Doxepin Alone or Combined With Ramelteon Versus Placebo for Improving Sleep Quality After Primary Total Knee Arthroplasty

Doxepin Versus Doxepin and Ramelteon Versus Placebo to Improve Sleep Quality After Primary Total Knee Arthroplasty: A Randomized Controlled Trial

Many patients experience poor sleep during recovery after total knee arthroplasty (TKA). Disturbed sleep can last weeks to months and may worsen pain, slow healing, and reduce overall quality of life. Few safe, effective, evidence-based options exist to improve sleep during this recovery period. This study aims to determine whether the medications doxepin, either alone or in combination with ramelteon, can improve sleep quality during early recovery after TKA. The investigators will also evaluate whether improved sleep leads to better pain control, knee function, and overall quality of life.

Study Overview

• Status: Not yet recruiting
• Conditions: Sleep Quality Post-TKA; Postoperative Knee Function; Quality of Life After Primary TKA
• Intervention / Treatment: Drug: Doxepin 6 mg; Drug: Ramelteon 8 mg; Drug: Placebo Tablets

Detailed Description

This randomized, placebo-controlled clinical trial seeks to answer the following question: Is doxepin or combination therapy consisting of doxepin plus ramelteon superior to placebo in terms of (1) sleep quality as measured by the Insomnia Severity Index, (2) postoperative knee function as measured by KOOS-JR, KOOS-PS, or (3) overall health-related quality of life during the first three months after total knee arthroplasty.

• Study Type: Interventional
• Enrollment (Estimated): 129
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Gerald Y Liao, MS; Phone Number: 617-710-7211; Email: liaog@uw.edu
• Study Contact Backup: Name: Nicholas M Hernandez, MD; Phone Number: 530-514-1275; Email: nichern@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98133
      • University of Washington Medical Center Hip & Knee Center
      • Contact: Portia Morgan; Phone Number: 206-668-3674; Email: morganp9@uw.edu
      • Principal Investigator: Nicholas M Hernandez, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Those receiving primary total knee arthroplasty (TKA)
• 80 years or less, age 18 or greater

Exclusion Criteria:

• History of cardiovascular bundle branch block
• Actively taking selecrtive serotoin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), or having treatment via counseling/psychotherapy for major depression or anxiety, bipolar, or psychotic disorder
• Pre-operative narcotics (defined as more than 1 prescription in the past 3 months)
• Self-reported use of alcohol in excess of >2 drinks/day (in men) and > 1 drink/day (in women)
• Use of prescription sleep aids (e.g., Ambien, Trazadone) prior to surgery (i.e., melatonin or other OTC sleep aids are permitted)
• History of major sleep disorder (e.g., obstructive sleep apnea (OSA), restless leg syndrome, narcolepsy)
• Pregnant, breastfeeding or planning to become pregnant in the next 3 months post-surgery. No pregnancy testing will be performed; screening will rely solely on participant self-report.
• Unable to take the study medication(s) due to contraindications with other medications the patient uses
• Have been diagnosed with (or are at risk of) narrow-angle or angle-closure glaucoma. In order to be eligible, participants must be able to report that they have had their eyes dilated within the past year without problems.
• Have severe urinary retention or difficulty emptying your bladder.
• Had glaucoma-related eye procedures (e.g., laser iridotomy)
• Ongoing use of glaucoma eye drops.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxepin 6 mg; Participants receive doxepin 6 mg and matching placebo orally once nightly for sleep during the first 6 weeks postoperative period following total knee arthroplasty.	Drug: Doxepin 6 mg; Doxepin 6 mg administered orally once nightly for sleep during the first 6 weeks of the postoperative period following total knee arthroplasty
Experimental: Doxepin 6 mg and Ramelteon 8mg; Participants receive doxepin 6 mg and ramelteon 8 mg orally once nightly for sleep during the first 6 weeks postoperative period following total knee arthroplasty.	Drug: Doxepin 6 mg; Doxepin 6 mg administered orally once nightly for sleep during the first 6 weeks of the postoperative period following total knee arthroplasty; Drug: Ramelteon 8 mg; Ramelteon 8 mg administered orally once nightly for sleep during the first 6 weeks of the postoperative period following total knee arthroplasty
Placebo Comparator: Placebo; Participants receive 2 matching placebos orally once nightly for sleep during the first 6 weeks postoperative period following total knee arthroplasty.	Drug: Placebo Tablets; Placebo administered orally once nightly for sleep during the first 6 weeks of the postoperative period following total knee arthroplasty

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insomnia Severity Index (ISI) scores (sleep quality)	Insomnia Severity Index (ISI) The Insomnia Severity Index is a 7-item self-reported questionnaire assessing the nature, severity, and impact of insomnia.; Score range: 0 to 28; Interpretation: Higher scores indicate worse insomnia severity Score categories: 0-7: No clinically significant insomnia; 8-14: Subthreshold insomnia; 15-21: Clinical insomnia (moderate severity); 22-28: Clinical insomnia (severe)	Baseline; 2 weeks postoperatively; 6 weeks postoperatively; 3 months postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS)	Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS): The KOOS-PS is a 7-item patient-reported outcome measure assessing knee-related physical function, including activities such as rising from bed, putting on socks, rising from sitting, bending to the floor, twisting/pivoting, kneeling, and squatting . Each item is scored on a 5-point Likert scale (None to Extreme). Scores are transformed to a normalized scale ranging from 0 to 100, with higher scores indicating worse physical function (greater disability).	Baseline; 2 weeks postoperatively; 6 weeks postoperatively; 3 months postoperatively.
Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR)	Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR): The KOOS-JR is a patient-reported outcome measure assessing knee pain, stiffness, and functional limitations during activities of daily living over the past week, including tasks such as twisting/pivoting, stair navigation, standing, rising from sitting, and bending . The instrument consists of 7 items scored on a 5-point Likert scale (None to Extreme). Raw scores (range 0-28) are summed and converted to an interval score ranging from 0 to 100, where 0 represents total knee disability and 100 represents perfect knee health (higher scores indicate better outcomes)	Baseline; 2 weeks postoperatively; 6 weeks postoperatively; 3 months postoperatively
Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10)	Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10): The PROMIS-10 is a 10-item patient-reported outcome measure assessing global physical health, mental health, pain, fatigue, and social functioning. Items are scored on 5-point Likert scales (e.g., Excellent to Poor; Not at all to Very much), with one pain item scored from 0 to 10. Raw scores are summed and converted to standardized T-scores for Global Physical Health and Global Mental Health, each ranging approximately from 0 to 100 (mean 50, standard deviation 10), where higher scores indicate better health status	Baseline; 2 weeks postoperatively; 6 weeks postoperatively; 3 months postoperatively

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-Day Hospital Readmission Status	Hospital readmission status within 90 days following primary total knee arthroplasty, defined as any unplanned inpatient admission to a hospital occurring within 90 days after the index procedure. This is a dichotomous outcome (Yes/No), where "Yes" indicates that a readmission occurred and represents a worse outcome.	Within 90 days postoperatively
Medication Compliance	Medication Compliance: Medication adherence assessed using patient self-report and pill counts when feasible. Self-reported adherence is measured by patient-reported proportion of prescribed doses taken, and pill counts are used to calculate the percentage of medication consumed relative to the prescribed amount. Adherence is expressed as a percentage from 0 to 100%, where higher values indicate better compliance.	2 weeks postoperatively; 6 weeks postoperatively
Length of Stay (LOS)	Length of Stay (LOS): Length of hospital stay following primary total knee arthroplasty, defined as the number of days from hospital admission to discharge (continuous variable, ≥0 days), where higher values indicate longer hospitalization (worse outcome).	Perioperative/Periprocedural
Discharge Destination	Discharge Destination: Discharge disposition following primary total knee arthroplasty, categorized as home versus skilled nursing facility. This is a categorical outcome where discharge to a skilled nursing facility represents a worse outcome compared to discharge home.	Perioperative/Periprocedural
Postoperative Mobility (Step Count)	Postoperative Mobility (Step Count): Postoperative mobility assessed by the number of steps taken during inpatient physical therapy sessions following primary total knee arthroplasty. Step count is recorded as the total number of steps ambulated (continuous variable, ≥0), where higher values indicate better functional recovery.	Perioperative/Periprocedural
Level of Assistance Required for Ambulation	Level of Assistance Required for Ambulation: Level of assistance required during inpatient physical therapy following primary total knee arthroplasty, categorized as independent, 1-person assist, 2-person assist, or maximal assist. This is an ordinal outcome where greater assistance requirements indicate worse functional recovery.	Perioperative/Periprocedural
Postoperative Falls	Postoperative Falls: Occurrence of patient falls during hospitalization or within the follow-up period after primary total knee arthroplasty, defined as any unintentional descent to the ground or lower level documented in the medical record. This is a dichotomous outcome (Yes/No), where "Yes" indicates a fall occurred and represents a worse outcome.	Perioperative/Periprocedural; 3 months postoperatively
Postoperative Delirium	Occurrence of delirium during hospitalization or follow-up after primary total knee arthroplasty, defined by clinical documentation of acute confusional state or use of delirium-related precautions (e.g., 1:1 sitter, physical restraints). This is a dichotomous outcome (Yes/No), where "Yes" indicates delirium occurred and represents a worse outcome.	Perioperative/Periprocedural; 3 months postoperatively
Pressure Ulcers (Bed Sores)	Pressure Ulcers (Bed Sores): Development of pressure ulcers during hospitalization or follow-up after primary total knee arthroplasty, defined as localized injury to the skin or underlying tissue documented in the medical record. This is a dichotomous outcome (Yes/No), where "Yes" indicates a pressure ulcer occurred and represents a worse outcome.	Perioperative/Periprocedural; 3 months postoperatively
Postoperative Opioid Consumption (Morphine Milligram Equivalents)	Postoperative Opioid Consumption (Morphine Milligram Equivalents): Total postoperative opioid use following primary total knee arthroplasty, calculated as cumulative morphine milligram equivalents (MME) administered during hospitalization and follow-up. This is a continuous variable (≥0 mg), where higher values indicate greater opioid consumption (worse outcome).	Perioperative/Periprocedural; 3 months postoperatively
Postoperative Medical Complications	Postoperative Medical Complications: Occurrence of medical complications following primary total knee arthroplasty, including myocardial infarction, venous thromboembolism, cerebrovascular accident, acute kidney injury, respiratory failure, urinary tract infection, pneumonia, gastrointestinal obstruction, and need for intensive care unit (ICU) admission during the same hospitalization. This is a composite dichotomous outcome (Yes/No), where "Yes" indicates that one or more complications occurred and represents a worse outcome.	Perioperative/Periprocedural
Postoperative Surgical Complications	Occurrence of surgical complications following primary total knee arthroplasty, including reoperation, periprosthetic fracture, dislocation, infection, and postoperative stiffness. This is a composite dichotomous outcome (Yes/No), where "Yes" indicates that one or more complications occurred and represents a worse outcome.	Perioperative/Periprocedural; 3 months postoperatively

Collaborators and Investigators

• Sponsor: University of Washington
• Investigators: Principal Investigator: Nicholas M Hernandez, MD, University of Washington

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: May 1, 2026
• First Submitted That Met QC Criteria: May 13, 2026
• First Posted (Actual): May 20, 2026

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Ethers, Cyclic; Ethers; Heterocyclic Compounds, 3-Ring; Oxepins; Dibenzoxepins; Doxepin; ramelteon
• Other Study ID Numbers: STUDY00024373

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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