons a low-cost analgesic modality,
which reduces postoperative edema and subsequent
1296 M. S. DAVEY ET AL.
pain levels, enabling reduced rescue analgesia in the
immediate postoperative period, as well as up to 6
weeks postoperatively.79 A previous systematic review
by Martimbianco et al.103 in 2014 reported significant
reductions in pain scores at 48 hours after ACLR in
patients who received cryotherapy versus control pa-
tients. Our study shows evidence in favor of the use of
cryotherapy after ACLR, with significant reductions in
VAS scores and rescue opioid consumption reported
when compared with control groups.
Limitations
Although this study evaluated the best-available evi-
dence in relation to pain reduction interventions after
ACLR, it is not without limitations. Because this was a
systematic review, a major limiting factor is the lack of
available data and the presence of heterogeneity among
the included studies. In the included pooled analyses, the
standardization of reporting limited our analysis. Thus,
some nerve blocks could not be added to comparisons at
certain time points, nor could we perform meta-analysis
on NBAs. Similarly, there is the potential of confounding
with different medications and dosing regimens with the
nerve blocks. However, we mitigated the heterogeneity by
including random-effects models to control for this.
Conclusions
Nerve blocks and regional anesthesia are the mainstay
treatment of postoperative pain after ACLR, with the
commonly used nerve blocks being equally efficacious.
Intra-articular injections consisting of bupivacaine and
an adjunct were found to reduce reported postoperative
pain scores up to 12 hours after ACLR, with signifi-
cantly lower postoperative opioid use. There was
promising evidence for the use of some oral and IV
medications, TXA, and NBAs, as well as cryotherapy, to
control pain and reduce postoperative opioid use.
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Appendix

Appendix Table 1. Pain Management Strategies After Anterior Cruciate Ligament Reconstruction: Study Characteristics

Group 1 Group 2 Group 3 Group 4

Authors LOE Risk of Bias Strategy n Strategy n Strategy n Strategy n
Nerve blocks
Abdallah et al.,17 2016 I Low ACB 52 FNB (single shot) 48 d d d d
Bailey et al.,18 2019 I Low FNB (single shot) 38 ACB 40 d d d d
Chisholm et al.,19 2014 I Moderate FNB (single shot) 41 SSNB 39 d d d d
El Ahl,20 2015 I Low FNB (single shot) 64 ACB 64 d d d d
Espelund et al.,21 2013 I Low Control 24 ACB 25 d d d d
Faiaz and Kamath,48 2019 I Moderate FNB (single shot) 41 ACB 35 d d d d
Faunø et al.,45 2015 I Moderate Control 23 SNB 22 d d d d
Frost et al.,20 2000 I Moderate Control 31 FNB (single shot) 29 d d d d

ACL PAIN: NETWORK META-ANALYSIS

Ghodki et al.,23 2018 I Moderate FNB (single shot) 30 ACB 30 d d d d
Guirro et al.,24 2013 I High Control 27 FNB (single shot) 26 d d d d
Harbell et al.,25 2016 I Moderate FNB (single shot) 32 FSNB 32 d d d d
Harris et al., 1997 I Moderate Control 10 FNB (single shot) 12 d d d d
Iskandar et al.,26 2003 I Moderate Control 40 FNB (single shot) 40 d d d d
Jansen et al.,27 2009 I Low FNB (single shot) 27 FSNB 28 d d d d
Kejriwal et al.,28 2018 I Moderate Control 30 SSNB 30 d d d d
Kristensen et al.,29 2014 I Low Control 27 FNB (single shot) 28 d d d d
Kurosaka et al.,30 2018 I Low Control 69 FNB (single shot) 60 d d d d
Lundblad et al.,31 2011 I Low Control 32 IPNB 30 d d d d
Lynch et al.,32 2019 I Moderate FNB (single shot) 30 ACB 30 d d d d
Matava et al.,33 2009 I Low Control 26 FNB (single shot) 31 d d d d
Mayr et al.,34 2007 I High Control 71 FNB (single shot) 36 d d d d
Mehdi et al.,46 2004 I Moderate Control 25 FNB (single shot) 25 d d d d
Mulroy et al.,35 2001 I Moderate Control 12 FNB (single shot) 41 d d d d
O’Leary et al.,36 2000 I Moderate Control 17 LPB 16 d d d d
Peng et al.,37 1999* I Low Control 28 FNB (continuous) 57 d d d d
Sahni et al.,38 2015 I Low Control 20 FNB (single shot) 60 d d d d
Schwarz et al.,47 1999 I Low Control 22 FNB (single shot) 22 d d d d
Seangleulur et al.,49 2019 I High ACB 28 FNB (single shot) 28 d d d d
Stebler et al.,39 2019 I Moderate Control 49 ACB 49 d d d d
Tierney et al., 1987 I High Control 10 FNB (single shot) 10 d d d d
Tran et al.,41 2005 I Low Control 18 FSNB 16 d d d d
Williams et al.,42 2006 I Moderate Control 78 FNB (single shot) 155 d d d d
Woods et al.,43 2006 II High Control 45 FNB (continuous) 45 d d d d
Wulf et al.,44 2010 I Moderate Control 34 FNB (single shot) 225 d d d d
Intra-articular injections
Hosseini et al.,54 2012 I Moderate Control 20 IAMB 20 IABT 20 d d
Joshi et al.,55 1993 I High Control 9 IAM 11 d d d d

1300.e1
Karlsson et al.,56 1995 I Moderate Control 10 IAB 10 IAM 10 IAMB 10
McCarthy et al., 2001 I Moderate Control 32 IAM 30 d d d d
(continued)
Appendix Table 1. Continued

1300.e2
Group 1 Group 2 Group 3 Group 4
Authors LOE Risk of Bias Strategy n Strategy n Strategy n Strategy n
Senthilkumaran et al.,57 2010 I Moderate IAB 30 IAMB 30 d d d d
Sivapurapu et al.,58 2017 I Low IAB 33 IAMB 31 IABC 29 d d
Stewart et al.,59 2005 I Low Control 19 IAM 25 IAMe 21 d d
Tetzlaff et al.,60 1999 I High IAB 10 IAM 10 IAMB 10 d d
Vintar et al.,61 2005 I Moderate Control 12 IARM 13 IARMK 13 d d
Yari et al.,62 2013 I Moderate IAB 10 IAMB 30
Nerve block adjuncts
Couture et al.,53 2004 I Moderate Control 27 Clonidine 28 d d d d
Ekmekci et al.,52 2013 I Moderate Control 51 Magnesium sulfate 56 d d d d
Ibrahim et al.,51 2019 I Low Control 30 Dexamethasone 30 d d d d
Oral medications
Barber and Gladu,66 1998 I Low Ketorolac 66 Acetaminophen and hydrocortisone 59 d d d d
Boonriong et al.,67 2010 I Moderate Control 32 Etoricoxib 35 Celecoxib 35 d d
Cho et al.,72 2019 I Low Control 47 Pregabalin 46 d d d d
Dahl et al.,64 2004 I Low Ibuprofen 17 Acetaminophen 20 d d d d
Dahl et al.,65 2012 I High Parecoxib 30 Dexamethasone 30 Dexamethasone and parecoxib 29
MacDonald et al.,69 2014 I High Opioid 44 Ibuprofen 44 Acetaminophen 41 d d
Mardani-Kivi et al.,70 2013

M. S. DAVEY ET AL.
I Low Control 31 Celecoxib 29 d d d d
Ménigaux et al.,71 2005 I Low Control 20 Gabapentin 20 d d d d
Nimmaanrat et al.,73 2012 I Moderate Control 29 Pregabalin 27 d d d d
Onda et al.,68 2016 I Moderate Celecoxib 53 Loxoprofen 53 Acetaminophen 54 d d
Tompkins et al.,74 2011 I Moderate Control 16 Zolpidem 13 d d d d
Other modalities
Menigaux et al.,78 2000 I Moderate Control 15 IV ketamine 30 d d d d
Peng et al.,37 1999* I Low Control 28 FNB 29 IV ketorolac 28 d d
Tranexamic acid
Chiang et al.,76 2019 I Low Control 149 TXA 151
Felli et al.,75 2019 I Low Control 40 TXA 40
Karaaslan et al.,77 2015 I Low Control 52 TXA 53
Compression and cryotherapy
Barber et al.,89 1998 I Low Control 49 Cryotherapy 51 d d d d
Cohn et al.,88 1989 I High Control 28 Cryotherapy 26 d d d d
Daniel et al.,87 1994 I Low Control 42 Cryotherapy 89 d d d d
Dervin et al.,86 1998 I Moderate Cryotherapy 38 Room-temperature cryotherapy 40 d d d d
Edwards et al.,85 1996 I High Control 24 Cryotherapy 26 Room-temperature cryotherapy 21 d d
Kijkunasathian et al.,84 2017 I Moderate Bandage 19 Compression 19 d d d d
Konrath et al.,83 1996 I High Control 27 Cryotherapy 50 Heat therapy 23 d d
Koyonos et al.,82 2014 I Low Control 26 Cryotherapy 27 d d d d
Ohkoshi et al.,80 1999 I Low Cryotherapy 7 Room-temperature cryotherapy 14 d d d d
Schröder and Pässler,81 1994 I Low Cryotherapy 21 Cryotherapy and compression 23 d d d d
Waterman et al.,79 2012 I Moderate Control 18 Cryotherapy 18 d d d d
ACB, adductor canal block; FNB, femoral nerve block; FSNB, femoral sciatic nerve block; IAB, intra-articular bupivacaine; IABC, intra-articular bupivacaine and clonidine; IABT, intra-
articular bupivacaine and tramadol; IAM, intra-articular morphine; IAMB, intra-articular morphine and bupivacaine; IAMe, intra-articular methadone; IARM, intra-articular ropivacaine
and morphine; IARMK, intra-articular ropivacaine, morphine, and ketorolac; IPNB, infrapatellar nerve block; IV, intravenous; LOE, level of evidence; LPB, lumbar plexus block; SNB, sciatic
nerve block; SSNB, subsartorial saphenous nerve block; TXA, tranexamic acid.
*Study performed duplicate analysis.
 ACL PAIN: NETWORK META-ANALYSIS 1300.e3

Appendix Fig 1. Network meta-analysis of nerve blocks.

(ACB, adductor canal block; CI, confidence interval; FNBc,
continuous femoral nerve block; FNBs, single-shot femoral
nerve block; FSNB, femoral sciatic nerve block; MD, mean
difference; SSNB, subsartorial saphenous nerve block; VAS,
visual analog scale.)
1300.e4 M. S. DAVEY ET AL.

Appendix Fig 1. (continued).

 ACL PAIN: NETWORK META-ANALYSIS 1300.e5

Appendix Fig 2. Network meta-analysis of intra-articular

injections. (CI, confidence interval; IAB, intra-articular bupi-
vacaine; IABC, intra-articular bupivacaine and clonidine;
IABT, intra-articular bupivacaine and tramadol; IAM, intra-
articular morphine; IAMB, intra-articular morphine and
bupivacaine; IAME, intra-articular methadone; IARM, intra-
articular ropivacaine and morphine; IARMK, intra-articular
ropivacaine, morphine, and ketorolac; MD, mean difference;
VAS, visual analog scale.)
1300.e6 M. S. DAVEY ET AL.

Appendix Fig 2. (continued).