August 21, 2017
Institutional Review Board, Hospital for Special Surgery
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Jacques T. YaDeau, MD, PhD
Chad Michael Brummett, MD
Enrique A. Goytizolo, MD
Danya DeMeo
Kara Fields
Douglas E. Padgett, MD
David H. Kim, MD
Jodie Curren, RN
Denesy Mancenido
Yi Lin, MD
Geoffrey H. Westrich, MD
Kethy M. JulesElysee, MD
Richard L. Kahn, MD
We plan to enroll 175 patients undergoing knee replacement. All patients will receive a standard anesthetic and pain medicine protocol. Half will additionally receive duloxetine, 60 mg, for 14 days. Half will additionally receive a placebo. The primary outcome is pain and opioid use at 14 days, determined by telephone call.
Telephone follow-up will continue until 3 months after the operation. No additional visits to HSS are required.
INCLUSION CRITERIA
Age 25 to 75 years
Planned use of regional anesthesia
Ability to follow study protocol
English speaking (Primary outcome obtained via telephone call and secondary outcomes include questionnaires validated in English only)
Patients planning on being discharged home or to a rehabilitation center that has agreed to participate
EXCLUSION CRITERIA
Use of duloxetine or other SNRIs, SSRIs, MAOIs, Tricyclic antidepressants, triptans (sumatriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan), lithium, buspirone, St. John’s Wort
Hepatic insufficiency
Hepatoxicity is reported as a side effect of duloxetine. “Median time to detection of transaminase elevation was about two months” (package insert 5.2
Renal insufficiency (ESRD, HD, estimated creatinine clearance < 30 ml/min)
Severe CRI may impair duloxetine clearance
CLcr=[(140-age (years)] x weight (kg)x0.85 (for female patients)/[72xserum creatinine (mg/dL)]
· Patients younger than 25 years old and older than 80
· Patients intending to receive general anesthesia
· Allergy or intolerance to one of the study medications
· Patients with an ASA of IV
· Chronic gabapentin/pregabalin use (regular use for longer than 3 months)
· Chronic opioid use (taking opioids for longer than 3 months)
· Patients with major prior ipsilateral open knee surgery.
One of the criticisms of the previous duloxetine study (by a reviewer for ‘Anesthesiology’) was “However, I think it should be added that this study was done in relatively 'uncomplicated' TKA patients and where duloxetine apparently was not effective. However, what is needed is studies in more 'difficult' patients such as pain catastrophizers, those receiving preoperative psychopharmacological agents or opioids, thereby calling for future duloxetine studies in such specific 'high-risk pain patients' ".
Exclusions from 2 previous similar studies of TKA patients at HSS were reviewed. For the duloxetine trial; of 189 patients who did not meet inclusion criteria, 27 (14.3%) were identified as chronic opioid users. For the ACB PAI trial; of 162 patients who did not meet inclusion criteria, 4 (2.5%) were identified as chronic opioid users.
Given these numbers, it is not practical to conduct an appropriately powered RCT among chronic opioid users, using current study design. However, we propose concurrently enrolling (for the duration of the main study) such chronic opioid-using patients into a pilot RCT, run in a parallel fashion, with separate randomization. This will be a sample of convenience, and will serve as a pilot study for possible future studies. We suspect that between 4 and 27 such patients will be eligible, and that not all will consent to enter into the study, so we will request n=15 for chronic opioid users.
Jacques T. YaDeau, MD, PhD
212-606-1206