Effectiveness of Bupivacaine, Ketorolac, Ketamine, vs Bupivacaine Alone in Reducing Postoperative Pocket Pain

Pain Management in Cardiac Implantable Electronic Device Insertion; Effectiveness of Bupivacaine, Ketorolac, Ketamine, vs Bupivacaine Alone in Reducing Postoperative Pocket Pain

Bupivacaine is the most widely used local anesthetic agent across majority of the Cardiac Implantable Electronic device (CIED) implant procedures in the United States. It is hypothesized that the combination of Bupivacaine-Ketorolac-Ketamine (BKK) is more effective in alleviating perioperative and postoperative pain as compared to the use of bupivacaine alone.

A few studies have been done to look for the effectiveness of BKK in abdominal surgical procedures. However, no study has been done to evaluate its efficacy and effectiveness in patients undergoing CIED insertion.

Study Overview

• Status: Not yet recruiting
• Conditions: Pain Management
• Intervention / Treatment: Drug: Bupivacaine alone OR Bupivacaine-Ketorolac-Ketamine (BKK) Combination

Detailed Description

Bupivacaine is a widely used local anesthetic and is often administered by spinal injection prior to major surgical procedures. Ketorolac is a potent NSAID which is used for the short-term relief of moderate to severe pain. It's used for long term duration is generally limited due to its potential to cause GI ulcers/perforation and renal failure. A single dose of perioperative Ketorolac has been found to be effective in reducing opioid consumption. Ketamine is NMDA receptor antagonist and is used for its anesthetic, analgesic, and psychotomimetic effects. It is primarily used for induction and maintenance of anesthesia and induces a trance like state providing pain relief, sedation, and amnesia.

Although an effective local anesthetic agent, bupivacaine has weak analgesic effect and is used in combination with several analgesic agents for effective perioperative and postoperative analgesia. A common drug used in this analgesic regimen usually includes opioids such as morphine, oxycodone, and fentanyl. Over the last few decades the United States has witnessed an opioid epidemic and post-surgical opioid prescription is one of the major contributors of this epidemic. An opioid free combination of Bupivacaine-Ketorolac-Ketamine (BKK) is thought to be effective in alleviating perioperative and postoperative pain.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92350
      • Loma Linda University Health
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Kansas City Heart Rhythm Institute
    • Overland Park, Kansas, United States, 66215
      • Overland Park Regional Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Both male and female patients
• Patients older than 18 years of age
• Patients undergoing new CIED (ICD, pacemaker, CRT-D or CRT-P)
• Patients willing to participate in the study

Exclusion Criteria:

• Patients with prior history of allergic reaction to any component of the drug; bupivacaine, ketorolac, or ketamine
• Pregnant or breastfeeding patients
• Prisoners
• Patients younger than 18 years of age
• Patients not willing to participate in the study
• Patients deemed not suitable or unstable for the study as per physician's discretion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Bupivacaine Alone; This is the control group of patients receiving 20 cc of 0.5% bupivacaine (Bupivacaine HCL 100 mg [5mg/ml] alone. The dose and number of doses of the medicines will be adjusted as per discretion of the operator.	Drug: Bupivacaine alone OR Bupivacaine-Ketorolac-Ketamine (BKK) Combination; The plan will be to stratify patients in two groups: intervention group receiving 20 cc combination of BKK (Bupivacaine HCl 60 mg [3 mg/mL], Ketorolac Tromethamine 24 mg [1.2mg/mL], Ketamine HCl 24 mg [1.2 mg/mL]) vs the control group receiving 20 cc of 0.5% bupivacaine (Bupivacaine HCL 100 mg [5mg/ml]. The dose can be repeated multiple times during the procedure as per operator's discretion. The patients will be further stratified into sub-groups based on type of procedure they had undergone. Analgesia/anesthesia strategy will be local infiltration of the drug along with a sedating agent based on institutional standard of care. The dose of the medicines will be adjusted as per discretion of the operator to maintain adequate anesthesia/analgesia during and after the procedure.
Experimental: Bupivacaine-Ketorolac-Ketamine (BKK) Combination; This is the intervention group of patients receiving 20 cc combination of BKK (Bupivacaine HCl 60 mg [3 mg/mL], Ketorolac Tromethamine 24 mg [1.2mg/mL], Ketamine HCl 24 mg [1.2 mg/mL]).The dose and number of doses of the medicines will be adjusted as per discretion of the operator.	Drug: Bupivacaine alone OR Bupivacaine-Ketorolac-Ketamine (BKK) Combination; The plan will be to stratify patients in two groups: intervention group receiving 20 cc combination of BKK (Bupivacaine HCl 60 mg [3 mg/mL], Ketorolac Tromethamine 24 mg [1.2mg/mL], Ketamine HCl 24 mg [1.2 mg/mL]) vs the control group receiving 20 cc of 0.5% bupivacaine (Bupivacaine HCL 100 mg [5mg/ml]. The dose can be repeated multiple times during the procedure as per operator's discretion. The patients will be further stratified into sub-groups based on type of procedure they had undergone. Analgesia/anesthesia strategy will be local infiltration of the drug along with a sedating agent based on institutional standard of care. The dose of the medicines will be adjusted as per discretion of the operator to maintain adequate anesthesia/analgesia during and after the procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparative efficacy/superiority of BKK compared to bupivacaine alone in reducing the pain intensity	The goal of this prospective open label study is to demonstrate a comparative efficacy/superiority of BKK compared to bupivacaine alone in reducing the pain intensity. Patient's pain will be assessed using a Visual Analog Scale either through a telephone call from the research team or via clinic follow-up visit. The visual analog scale (VAS) determines pain from 0 to 10 with 0 indicating no pain (Better outcome) and 10 indicating worse pain in their life indicating (worse outcome).	Upto 1 week
Comparative efficacy/superiority of BKK compared to bupivacaine alone in providing comfort	The goal of this prospective open label study is to demonstrate a comparative efficacy/superiority of BKK compared to bupivacaine alone in providing comfort. Patient's comfort will be assessed using a verbal rating score either through a telephone call from the research team or via clinic follow-up visit. The comfort score determines patients comfort from 0 to 100 with 0 indicating extremely uncomfortable (Worse outcome) and 100 indicating extremely comfortable (Better outcome).	Upto 1 week
Comparative efficacy/superiority of BKK compared to bupivacaine alone in Quality of Life (QoL)	The goal of this prospective open label study is to demonstrate a comparative efficacy/superiority of BKK compared to bupivacaine alone in Quality of Life. Patient's Quality of Life will be assessed using a QoL score (EQ5-5D-5L) either through a telephone call from the research team or via clinic follow-up visit. The Quality of life questionnaire (EQ-5D-5L) has five response levels : no problems (Level 1); slight; moderate; severe; and extreme problems (Level 5), with low values suggesting better outcomes and higher values suggesting worse outcomes.	Upto 1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital readmission rates	Hospital readmission rates due to device implantation related pain or surgical site infection will be analyzed.	Until 7 days (Until the end of the sutdy)
Adverse Effects	Rates of adverse effects, including allergic reaction, worsening of the renal function, presyncope/syncope, HTN, drug-drug interaction or any patient reported side effects will be analyzed.	Until 7 days (Until the end of the sutdy)
Cost comparison of medications	Cost of medications will be compared.	Upto 1 week
Amount of pain medication used	Amount of pain medication used will be analyzed	Upto 1 week

Collaborators and Investigators

• Sponsor: Kansas City Heart Rhythm Research Foundation
• Collaborators: Cardiac Arrhythmia Service, Loma Linda University Health, Loma Linda, CA
• Investigators: Principal Investigator: Dhanunjaya Lakkireddy, MD, Kansas City Heart Rhythm Institute

Publications and helpful links

General Publications

• Neuman MD, Bateman BT, Wunsch H. Inappropriate opioid prescription after surgery. Lancet. 2019 Apr 13;393(10180):1547-1557. doi: 10.1016/S0140-6736(19)30428-3.
• De Oliveira GS Jr, Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg. 2012 Feb;114(2):424-33. doi: 10.1213/ANE.0b013e3182334d68. Epub 2011 Sep 29.
• Mariano ER, Dickerson DM, Szokol JW, Harned M, Mueller JT, Philip BK, Baratta JL, Gulur P, Robles J, Schroeder KM, Wyatt KEK, Schwalb JM, Schwenk ES, Wardhan R, Kim TS, Higdon KK, Krishnan DG, Shilling AM, Schwartz G, Wiechmann L, Doan LV, Elkassabany NM, Yang SC, Muse IO, Eloy JD, Mehta V, Shah S, Johnson RL, Englesbe MJ, Kallen A, Mukkamala SB, Walton A, Buvanendran A. A multisociety organizational consensus process to define guiding principles for acute perioperative pain management. Reg Anesth Pain Med. 2022 Feb;47(2):118-127. doi: 10.1136/rapm-2021-103083. Epub 2021 Sep 22.
• Wolfe RC, Spillars A. Local Anesthetic Systemic Toxicity: Reviewing Updates From the American Society of Regional Anesthesia and Pain Medicine Practice Advisory. J Perianesth Nurs. 2018 Dec;33(6):1000-1005. doi: 10.1016/j.jopan.2018.09.005. No abstract available.
• Nair GM, Birnie DH, Sumner GL, Krahn AD, Healey JS, Nery PB, Kalfon E, Verma A, Ayala-Paredes F, Coutu B, Becker G, Philippon F, Eikelboom J, Sandhu RK, Sapp J, Leather R, Yung D, Thibault B, Simpson CS, Ahmad K, Sturmer M, Kavanagh K, Crystal E, Wells GA, Essebag V; BRUISE CONTROL Investigators. Post-operative pain following cardiac implantable electronic device implantation: insights from the BRUISE CONTROL trials. Europace. 2021 May 21;23(5):748-756. doi: 10.1093/europace/euaa349.
• Clerc S, Vuilleumier H, Frascarolo P, Spahn DR, Gardaz JP. Is the effect of inguinal field block with 0.5% bupivacaine on postoperative pain after hernia repair enhanced by addition of ketorolac or S(+) ketamine? Clin J Pain. 2005 Jan-Feb;21(1):101-5. doi: 10.1097/00002508-200501000-00012.

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2023
• Primary Completion (Anticipated): October 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: September 16, 2022
• First Submitted That Met QC Criteria: October 7, 2022
• First Posted (Actual): October 12, 2022

Study Record Updates

• Last Update Posted (Estimate): March 10, 2023
• Last Update Submitted That Met QC Criteria: March 8, 2023
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Anesthetics, Local; Ketamine; Ketorolac; Bupivacaine
• Other Study ID Numbers: KCHRRF-PAINFREE POCKET-0016

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.: No