Effect of Duloxetine on Opioid Use After Total Knee Arthroplasty

• Sponsor: Hospital for Special Surgery, New York (Other)
• Overall Status: Completed
• CT.gov ID: NCT03271151
• Collaborator: (none)
• Enrollment: 160
• Location: 1
• Arms: 2
• Actual Duration (Months): 40.4
• Patients Per Site Per Month: 4

Study Details

Study Description

Brief Summary

Post-discharge pain after total knee arthroplasty remains problematic; many patients have excessive pain at the 2 week time point (and often thereafter). Reduction in opioid use has become a national goal, due to the 'epidemic' in opioid misuse.

In addition to enrolling non-opioid users, we will enroll up to 15 chronic opioid users.

Condition or Disease	Intervention/Treatment	Phase
Joint Disease; Pain, Acute; Pain, Chronic	Drug: Cymbalta; Other: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Duloxetine on Opioid Use After Total Knee Arthroplasty: A Double-blinded Randomized Control Trial
• Actual Study Start Date: Sep 28, 2017
• Actual Primary Completion Date: Dec 3, 2020
• Actual Study Completion Date: Feb 10, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Duloxetine ("Cymbalta") Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in large part due to the rise of local infiltration analgesia. Studies using epidural analgesia may also lack generalizability given the infrequent use of epidural analgesia at other institutions. For these reasons, we plan to use adductor canal nerve blockade + local infiltration analgesia for management of immediate postoperative pain. Patients will receive spinal anesthesia as the primary anesthetic. It is particularly important to study duloxetine ("Cymbalta") in the context of local infiltration analgesia, as patients receiving local infiltration analgesia receive increased doses of opioids, compared to patients receiving epidural analgesia.	Drug: Cymbalta; Duloxetine ("Cymbalta") is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) that is an effective treatment for painful diabetic neuropathy. It is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain
Placebo Comparator: Placebo Placebo to compare pain scores and opioid use againts Duloxetine	Other: Placebo; Placebo to compare outcomes against Duloxetine

Outcome Measures

Primary Outcome Measures

1. Opioid Use [Post-operative day 14]

   Opioid use (measured in cumulative morphine equivalents)

2. Pain Scores [Post-operative day 14]

   Numerical Rating Score pain with movement. Minimum value of 0, maximum value of 10. Higher scores mean more pain and worse outcome.

Secondary Outcome Measures

1. Pain Phenotype [Day of surgery]

   2011 Survey Criteria for Fibromyalgia. Minimum value of 0, and maximum value of 12. A higher score means a worse outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

• Current 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

o 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 < 50 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 75

• 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)

• Patients with major prior ipsilateral open knee surgery.

• Chronic opioid use (taking opioids for longer than 3 months)

• However, patients using chronic opioids may enroll in a parallel pilot study entitled 'effect of duloxetine on opioid use after total knee athroplasty among patients exposed to opioids- a pilot study'. The chronic opioid users will be allowed to continue their customary analgesics. The pilot study is otherwise identical to the main study.

• This study will enroll up to 15 chronic opioid users. After that, all chronic opioid users are excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital for Special Surgery	New York	New York	United States	10021

Sponsors and Collaborators

• Hospital for Special Surgery, New York

Investigators

• Principal Investigator: Jacques T YaDeau, MD, Phd, Hospital for Special Surgery, New York

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 27, 2021

More Information

Publications

None provided.

• Responsible Party: Hospital for Special Surgery, New York
• ClinicalTrials.gov Identifier: NCT03271151
• Other Study ID Numbers: 2017-0655
• First Posted: Sep 1, 2017
• Last Update Posted: Apr 26, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Joint Diseases; Acute Pain; Chronic Pain; Duloxetine Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Duloxetine ("Cymbalta")	Placebo
Arm/Group Description	Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in large part due to the rise of local infiltration analgesia. Studies using epidural analgesia may also lack generalizability given the infrequent use of epidural analgesia at other institutions. For these reasons, we plan to use adductor canal nerve blockade + local infiltration analgesia for management of immediate postoperative pain. Patients will receive spinal anesthesia as the primary anesthetic. It is particularly important to study duloxetine ("Cymbalta") in the context of local infiltration analgesia, as patients receiving local infiltration analgesia receive increased doses of opioids, compared to patients receiving epidural analgesia. Cymbalta: Duloxetine ("Cymbalta") is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) that is an effective treatment for painful diabetic neuropathy. It is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain	Placebo to compare pain scores and opioid use againts Duloxetine Placebo: Placebo to compare outcomes against Duloxetine
Period Title: Overall Study
STARTED	80	80
COMPLETED	78	77
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Duloxetine ("Cymbalta")	Placebo	Total
Arm/Group Description	Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in large part due to the rise of local infiltration analgesia. Studies using epidural analgesia may also lack generalizability given the infrequent use of epidural analgesia at other institutions. For these reasons, we plan to use adductor canal nerve blockade + local infiltration analgesia for management of immediate postoperative pain. Patients will receive spinal anesthesia as the primary anesthetic. It is particularly important to study duloxetine ("Cymbalta") in the context of local infiltration analgesia, as patients receiving local infiltration analgesia receive increased doses of opioids, compared to patients receiving epidural analgesia. Cymbalta: Duloxetine ("Cymbalta") is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) that is an effective treatment for painful diabetic neuropathy. It is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain	Placebo to compare pain scores and opioid use againts Duloxetine Placebo: Placebo to compare outcomes against Duloxetine	Total of all reporting groups
Overall Participants	80	80	160
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	41 51.3%	42 52.5%	83 51.9%
>=65 years	39 48.8%	38 47.5%	77 48.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63 (11)	64 (7)	63 (9)
Sex: Female, Male (Count of Participants)
Female	40 50%	35 43.8%	75 46.9%
Male	40 50%	45 56.3%	85 53.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 5%	2 2.5%	6 3.8%
Not Hispanic or Latino	76 95%	78 97.5%	154 96.3%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Opioid Use
Description	Opioid use (measured in cumulative morphine equivalents)
Time Frame	Post-operative day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Duloxetine ("Cymbalta")	Placebo
Arm/Group Description	Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in large part due to the rise of local infiltration analgesia. Studies using epidural analgesia may also lack generalizability given the infrequent use of epidural analgesia at other institutions. For these reasons, we plan to use adductor canal nerve blockade + local infiltration analgesia for management of immediate postoperative pain. Patients will receive spinal anesthesia as the primary anesthetic. It is particularly important to study duloxetine ("Cymbalta") in the context of local infiltration analgesia, as patients receiving local infiltration analgesia receive increased doses of opioids, compared to patients receiving epidural analgesia. Cymbalta: Duloxetine ("Cymbalta") is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) that is an effective treatment for painful diabetic neuropathy. It is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain	Placebo to compare pain scores and opioid use againts Duloxetine Placebo: Placebo to compare outcomes against Duloxetine
Measure Participants	78	77
Mean (Standard Deviation) [Oral Morphine Equivalent (mg)]	288 (226)	432.5 (374)

2. Primary Outcome

Title	Pain Scores
Description	Numerical Rating Score pain with movement. Minimum value of 0, maximum value of 10. Higher scores mean more pain and worse outcome.
Time Frame	Post-operative day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Duloxetine ("Cymbalta")	Placebo
Arm/Group Description	Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in large part due to the rise of local infiltration analgesia. Studies using epidural analgesia may also lack generalizability given the infrequent use of epidural analgesia at other institutions. For these reasons, we plan to use adductor canal nerve blockade + local infiltration analgesia for management of immediate postoperative pain. Patients will receive spinal anesthesia as the primary anesthetic. It is particularly important to study duloxetine ("Cymbalta") in the context of local infiltration analgesia, as patients receiving local infiltration analgesia receive increased doses of opioids, compared to patients receiving epidural analgesia. Cymbalta: Duloxetine ("Cymbalta") is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) that is an effective treatment for painful diabetic neuropathy. It is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain	Placebo to compare pain scores and opioid use againts Duloxetine Placebo: Placebo to compare outcomes against Duloxetine
Measure Participants	78	77
Mean (Standard Deviation) [score on a scale (NRS)]	4.2 (2)	4.8 (2.2)

3. Secondary Outcome

Title	Pain Phenotype
Description	2011 Survey Criteria for Fibromyalgia. Minimum value of 0, and maximum value of 12. A higher score means a worse outcome.
Time Frame	Day of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Duloxetine ("Cymbalta")	Placebo
Arm/Group Description	Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in large part due to the rise of local infiltration analgesia. Studies using epidural analgesia may also lack generalizability given the infrequent use of epidural analgesia at other institutions. For these reasons, we plan to use adductor canal nerve blockade + local infiltration analgesia for management of immediate postoperative pain. Patients will receive spinal anesthesia as the primary anesthetic. It is particularly important to study duloxetine ("Cymbalta") in the context of local infiltration analgesia, as patients receiving local infiltration analgesia receive increased doses of opioids, compared to patients receiving epidural analgesia. Cymbalta: Duloxetine ("Cymbalta") is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) that is an effective treatment for painful diabetic neuropathy. It is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain	Placebo to compare pain scores and opioid use againts Duloxetine Placebo: Placebo to compare outcomes against Duloxetine
Measure Participants	80	80
Median (Inter-Quartile Range) [score on a scale]	2	2

Adverse Events

Time Frame	3 months
Arm/Group Title	Duloxetine ("Cymbalta")		Placebo
Arm/Group Description	Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in large part due to the rise of local infiltration analgesia. Studies using epidural analgesia may also lack generalizability given the infrequent use of epidural analgesia at other institutions. For these reasons, we plan to use adductor canal nerve blockade + local infiltration analgesia for management of immediate postoperative pain. Patients will receive spinal anesthesia as the primary anesthetic. It is particularly important to study duloxetine ("Cymbalta") in the context of local infiltration analgesia, as patients receiving local infiltration analgesia receive increased doses of opioids, compared to patients receiving epidural analgesia. Cymbalta: Duloxetine ("Cymbalta") is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) that is an effective treatment for painful diabetic neuropathy. It is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain		Placebo to compare pain scores and opioid use againts Duloxetine Placebo: Placebo to compare outcomes against Duloxetine
All Cause Mortality
	Duloxetine ("Cymbalta")		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/80 (0%)		0/80 (0%)
Serious Adverse Events
	Duloxetine ("Cymbalta")		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/80 (0%)		0/80 (0%)
Other (Not Including Serious) Adverse Events
	Duloxetine ("Cymbalta")		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/80 (2.5%)		3/80 (3.8%)
General disorders
Hallucinations	1/80 (1.3%)	1	1/80 (1.3%)	1
Increased diaphoresis, blood pressure, complaints of diarrhea decreased unration and tooth pain	0/80 (0%)	0	1/80 (1.3%)	1
Acne	0/80 (0%)	0	1/80 (1.3%)	1
Reproductive system and breast disorders
Unable to Ejaculate	1/80 (1.3%)	1	0/80 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.