A Comparison of Lidocaine, Esmolol, and Placebo Without Use of a Tourniquet for Relieving Pain From Intravenous Administration of Propofol
Phase: PHASE2
Conditions: Injection Site Irritation, Pain
Sponsor: Wake Forest University Health Sciences

 
 
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A Comparison of Lidocaine, Esmolol, and Placebo Without Use of a 
Tourniquet for Relieving Pain from Intravenous Administration of Propofol 
 
 
IRB00063576NCT 
 
 
NCT 04356352 
 
 
IRB Approval Date:  08JUN2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Study Title: A Comparison of Lidocaine, Esmolol, and Placebo Without Use 
of a Tourniquet for Relieving Pain from Intravenous Administration of 
Propofol 
 
Principal Investigator, Co-investigator(s):  Michael Norton, MD; Wesley Templeton, MD; 
Leah Templeton, MD; Deborah Whelan, MD; Justin Traunero, MD; Sarah Kittner, MD; Jordan 
Rejeski, MD; Richard Flowers, DNP, CRNA; Grace Simpson, CRNA; John Korona, MD;  Susan 
Vishneski, MD; Scott Miller, MD; Randy Calicott, MD; John Bradshaw, MD; Rohesh Fernando, 
MD 
 
Sponsor or funding source: Department of Anesthesiology 
 
Background 
 
It has long been known that propofol causes pain on intravenous injection (1).  This pain is 
multifactorial in origin, stemming from direct mucosal irritation as well as stimulation of 
nociceptive sensory nerve fibers in the venous adventitia (2).  Lidocaine has frequently been 
administered either in advance or concomitantly with propofol to attenuate this response.  
Studies have noted varying degrees of success with this technique but have clearly demonstrated 
an improvement in propofol injection pain when lidocaine is administered in combination with 
venous occlusion by a tourniquet (3, 4, 5, 6, 7). 
 
Adrenergic signaling pathways participate in the neurotransmission and modulation of pain.  
2 
agonists have been shown to work synergistically with opioids to exert anti-nociceptive effects 
(8), and 
1 antagonists possess similar properties (9).  Esmolol has been shown to decrease 
perioperative anesthetic and narcotic requirements (10, 11), and one study showed that 
perioperative esmolol administration decreased postoperative opioid requirements for up to three 
days after surgery (12).  Another study demonstrated that an intraoperative esmolol infusion 
decreased emergence times, postoperative narcotic requirements, and the time to discharge after 
ambulatory surgery (13).  Esmolol has also been found useful for decreasing pain upon injection 
of a venous irritant: it decreases the pain associated with rocuronium injection (14) and may be 
even more effective than lidocaine at attenuating propofol injection pain when used in 
combination with a tourniquet (15).  Importantly, it has proven to be effective at blunting the 
cardiovascular response to a noxious stimulus without causing clinically significant bradycardia 
and hypotension (16). 
 
Despite the results of the above cited studies, most clinicians seldom use a tourniquet when 
giving lidocaine to attenuate propofol injection pain.  In addition, esmolol’s utility in preventing 
this pain has not been studied in the absence of a tourniquet.  The goal of the present study is to 
determine whether lidocaine or esmolol is effective at preventing propofol injection pain when a 
tourniquet is not used. 
 
In clinical practice, we commonly administer IV lidocaine from premixed syringes containing 
100 mg of the drug dissolved in 5 ml. Most providers administer 1 mg/kg body weight, and few 
if any will open a second syringe when patients weigh more than 100 kg. Since the goal of this 
trial is to observe the clinical efficacy of this drug when administered the way it is usually done 

 
 
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by practicing clinicians, we decided to administer 1 mg/kg lidocaine to a maximum of 100 mg. 
In order to maintain blinding and consistency in this trial, we decided esmolol should be 
administered to a maximum of 50 mg since it will be mixed to half the concentration of the 
lidocaine -- this ensures that an equal volume of study drug will be administered, thus helping us 
maintain double blinding. 
 
The study will include three arms: lidocaine, esmolol, and placebo.  Eligible patients will be 18-
60 years old, ASA physical status 1-3, and scheduled for an elective surgical procedure.  Patients 
will be randomized to receive lidocaine, esmolol, or placebo.  Both the patients and the 
administering/observing providers will be blinded to the study drug or placebo being 
administered. 
 
Objectives 
 
Our primary hypothesis is that esmolol and lidocaine, when given without the use of a 
tourniquet, provide relief of propofol injection pain that is superior to placebo when assessed 
using our propofol pain scoring tool. 
 
Setting 
This study is taking place at Wake Forest Baptist Medical Center in the perioperative setting.  
Subjects will already be planning on having an elective surgical procedure and be anticipating 
having a general anesthetic receiving propofol as part of that procedure.   
 
Subjects selection criteria 
 
Inclusion criteria 
● 18-60 years of age 
● ASA 1-3 
● Elective surgical procedure 
 
Exclusion criteria 
● BMI ≥ 45 
● Pregnancy 
● Requirement for RSI or awake intubation 
● Suspected or known difficult airway 
● Any use of opioids in the last week 
● Significant cardiopulmonary or hepatic dysfunction 
● Hypersensitivity to study medications 
 
Study Procedures, Interactions and Interventions 
● Obtain informed consent and randomize patient into one of three groups (lidocaine, 
esmolol, placebo) 
● Dose medications based on actual body weight 
● Start 20 gauge IV in either extremity and hang lactated ringers (LR) 
● Administer no sedative or analgesic (i.e., no Versed or fentanyl) prior to induction 
● Place standard monitors and preoxygenate patient 

 
 
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● Administer study medication as a bolus 
o 1 mg/kg lidocaine to a max of 100 mg, 0.5 mg/kg esmolol to a max of 50 mg, or 
placebo 
o Lidocaine will be 20 mg/ml and esmolol will be 10 mg/ml 
▪ 
These concentrations allow us to simply administer 0.05 ml solution per 
kg regardless of which group the patient has been randomized into – 100 
kg patient would receive 5 ml solution that would contain 100 mg 
lidocaine (= 1 mg/kg), 50 mg esmolol (= 0.5 mg/kg), or saline 
o Allow patient’s IV to run freely 
● 20-30 seconds after administration of study medication, bolus 0.5 mg/kg propofol to a 
max of 50 mg 
● Record patient’s pain over the next thirty seconds 
o Use the pain scale previously published by McCrirrick and Hunter (Anaesthesia 
1990;45(6):443-4). 
▪ 
0 = no pain 
▪ 
1 = mild pain 
● Pain reported in response to questioning AND NOT accompanied 
by a physical sign (grimacing, withdrawal, tears, etc.) 
▪ 
2 = moderate pain 
● Pain reported in response to questioning AND accompanied by a 
physical sign 
● Pain reported spontaneously AND NOT accompanied by a 
physical sign 
▪ 
3 = severe pain 
● Pain eliciting a strong vocal response 
● Pain reported spontaneously AND accompanied by a physical sign 
● Proceed with induction at the discretion of the attending anesthesiologist 
o If patient requires a NDMB, use vecuronium instead of rocuronium (due to 
venous irritation caused by rocuronium) 
● Record vital signs every minute after induction for ten minutes 
o Also record administration of any medications given to treat hemodynamic 
derangements during this time frame (phenylephrine, ephedrine, propofol, etc.) 
o Do not administer esmolol for tachycardia during this time frame unless the 
patient shows evidence of myocardial ischemia or other significant derangements 
 
Sample Size 
 
150 patients (50 in each arm) is anticipated to be needed in this study.  
 
Outcome Measure 
 
Our primary outcome measure will be the proportion of patients with pain using a pain scoring 
system previously used by studies looking at various remedies to decrease propofol injection 
pain (15, 17).  In this scoring system, patients are observed and their responses and behaviors are 
rated according a specific rubric (Table 1) (17).  This assessment will be performed by a blinded 

 
 
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member of the study team following administration of a sub-induction dose of propofol, 0.5 
mg/kg up to 50 mg, just prior to full induction. 
 
Our secondary outcome measure will be heart rate, blood pressure, and SpO2 every minute 
following induction.  We will record vital signs each minute for the first 10 minutes following 
induction. 
 
Analytical Plan 
 
In preparation for this study, we obtained pilot data using five patients in each of the three 
proposed study arms.  As shown in Table 2, lidocaine and esmolol both decreased the incidence 
of propofol injection pain in relation to placebo.  Given that 40% (95% CI 0-83%) and 60% 
(95% CI 17-100%) patients given lidocaine and esmolol respectively reported little to no pain 
defined as a pain score of 0 on our propofol pain injection while 0% of patients who received 
placebo reported no pain, we used a sample size calculator for proportions with a 25% difference 
considered clinically significant, 90% power, and a 95% confidence level to determine a sample 
size of 32.  In order improve our certainty we will increase this to 50 patients per group. 
 
We will perform descriptive statistics on all demographic data. We will perform an individual 
comparison of all three groups using Pearson’s chi-square test with Bonferroni correction for 
multiple comparisons.  Other inferential statistics will be performed as necessary. 
 
 
Human Subjects Protection 
 
Subject Recruitment Methods 
Subjects will be identified through the daily review of the preanesthesia assessment clinic as well 
as the daily surgical schedule for those meeting inclusion criteria.  They will then be approached 
by a member of the research staff regarding their participation.   
 
Informed Consent 
Written informed consent will be obtained by a member of the research staff discussing this 
study in depth with them.  Adequate time will be given for the subject to consider their 
participation.  The risk of harm or discomfort that may occur as a result of taking part in this 
research study is not expected to be more than in daily life or from routine physical or 
psychological examinations or tests.  The rights and welfare of study will be protected through 
the use of measures to maintain the confidentiality of study information.  Study results will be 
presented or published in lieu of providing individual subjects additional information regarding 
the study. 
 
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that could 
directly identify subjects, and maintaining all study information in a secure manner.  To help 
ensure subject privacy and confidentiality, only a unique study identifier will appear on the data 

 
 
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collection form.  Any collected patient identifying information corresponding to the unique study 
identifier will be maintained on a linkage file, store separately from the data.  The linkage file 
will be kept secure, with access limited to designated study personnel.  Following data collection 
subject identifying information will be destroyed per institutional guidelines (investigator 
initiated research data maintained for 6 years) consistent with data validation and study design, 
producing an anonymous analytical data set.  Data access will be limited to study staff.  Data and 
records will be kept locked and secured, with any computer data password protected.  No 
reference to any individual participant will appear in reports, presentations, or publications that 
may arise from the study. 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study 
staff.  Wes Templeton will serve as a project mentor and will be involved in planning the study, 
navigating the IRB process, collecting and analyzing data, and preparing and submitting the 
manuscript. 
 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB and sponsor or appropriate government agency if appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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References 
 
1. Tan CH, Onsiong MK: Pain on injection of propofol. Anaesthesia 1998; 53:468-76. 
2. Desousa KA: Pain on propofol injection: causes and remedies. Indian J Pharmacol 2016; 48:617-
23. 
3. Ewart MC, Whitwam JG: Prevention of pain during injection of propofol. Lancet 1990; 335:798-
9. 
4. Kaya S, Turhanoglu S, Karaman H, Özgün S, Basak N: Lidocaine for prevention of propofol 
injection-induced pain: a prospective, randomized double-blind, controlled study of the effect of 
duration of venous occlusion with a tourniquet in adults. Curr Ther Res Clin Exp 2008; 69:29-35. 
5. Massad IM, Abu-Ali HM, Abu-Halaweh SA, Badran IZ: Venous occlusion with lidocaine for 
preventing propofol induced pain: a prospective double-blind randomized study. Saudi Med J 
2006; 27:997-1000. 
6. Picard P, Tramèr MR: Prevention of pain on injection with propofol: a quantitative systematic 
review. Anesth Analg 2000; 90:963-9. 
7. Sasaki T, Okamura S, Kisara A, Ito M, Yogosawa K, Yagishita Y, Yogosawa T: Effect of lidocaine on 
pain caused by injection of propofol: comparison of three methods at two injection rates. J 
Anesth 1999; 13:14-6. 
8. Yaksh TL: Pharmacology of spinal adrenergic systems which modulate spinal nociceptive 
processing. Pharmacol Biochem Behav 1985; 22:845-58. 
9. Davidson EM, Doursout MF, Szmuk P, Chelly JE: Antinociceptive and cardiovascular properties of 
esmolol following formalin injection in rats. Can J Anaesth 2001; 48:59-64. 
10. Dhir R, Singh MR, Kaul TK, Tewari A, Oberoi R: Effect of intravenous esmolol on analgesic 
requirements in laparoscopic cholecystectomy. J Anaesthesiol Clin Pharmacol 2015; 31:375-9. 
11. Johansen JW, Flaishon R, Sebel PS: Esmolol reduces anesthetic requirement for skin incision 
during propofol/nitrous oxide/morphine anesthesia. Anesthesiology 1997; 86:364-71. 
12. Chia YY, Chan MH, Ko NH, Liu K: Role of -blockade in anaesthesia and postoperative pain 
management after hysterectomy. Br J Anaesth 2004; 93:799-805. 
13. White PF, Wang B, Tang J, Wender RH, Naruse R, Sloninsky A: The effect of intraoperative use of 
esmolol and nicardipine on recovery after ambulatory surgery. Anesth analg 2003; 97:1633-8. 
14. Ergıl J, Akelma FK, Özkan D, Aydin GB, Gürel A, Akinci M: Effects of pretreatment with esmolol 
and lidocaine on injection pain and rocuronium-induced withdrawal response. Turk J Med Sci 
2015; 45:959-63. 
15. Salman EA, Tıtız L, Akpek E, Arslan G: Pretreatment with a very low dose of intravenous esmolol 
reduces propofol injection pain. Agri 2013; 25:13-8. 
16. Miller DR, Martineau RJ, Wynands JE, Hill J: Bolus administration of esmolol for controlling the 
haemodynamic response to tracheal intubation: the Canadian multicentre trial. Can J Anaesth 
1991; 38:849-58. 
17. McCrirrick A, Hunter S: Pain on injection of propofol: the effect of injectate temperature. 
Anaesthesia 1990; 45:443-4. 
 
 

 
 
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Appendix 
Table 1. 
 
Pain score 
Degree of pain 
Response 
0 
None 
Negative response to questioning. 
1 
Mild 
Pain reported in response to questioning only, without any 
behavioral signs (withdrawal of extremity, grimacing, etc.) 
2 
Moderate 
Pain reported in response to questioning and accompanied by a 
behavioral sign OR pain reported spontaneously without 
questioning 
3 
Severe 
Strong vocal response OR spontaneous response accompanied by 
a behavioral sign 
 
 
 
 
Table 2. 
 
 
Esmolol 
Lidocaine 
Placebo 
Patients reporting pain 
2 
3 
5 
Total patients 
5 
5 
5 
Incidence of pain 
40% 
60% 
100%