Effect of a Postoperative Multimodal Analgesic Protocol Predominantly Based on Non-Opioid Medications vs Opioid-Based Analgesia on Pain After Minimally Invasive Ankle Surgery: A Noninferiority Randomized Clinical Trial
Phase: NA
Conditions: Ankle (Ligaments); Instability (Old Injury), Ankle Sprain, Talus Osteochondral Defect, Opioid Analgesia, Non-Opioid Pain Management
Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Opioid‑Sparing vs Opioid‑Based Analgesia After Ankle
Arthroscopy/Mini‑Open Procedures: A Single‑Centre,
Randomized, Non‑Inferiority Trial Protocol
Zhejiang University School of Medicine, Second Hospital (Orthopaedics)
Version: 1.0 | Date: 2025‑11‑06
Trial registration: ClinicalTrials.gov/ChiCTR: to be registered
NCT number:NCT07154433

Trial Synopsis
Item
Description
Design
Prospective, parallel‑group, 1:1 randomization;
single‑centre, assessor‑blinded, non‑inferiority
RCT.
Population
Adults 18–65 years undergoing unilateral ankle
arthroscopy or mini‑open (≤2 cm) procedures;
ASA I–II; BMI 16–32 kg/m².
Sample size
110 participants (55 per arm), allowing ~10%
attrition; non‑inferiority margin 1.0 point on 0–
10 NRS at 24 h.
Intervention
Opioid‑sparing protocol (patient education,
celecoxib 400 mg post‑op then 200 mg BID;
acetaminophen 500 mg Q6H PRN; rescue
oxycodone/acetaminophen 5/325 mg Q6H, ≤10
tablets).
Control
Usual care with opioid‑centred prescribing (e.g.,
oxycodone/acetaminophen Q6H per surgeon
discretion), without standardized
NSAIDs/acetaminophen guidance.
Primary endpoint
NRS pain intensity at 24 hours post‑operation (0–
10).
Key secondary endpoints
AUC of NRS within 24 h (2, 6, 12, 24 h);
cumulative oral morphine equivalents (OMEs) at
discharge and day 6; time‑course of NRS (2 h,
days 2–6); opioid‑related adverse effects;
satisfaction (4‑level Likert); PROMIS‑PI‑SF‑8a &
PROMIS‑SD‑SF‑4a on day 6; proportion receiving
rescue oxycodone/acetaminophen; SAEs; day‑1
hepatic/renal abnormalities.
Randomization/Stratification
Centralized REDCap™randomization; permuted
blocks; stratified by procedure type (arthroscopy
vs mini‑open).
Blinding
Outcome assessors and statisticians blinded;
patients and treating surgeons unblinded due to
educational component.
Analysis
Primary ANCOVA adjusted for baseline NRS,
peripheral nerve block, and procedure type; ITT
primary, PP sensitivity; NI if upper 95% CI < +1.0;
multiplicity for secondary endpoints controlled
by BH FDR 10%.
List of Abbreviations
Abbreviation
Definition
AE/SAE
Adverse event/Serious adverse event
ANCOVA
Analysis of covariance

AUC
Area under the curve
BMI
Body mass index
CI
Confidence interval
DSMB
Data Safety Monitoring Board
GCP
Good Clinical Practice
ICH
International Council for Harmonisation
ITT / PP
Intention‑to‑treat / Per‑protocol
MME / OME
Morphine milligram equivalents / Oral
morphine equivalents
NRS
Numeric rating scale (0–10)
NSAIDs
Non‑steroidal anti‑inflammatory drugs
OSP
Opioid‑sparing protocol
PNB
Peripheral nerve block
PROMIS‑PI‑SF‑8a
Patient‑Reported Outcomes Measurement
Information System—Pain Interference
Short Form 8a
PROMIS‑SD‑SF‑4a
PROMIS—Sleep Disturbance Short Form 4a
RCT
Randomized controlled trial
REDCap™
Research Electronic Data Capture

1. Background and Rationale
Ankle injuries are among the most common sports‑related conditions. Approximately two
million new ankle sprains occur annually, with ~one‑third progressing to chronic ankle
instability that may require operative management. Minimally invasive ankle procedures—
arthroscopy and mini‑open techniques—have become mainstream but frequently rely on
postoperative opioids, with wide prescribing variability and limited standardization of
opioid‑sparing pathways.
Excessive opioid prescribing contributes to the global opioid epidemic; orthopaedics
accounts for a substantial share of opioid prescriptions. In China, a large national survey
(>26,000 patients) reported postoperative opioid use of ~68% and peripheral nerve block
(PNB) use of only ~3.3%. Moderate‑to‑severe pain on postoperative day 1 was ~54.1% in
orthopaedic patients, highlighting the need for optimization toward safer, multimodal,
opioid‑sparing care.
Multiple studies suggest that opioid‑sparing multimodal protocols can substantially reduce
opioid consumption without compromising analgesia or satisfaction. For instance, a
JAMA‑reported RCT in arthroscopy demonstrated markedly lower opioid use (median 0 mg
vs 40 mg) with comparable pain control and fewer adverse effects; similar findings have
been observed in forefoot and hand/wrist procedures. Evidence specific to ankle
procedures remains limited, warranting a well‑designed trial.
2. Objectives
2.1 Primary Objective
To test non‑inferiority of the opioid‑sparing protocol vs opioid‑based usual care on 24‑hour
postoperative NRS pain (0–10) among adults aged 18–65 years; non‑inferiority margin: 1.0
point.
2.2 Secondary Objectives
To compare: (i) AUC of NRS over 24 h (2, 6, 12, 24 h); (ii) cumulative OMEs at discharge and
on day 6; (iii) NRS trajectories at 2 h and days 2–6; (iv) opioid‑related adverse events
(nausea, vomiting, dizziness, constipation, respiratory depression) and durations; (v)
4‑level satisfaction; (vi) PROMIS‑PI‑SF‑8a and PROMIS‑SD‑SF‑4a at day 6; (vii) proportion
dispensed rescue oxycodone/acetaminophen and usage; (viii) SAE rates; (ix) day‑1
hepatic/renal abnormalities (AST/ALT > 2×ULN or Tbil/Cr > 1.5×ULN).
3. Trial Design
Single‑centre, prospective, randomized, assessor‑blinded, parallel‑group, non‑inferiority
trial with 1:1 allocation to an opioid‑sparing multimodal protocol vs opioid‑based usual
care. Stratification by procedure type (arthroscopy vs mini‑open).

3.1 Study Setting
Zhejiang University School of Medicine, Second Hospital (Department of Orthopaedics),
inpatient wards and outpatient follow‑up.
3.2 Eligibility Criteria
Inclusion criteria:
Category
Criteria
Age/Sex
18–65 years, any sex; written informed
consent.
Surgery
Unilateral ankle arthroscopy or mini‑open
procedure (incision ≤2 cm); expected
duration ≤3 h.
General condition
ASA I–II; BMI 16–32 kg/m².
Exclusion criteria:
No.
Criteria
1
Known allergy/contraindication to
study‑related medications.
2
Surgery duration > 3 hours.
3
Preoperative chronic opioid use.
4
Pregnant or breastfeeding.
5
Screening labs: ALT or AST > 2×ULN; Cr >
1.5×ULN; Tbil > 1.5×ULN.
3.3 Recruitment, Consent, and Screening
Eligible patients presenting for ankle surgery will be pre‑screened from operative schedules.
Trained research staff will contact candidates in clinic or by phone/email before surgery,
explain the study, and obtain written informed consent on or before the day of surgery.
Screening logs will record included, excluded, and erroneously missed‑randomized cases.
3.4 Allocation and Randomization
Centralized 24‑hour REDCap™system with concealed permuted blocks, stratified by
procedure type. Randomization is targeted as close to the surgical day as feasible.
3.5 Interventions
3.5.1 Opioid‑ Sparing Protocol (Intervention)
• Immediately post‑op: celecoxib 400 mg PO once, then 200 mg BID.
• Acetaminophen 500 mg PO Q6H as needed.
• Rescue only if inadequate analgesia: oxycodone/acetaminophen 5/325 mg PO Q6H
(maximum 10 tablets).
• Patient education infographic covering correct use, opioid risks, storage and disposal.

3.5.2 Usual Care (Control)
Opioid‑centred prescribing per surgeon discretion (e.g., oxycodone/acetaminophen Q6H).
No standardized guidance or routine prescription of NSAIDs/acetaminophen for
mild‑to‑moderate pain.
3.6 Strategies to Improve Adherence
Printed medication schedules, daily diary for pain and medication through day 6, and
structured nurse/CRC reminders during inpatient stay and via tele‑follow‑up after
discharge.
3.7 Outcomes
Primary endpoint
NRS pain at 24 hours post‑operation (0–10).
Secondary endpoints
AUC of NRS within 24 hours (2, 6, 12, 24 h); cumulative OMEs at discharge and day 6; NRS
at 2 h and days 2–6; opioid‑related adverse effects and durations; satisfaction (4‑level
Likert); PROMIS‑PI‑SF‑8a and PROMIS‑SD‑SF‑4a at day 6; proportion receiving rescue
oxycodone/acetaminophen and usage; SAE rates; day‑1 hepatic/renal abnormalities.
3.8 Participant Timeline
Schedule of enrolment, interventions, and assessments (SPIRIT‑style):
Procedure/Assessment
Pre‑op
Intra‑op
2 h
6 h
12 h
24 h
Days
2–5
Day
6
Informed consent,
demographics,
comorbidities, CrCl
X
Surgical details
X
NRS (0–10)
X
(baseline)
X
X
X
X
X
X
PROMIS‑PI‑SF‑8a
X
(baseline)
X
PROMIS‑SD‑SF‑4a / ISI
X
(baseline)
X
Opioid‑related adverse
events
X
X
X
OMEs consumed
X
X
X
Satisfaction (Likert)
X
Total analgesic cost
X
3.9 Blinding
Due to the educational component, patients and treating clinicians cannot be blinded.
Outcome assessors and statisticians will remain blinded to allocation.

4. Sample Size and Statistical Analysis
4.1 Sample Size
Based on arthroscopy/minimally invasive ankle populations, the SD of 24‑h NRS is ~1.3.
With a one‑sided α = 0.05, 80% power, and a non‑inferiority margin of 1.0, the required
sample size is 50 per arm. Allowing ~10% attrition yields 55 per arm (total n = 110).
4.2 Statistical Methods
Primary analysis uses ANCOVA with treatment as factor and baseline NRS, PNB, and
procedure type as covariates; the treatment effect is reported as adjusted mean difference
with 95% CI. Non‑inferiority is concluded if the upper CI bound is < +1.0. If the entire CI is <
0, superiority will be declared. Secondary analyses include: t‑test for AUC; log‑linear
regression for cumulative OMEs; linear mixed‑effects models for repeated NRS;
proportional odds models for satisfaction; risk ratios for adverse events. Analyses follow
ITT primarily, with PP as sensitivity. Missing data ≤5% will be handled by single regression
imputation; >5% by multiple imputation. P values are two‑sided at 0.05, with Benjamini–
Hochberg FDR control at 10% across secondary endpoints. Analyses will be performed in R
(v4.4.0) and SPSS (v29).
5. Data Management
Data will be captured via eCRF in REDCap™hosted by the sponsor site. Site‑level accounts
will be provisioned for data entry of demographics, peri‑operative medications, analgesia,
NRS scores, opioid consumption, adverse events, and adherence. Data must be entered
within 48 hours of occurrence; automatic range, consistency, and missingness checks will
be enforced. Each site can access only its own data; the central data team has export and
analysis permissions.
Data queries will be issued for missing/implausible entries; sites must respond and resolve
within specified windows. Paper source documents and consent forms are stored in locked
cabinets with access limited to authorized staff. REDCap™enforces role‑based access and
password protection; routine server backups occur within China in compliance with the
Personal Information Protection Law and Data Security Law.
6. Monitoring and Safety
6.1 Ethics Approval and Consent
The protocol, CRFs, informed consent documents, and recruitment materials will be
submitted to the ethics committees of participating institutions prior to initiation. Any
substantial amendments will undergo prior approval.

6.2 Confidentiality
Participants will be identified by unique study codes; direct identifiers (e.g., names, ID
numbers) will not be recorded in REDCap™. De‑identified data will be used for analysis and
publications.
6.3 Adverse Events
All AEs and SAEs will be documented. Research staff will report study‑related SAEs within
24 hours to the coordinating centre, which will assess relatedness and, when required,
notify the ethics committee.
6.4 DSMB
An independent DSMB (orthopaedics, anaesthesiology, clinical pharmacology) will
periodically review safety, adherence, and study conduct, and may recommend pausing or
terminating the trial.
7. Organisation and Responsibilities
Sponsor: Department of Orthopaedics, Second Affiliated Hospital of Zhejiang University
School of Medicine. Principal Investigator: Zongyou Pan, MD (Associate Chief Physician).
Coordinating Centre: Zhejiang University Clinical Research Centre (protocol coordination,
data management, monitoring, ethics coordination, statistics). Each participating unit will
designate an orthopaedic PI, an anaesthesia co‑PI, and a study coordinator.
8. Dissemination
Results will be disseminated in peer‑reviewed journals and conferences following
CONSORT‑NI and ICH‑E9(R1) reporting standards. Authorship will follow ICMJE criteria.
De‑identified datasets may be shared upon reasonable request and approval by the PI and
sponsor.
9. Declarations
Competing interests: None declared.
Funding: To be specified.
Protocol version/date: Version 1.0, 2025‑11‑09.
Trial registration: To be provided prior to first patient in.
SPIRIT checklist and participant information/consent forms: available upon request.

Informed Consent Form for Clinical
Research
The Second Affiliated Hospital, Zhejiang University School of Medicine
Introduction
Dear Patient,
We invite you to participate in a clinical research study entitled:
“Multimodal Non‑Opioid Analgesia vs. Opioid‑Based Analgesia on Postoperative Pain
Following Minimally Invasive Ankle Surgery: A Non‑Inferiority Randomized Clinical Trial.”
Before you decide whether to participate, please carefully read the following information. It
explains the purpose of this study, its procedures and duration, potential benefits and risks,
as well as your rights.
1. Background and Purpose
Opioid analgesics are commonly used in orthopedics, but their use carries risks such as
nausea, vomiting, drowsiness, constipation, hypotension, and even serious issues such as
addiction, misuse, and life‑threatening respiratory depression.
Ankle sprains are common sports injuries. About one‑third of cases develop into chronic
ankle instability, and one‑third of those are accompanied by cartilage injury. Minimally
invasive arthroscopic ligament repair (or microfracture) is now widely used, but there is no
standardized perioperative pain management protocol.
Multimodal analgesia—using a combination of different pain control strategies—can reduce
the postoperative opioid burden. Some studies suggest that non‑opioid regimens can
provide pain relief comparable to opioids, with fewer side effects.
This study aims to compare the efficacy and safety of a non‑opioid regimen with a
traditional opioid regimen after ankle arthroscopy, providing evidence for safer, more
effective pain management and reducing opioid use.
2. Study Site and Duration
This study is conducted in the Department of Orthopedics, Second Affiliated Hospital,
Zhejiang University School of Medicine.
‑ Duration: 2 years

‑ Start date: upon ethics approval
‑ End date: May 31, 2027
3. What You Will Need to Do
1. Before enrollment, your physician will review your medical history and perform
preliminary examinations.
2. If you are eligible, you may voluntarily join this study and sign this informed consent
form. If you choose not to participate, you will continue to receive routine medical care.
3. If you agree to participate:
‑ You will sign the consent form.
‑ After surgery, you will take analgesics according to group allocation:
• Opioid group: oxycodone/acetaminophen (325 mg/5 mg) every 6 hours.
• Non‑opioid group: immediately after surgery, acetaminophen 500 mg + celecoxib 400
mg; if surgery is completed before 14:00, celecoxib 200 mg will be given again that evening.
Thereafter, celecoxib 200 mg BID + acetaminophen 500 mg Q6H (not exceeding 3000
mg/day).
‑ Postoperative pain will be assessed at 2, 6, 12, and 24 hours using NRS (pain scores), and
questionnaires will be completed on days 1–6, along with records of medication use and
adverse effects.
4. Possible Benefits
‑ This study may identify an analgesic regimen that effectively controls pain, reduces side
effects, and minimizes opioid use.
‑ You may benefit from improved pain management education and closer follow‑up after
surgery.
‑ However, there may be no direct personal benefit from participating.
5. Possible Risks and Safety Measures
‑ You may experience adverse effects related to medications (e.g., dizziness, nausea,
constipation).
‑ If you develop any discomfort or changes in your condition, notify your physician
immediately. Appropriate medical treatment will be provided.
6. Costs
All treatments and examinations will be charged according to standard hospital fees.
7. Compensation and Insurance
There is no financial compensation for participating in this study.

8. Alternatives
If you choose not to participate, you will continue your standard clinical treatment with no
impact on your care.
9. Confidentiality
Your medical records and study data will be securely stored in the hospital. Only the
investigators, the ethics committee, auditors, inspectors, or regulatory authorities may
review them. Reports and publications from this study will not reveal your personal
identity.
10. Withdrawal from the Study
Participation is voluntary. You may refuse or withdraw at any time without affecting your
medical care or your relationship with your physician.
You may also be withdrawn from the study if:
1. You do not follow the physician’s instructions.
2. You develop a condition requiring alternative treatment.
3. The investigator decides that withdrawal is in your best interest.
11. Ethics Committee
This study has been reviewed and approved by the Ethics Committee of the Second
Affiliated Hospital, Zhejiang University School of Medicine.
For any concerns regarding your rights as a participant, please contact:
‑ Daytime: 0571‑87783759
‑ After hours: 13757118366
‑ Email: HREC2013@126.com
Consent
I confirm that I have read and understood the information above. I voluntarily agree to
participate in this study, accept the treatment procedures described, and consent to the use
of my medical data for research publication.
Participant Signature: ___________________ Contact: _____________ Date: ________
Legal Representative (if applicable): ___________________ Relationship: _______ Contact:
__________ Date: ________
Witness (if applicable): ___________________ Contact: _____________ Date: ________

Investigator Statement:
I confirm that I have explained the details of this study to the participant, including rights,
possible benefits, and risks. A signed copy of the informed consent form has been provided
to the participant.
Investigator Signature: ___________________ Contact: _____________ Date: ________