Optimizing the Use of Ketamine to Reduce Chronic Postsurgical Pain

Study Overview
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Brief Summary
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The study utilizes a 3-arm placebo-controlled RCT to study the effectiveness of ketamine in reducing chronic post-mastectomy pain. Participants randomized to the first arm will receive a 0.35 mg/kg dose after induction, followed by a 0.25 mg/kg/hr infusion during surgery (up to a maximum of 6 hours) and continued for 2 hours postoperatively. Participants in the second arm will receive a single dose of 0.6 mg/kg of ketamine in the post-anesthesia care unit, and the final group will serve as the control group and receive saline (no ketamine).

Detailed Description
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This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to study the effectiveness of ketamine in reducing PMPS. In a 3-arm, parallel-group study, approximately 750 adult women undergoing mastectomy or prophylactic mastectomy for oncologic reasons will be randomized to one of three arms. Participants in the first arm will receive continuous ketamine infusion starting after anesthetic induction (0.35 mg/kg dose after induction, followed by a 0.25 mg/kg/hr infusion during surgery (with a maximum infusion of 6 hours) plus a postoperative saline dose, and continuation of 0.25 mg/kg/hr ketamine infusion for 2 hours postoperatively). Participants in the second arm will receive a dose of saline after induction, followed by a saline infusion during the surgery plus a single dose of 0.6 mg/kg of ketamine in the PACU, and 2 hours of saline infusion after surgery. The final group will serve as the control group and receive an intraoperative dose of saline, followed by saline infusion plus a postoperative saline dose and 2 hours of saline infusion after surgery. Participants will be followed at 1 and 7 days and 1, 3, 6, and 12 months after surgery.

Official Title
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Optimizing the Use of Ketamine to Reduce Chronic Postsurgical Pain

Conditions
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Chronic Postsurgical Pain

Intervention / Treatment
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* Drug: Continuous ketamine infusion
* Drug: Ketamine + Saline
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Woman 18 years of age or older Undergoing elective breast surgery for oncologic indication as follows: unilateral or bilateral mastectomy, prophylacticmastectomy, +/- lymph node dissection, +/- immediate or delayed reconstruction. No distant metastases Exclusion Criteria: History of cognitive impairment or clinical signs of altered mental status (AMS) that may interfere with adherence to study procedures and/or participant safety. Clinical signs of AMS may include but are not limited to: confusion, amnesia, disorientation, fluctuating levels of alertness, etc. Past ketamine or phencyclidine misuse or abuse Schizophrenia or history of psychosis History of post-traumatic stress disorder Known sensitivity or allergy to ketamine Liver or renal insufficiency History of uncontrolled hypertension, chest pain, cardiac arrhythmia, stroke, head trauma, intracranial mass or hemorrhage, glaucoma, porphyria, uncontrolled thyroid disease, or other contraindication to ketamine Lamotrigine, alfentanil, physostigmine, or 4-aminopyridine use Currently Pregnant Body mass index (BMI) equal to or greater than 41 Non-English or non-Spanish speaker Currently participating in another pain interventional trial Unwilling to comply with all study procedures and be available for the duration of the study Patient is American Society of Anesthesiologists (ASA) physical status 4, 5, or 6 Patient has started or undergone hormone therapy for gender transition into male. Patient scheduled for any bilateral (or greater) flap reconstruction

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 Continuous ketamine infusion group<br>Continuous ketamine infusion (0.35 mg/kg after induction, followed by 0.25 mg/kg/hr until 2 hours after surgery) plus saline IV dose in post-anesthesia care unit | Drug: Continuous ketamine infusion<br>* Continuous ketamine infusion (0.35 mg/kg after induction, followed by 0.25 mg/kg/hr until 2 hours after surgery) plus saline IV dose in post-anesthesia care unit<br>|
| Active Comparator: Arm 2 Ketamine + Saline group<br>Saline dose and infusion intraoperatively, then single-dose IV ketamine (0.60 mg/kg) in post-anesthesia care unit plus 2 hours of saline administration after surgery | Drug: Ketamine + Saline<br>* Saline dose and infusion intraoperatively, then single-dose IV ketamine (0.60 mg/kg) in post-anesthesia care unit plus 2 hours of saline administration after surgery<br>|
| Placebo Comparator: Arm 3 Placebo group<br>Placebo, Saline dose and infusion intraoperatively, then saline IV dose in post-anesthesia care unit plus 2 hours of saline administration after surgery | Other: Placebo<br>* Placebo, Saline dose and infusion intraoperatively, then saline IV dose in post-anesthesia care unit plus 2 hours of saline administration after surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BPI pain severity subscale score | The Brief Pain Inventory short form (BPI) pain severity subscale assesses pain at its worst, least, average, and current in the past 24 hours. The score ranges from 0 to 10 for each item. The average of the four items will be used. The BPI scale defines pain as follows: Worst Pain Score: 1 - 4 = Mild Pain. Worst Pain Score: 5 - 6 = Moderate Pain. Worst Pain Score: 7 - 10 = Severe Pain. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BPI pain severity and pain interference subscales score | BPI assesses pain severity and interference. The interference subscale measures how much pain has interfered with general activities such as walking and working. Additionally, it inquires about interference in mood, enjoyment of life, relationships, and sleep. The BPI scale defines pain as follows: Worst Pain Score: 1 - 4 = Mild Pain. Worst Pain Score: 5 - 6 = Moderate Pain. Worst Pain Score: 7 - 10 = Severe Pain. | Baseline, 1 and 7 days and 1, 3*, 6, and 12 months after surgery | 
| Incidence of PMS: BPI average pain score | The BPI pain severity subscale assesses pain at its worst, least, average, and current in the past 24 hours. We will use participant's average pain item to assess incidence of PMPS. A score greater than 3 (0-10 scale) will be considered clinically meaningful chronic pain. | Baseline, 3, 6, and 12 months after surgery | 
| Pain in the surgical site (chest wall, axilla, and/or arm): BCPQ Score | The Breast Cancer Pain Questionnaire (BCPQ) assesses pain location, frequency, and severity as well as sensory disturbance after breast surgery. The BCPQ queries patients about pain severity (scores 1-10) and frequency (scores 5 [constantly], 4 [daily], 3 [occasionally], 2 [weekly], 1 [monthly], and 0 [never]) in four surgically related body areas (breast, axilla, chest wall, arm). | 7 days and 1, 3, 6, and 12 months after surgery | 
| PROMIS Depression and Anxiety Short Form Scores | Anxiety and depressive symptoms are prevalent in patients undergoing surgery for breast cancer and are risk factors for PMPS. The PROMIS assessments are designed to measure anxiety and depression symptoms. Each assessment will generate a raw score based on participant-reported answers, where the raw score is then converted into a t-score ranging from 0-100; higher scores indicate greater symptoms of anxiety and depression. | Baseline, 7 days and 1, 3, 6, and 12 months after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-Mastectomy, Ketamine, Mastectomy