Traditional vs. Nonopioid Analgesia After Anterior Cruciate Ligament Reconstruction
Phase: PHASE2
Conditions: Anterior Cruciate Ligament Injury
Sponsor: Henry Ford Health System

Can We Eliminate Opioids After Anterior Cruciate Ligament Reconstruction? 
A Prospective, Randomized Controlled Trial 
 
Study Protocol: 
 
This study was designed as a prospective RCT in accordance with the CONSORT (Consolidated 
Standards of Reporting Trials) statement.25 The hypothesis was formulated before collection of 
data. The study was reviewed and approved by our institutional review board (IRB No. 12315) 
and was registered at ClinicalTrials.gov (NCT03818932). 
 
Between February 2019 and January 2020, a total of 90 patients undergoing primary ACLR by 2 
fellowship-trained sports surgeons at a single academic center were screened for study 
eligibility (V.M., K.R.O.). Ultimately, 62 patients with a torn ACL consented to participate. The 
inclusion criteria consisted of patients aged >14 years and patients undergoing primary ACLR. 
Patients were excluded if they had a history of opioid abuse documented in the medical record, 
recent or current pregnancy, contraindication to the use of nonsteroidal anti-inflammatory 
drugs (NSAIDs) (eg, renal impairment, peptic ulcer disease, gastrointestinal bleeding), 
intolerance or allergy to any of the component medications, or history of same-joint surgery for 
any reason in the previous year or if they were under- going revision surgery. All concomitant 
meniscal and cartilage procedures were recorded. 
 
Randomization and Masking 
Patients who consented to participate were randomly assigned preoperatively to either an 
opioid or a multimodal nonopioid pain regimen with a 1:1 allocation ratio using adaptive 
randomization computer software (Adaptive Randomization; MD Anderson Cancer Center). 
Patients declined to participate for a number of reasons including reluctance to participate in a 
research study and inability or lack of interest in maintaining compliance with study protocol. 
At 1 week before surgical intervention, surgeons were notified by secure email of the patient’s 
group designation. 
 
Interventions 
Patients underwent an arthroscopically assisted ACLR using bone-patellar tendon-bone 
autograft or hamstring autograft via anatomic femoral and tibial tunnels. The patients 
individually determined their graft choice after an informed discussion on potential options 
with their surgeon. Within 2 hours preoperatively, both groups received 1-time doses of 400 mg 
of celecoxib orally, 975 mg of acetaminophen orally, 300 mg of gabapentin orally, 8 mg of 
dexamethasone intravenously, and 50 mg of tramadol orally. All ACLRs were performed with 
the patient under preoperative blocks at the discretion of the anesthesiologist (4 femoral nerve 
blocks, 58 adductor canal nerve blocks). 
Intraoperatively, a local infiltration cocktail was injected evenly in 2-mL increments along the 
incision and the subcutaneous tissues before wound closure using a 20-mL syringe with a 1-
inch, 22-gauge needle. The local infiltration cock- tail consisted of the following: 150 mg (30 mL) 
of 0.50% ropivacaine, 30 mg (1 mL) of ketorolac, and 1 mg (1 mL) of epinephrine.22 
7/19/2022

Patients in the multimodal nonopioid group received a novel nonopioid multimodal analgesic 
protocol previously described.19 Acetaminophen and NSAIDs (ketorolac and meloxicam) were 
used to target the pain cascade and post- operative inflammation, respectively. Gabapentin 
was used to address neuropathic pain and diazepam to control muscle cramps and spasm. 
Medication dosage and frequency are described in Table 1. It must be noted that patients in the 
multimodal nonopioid group received 1 dose of 50 mg (5 morphine milligram equivalents 
[MME]) of tramadol before surgery. 
 
Patients enlisted in the opioid group were prescribed 40 pills, each containing 5 mg of 
hydrocodone and 325 mg of acetaminophen, and were instructed to take 1 or 2 pills orally 
every 4 to 6 hours as needed for moderate to severe postoperative pain. This was the standard 
of care at the authors’ institution, and patients in the opioid arm received no other pain 
medications. 
 
Patients were discharged home on the day of surgery per their group designation pain protocol. 
All patients were encouraged to contact the on-call physician if pain was unbearable or they 
were experiencing any complications. Patients in both groups were given instructional 
pamphlets on the effects of opioids, ways to effectively manage pain postoperatively, and pain 
treatment goals after surgery. 
 
Outcomes 
Data collection was performed by observers who were blinded to group randomization. 
Patients were instructed to complete the PROMIS PI-SF questionnaire preoperatively. After 
surgery, a mobile messaging-based software (Mosio; Mosio Inc) was used to collect patient 
data. Surveys were sent to patients 3 times a day for 10 days postoperatively. A 10-day follow-
up was selected to evaluate pain control in the acute postoperative period when patients are 
typically most susceptible to surgical pain. 
 
Patients were asked to report their current pain level 3 times per day using a VAS score (range, 
0-10, where 10 = maximum). Patients were asked to report medical side effects each evening, 
as well as how many opioid pills were taken in the last 24 hours (if applicable). Opioid 
consumption was con- verted to MME. At the first postoperative visit (7-10 days), patients 
completed the PROMIS PI-SF questionnaires. The following variables were obtained from 
medical records: demographic characteristics, smoking status, anxiety/depression status, 
workers’ compensation status, history of opioid abuse, and preoperative opioid consumption. 
 
Statistical Plan:  
The primary outcome of this study was an average daily pain difference of 1.3 points on the 
VAS score, as a previous study has demonstrated that this difference represents the minimal 
clinically important difference for the VAS pain score.8 Prestudy power analysis, using a power 
of 80% (b level = .80, a level = .05), revealed that a minimum of 25 patients per group (n = 50) 
would be necessary to properly evaluate the primary hypothesis. A sample size of 90 patients 
(45 per group) was selected to account for patients with incomplete data collection (eg, lost to 
follow-up). Secondary outcomes included patient-reported outcomes, demographic 

differences, complications, and patient satisfaction. There was no crossover of patients 
between study arms. 
 
Continuous data were summarized using mean and standard deviation for normally distributed 
variables and median with interquartile range for nonnormally distributed variables; categorical 
data were reported as counts with percentages. For continuous variables, univariate 2- group 
comparisons were performed using independent 2- sample t tests when the variable was 
normally distributed and Wilcoxon rank sum tests when the variable was non- normally 
distributed. For categorical variables, univariable 2-group comparisons were performed using 
the chi- square test when expected cell counts were 􏰀5 and the Fisher exact test when 
expected cell counts were \5. The Pearson coefficient (r) was used to establish correlation 
between outcome measures. Correlation strength was defined as very high (r = 0.90-1.00), high 
(r = 0.70-0.89), moderate (r = 0.50-0.69), and low (r = 0.30-0.49).20 Repeated-measures 
analyses were performed using mixed models and included the effects of time and group and 
the interaction between time and group. Models were then adjusted using specified variables 
selected a priori in an attempt to adjust for possible confounders. Predicted means resulting 
from the adjusted models were plotted for the outcome variables. If needed, significant 
interaction effects were analyzed using post hoc comparisons using a Tukey-Kramer P value 
correction. Predicted means resulting from the adjusted models were plotted for the outcome 
variables. Statistical significance was set at P \ .05 for group comparisons and main effect 
testing and P \ .10 for interaction testing. All analyses were per- formed using SAS Version 9.4 
(SAS Institute Inc). 
Results
A total of 62 patients were included. One week following surgery, patients reported a mean VAS level of 3.2 ± 2.3 
and required on average 2.6 ± 3.6 breakthrough oxycodone pills (8.6 ± 12.0 morphine equivalents). Forty-five 
percent of patients did not require any breakthrough prescription opioids and reported satisfaction with pain 
management. Patients who required opioids were more likely to have a history of anxiety/depression (44.2% vs 
23.8%, P = .012) and reported greater pain scores as compared with nonusers (3.94 ± 2.5 vs 2.41 ± 1.75, P 
= .016). The most common side effect of the pain protocol was feeling drowsy (23.5%). All patients were satisfied 
with their pain management postoperatively.