The use of duloxetine around the time of total knee arthroplasty has emerged as a
promising intervention to help with pain management after surgery and in particular as an
opioid sparing agent. Duloxetine is an antidepressant with serotonin and norepinephrine
reuptake inhibition effects that also independently exerts an analgesic effect.
Duloxetine is Health Canada approved for several indications including pain arising from
osteoarthritis of the knee. Pain inhibition action of duloxetine is believed to be a
result of potentiation of descending inhibitory pain pathways within the central nervous
system. Existing studies examining duloxetine use at the time of surgery has demonstrated
statistically significant but less clinically meaningful impacts on opioid sparing and
pain reduction. The deficiencies in study design of existing studies have either
underdosed duloxetine (30mg instead of the recommended 60mg) and/or utilized non-standard
duration of therapy (started too late, continued for only 2 weeks). Our study seeks to
definitively address whether duloxetine administered 2 weeks preoperatively at 60mg once
daily, in addition to standard analgesic practice, will decrease opioid consumption at 1
week postoperatively.
Prospective, randomized, blinded (investigators, clinicians, participant, data
collectors/analysts) trial.
Primary Outcome
•Cumulative opioid consumption at 1 week post-operatively.
Secondary Outcomes
Nausea/vomiting
Discharged according to plan (ie. same day went home same day, or day 1 went home
day 1) and if not, reason
Pain at rest and with activity (NRS-11) at 1, 6, and 12 weeks and 4.5 months
Additional analgesic use (anti-neuropathic medications, family physician or
orthopaedic surgeon opioid prescription)
Physical function (BPI, Oxford Knee Scale, range of motion
Emotional function (GAD-7, PHQ-9 at 6 weeks and 12 weeks)
Number of rehabilitation sessions attended (in-person or virtual)
Patient satisfaction (PGIC) at 1, 6, and 12 weeks after medication initiation
Presence of neuropathic pain (S-LANSS) at 6 and 12 weeks
Presence of chronic post-surgical pain at 12 weeks (based on NRS > 0)
Adverse events relating to study medication (dizziness, drowsiness, nausea,
vomiting, insomnia)
Intervention adherence
Interventional medication supply: Duloxetine 60mg OD for 2 weeks preoperatively then 60mg
OD for 6 weeks post-surgery.
Standard of care: On the day of surgery, participants will be premedicated with
acetaminophen (1000mg) and celecoxib (400mg). Per standard of care, all participants will
receive an ultrasound guided adductor canal catheter (bolus ropivacaine 0.5% 10ml). This
will be followed by a spinal anesthetic with mepivacaine 2% 3ml and 10mcg of fentanyl.
Intraoperative sedation will consist of a propofol infusion titrated to SAS (Sedation
Agitation Scale) of 3-4.
All TKAs will be performed using a standard medial parapatellar approach and the same
cemented total knee system. Tourniquet will be applied and used as part of the case.
Periarticular local infiltration will be used per standard practice using ropivacaine
0.2% with 1:200 000 epinephrine up to 50ml.
Post-surgery: Participants will be evaluated on POD-0, POD-1 and POD-2 while in hospital
or at home through phone call and at 1, 6, and 12 weeks.
Participant satisfaction will be assessed using the Patients' Global Impression of Change
(PGIC) Scale at 1, 6, and 12 weeks post-surgery.
Pain scores and opioid consumption will be recorded daily for 1 week post-operatively.
Patients will record their pain and opioid consumption on a weekly basis until week 12
post-operatively.
Physical function, emotional function, and presence of neuropathic pain will be collected
at 6 and 12 weeks.
Active and passive range of motion will be assessed by orthopedic surgeon using
goniometer at 6 (+/-1 week) and 12 (+/-1 week) weeks and 4.5 month (+/-2 weeks)
postoperatively.
Group 1: Intervention Duloxetine 60mg OD for 2 weeks preoperatively then 60mg OD for 6
weeks post-surgery.
Group 2: Control Placebo OD for 2 weeks preoperatively then OD for 6 weeks post-surgery.
Both Groups:
On the day of surgery, standard post-anesthetic care unit (PACU) orderset will be
employed and the postoperative analgesic regimen will follow standard of care including:
acetaminophen 1g QID, celecoxib 200mg BID, and hydromorphone 1-3mg PO q2h PRN.
Nurse administered IV hydromorphone push (0.3mg) followed by IV PCA hydromorphone if
pain is not controlled
ACB catheter ropivacaine 0.15% at 5cc/hr, stopped at 6:00am on POD-1
Participants will be discharged on POD-0, POD-1 or POD-2 with acetaminophen 1000mg TID,
celecoxib 100mg BID, and hydromorphone (2-4mg PO q4h PRN). Patients for same-day
discharge (POD-0) will have ACB catheter bolus of 10cc of 0.5% ropivacaine prior to
removal.