LIMIT Trial - Lidocaine With Intramuscular Injection of Benzathine Penicillin G for Treponema Pallidum Treatment (LIMIT)

There is evidence to suggest that lidocaine can help reduce the pain associated with intramuscular injections of benzathine penicillin G (BPG) or Bicillin, used to treat syphilis infections. A study published in the Journal of Family Practice in 2001 compared the pain experienced during bicillin injections with and without the use of lidocaine. The study found that patients who received lidocaine injections before receiving bicillin reported significantly less pain compared to those who received bicillin injections without lidocaine. Per the International Union against Sexually Transmitted Infections (IUSTI) European Guidelines for syphilis management, lidocaine has been used as a diluent for BPG since 1998. In the United States (US), BPG often comes prepackaged and lidocaine is unable to be used as a diluent with the same ease as it is in Europe. In light of this, we propose a randomized controlled trial of benzathine penicillin G with and without lidocaine to quantify any site pain reduction with lidocaine in patients being treated for syphilis.

This study is a randomized, double blinded, placebo controlled trial. During this study, patients needing BPG treatment for syphilis will be screened for any penicillin allergies and consented to their participation. Each participant will receive 2 injections of BPG, 1.2 million units each (2x1.2 million units = 2.4 million units, the standard dose for syphilis treatment), as intramuscular injections, one in each gluteal muscle, with one of the injections randomly having 0.5ml of 1% lidocaine added while the other has 0.5 ml normal saline solution. The side of each injection will be randomized by the medical assistant (MA)/nurse filling the vials and the injecting MA will be blinded, as well as the study participant, as to which vial contains lidocaine and which contains normal saline. The participants will then be asked to rate their pain from 0-10 on each site of injection at 10 minutes post injection, then again at 24 hours after injection via email electronic survey (via RedCap). The differences in pain from the two injections will be compared and analyzed to see if lidocaine reduces pain associated with BPG injections compared to the control of normal saline added to BPG.

Study Overview

• Status: Not yet recruiting
• Conditions: Syphilis Infection; Benzathine Penicillin Adverse Reaction
• Intervention / Treatment: Drug: Lidocaine; Drug: normal Saline

Detailed Description

The purpose of the study is to test the question of: Does the addition of 0.5ml 1% lidocaine compared to 0.5 ml normal saline solution to 1.2 million units of benzathine penicillin G affect the pain experienced by individuals being treated for Treponema pallidum (syphilis) infections at 10 minutes and 24 hours post injection?

Background

Prior Literature and Studies, and Rationale for this Study

There is evidence to suggest that lidocaine can help reduce the pain associated with intramuscular injections of benzathine penicillin G or bicillin, used to treat syphilis infections. A study published in the Journal of Pediatric Infectious Diseases in 1998 found that the use of lidocaine as a diluent of BPG significantly reduced the pain of injection. Another study by Estrada et al in 2019 looked at the addition of 1% mepivicaine as diluent for PGB vs PGB alone and showed that mepivicaine significantly decreased pain experienced by participants. Per the IUSTI European Guidelines for Syphilis management, lidocaine is used as a diluent for benzathine penicillin G since 1998. No studies have been performed thus far looking at prefilled benzathine penicillin G syringes and the possibility of inserting lidocaine to the injection to decrease the pain experienced by individuals being treated for syphilis infections, instead of using lidocaine as a diluent which is not possible for the BPG formulations present here in the US.

Study Objectives

Primary Aim To see if there is any benefit of adding 0.5 ml 1% lidocaine to prepackaged Benzathine Penicillin G, with respect to pain, compared to standard of care, in the treatment of Treponema pallidum infections, both 10 minutes and 24 hours after injection.

Secondary Aim To see if there are any adverse effects of adding 0.5 ml 1% lidocaine to prepackaged Benzathine Penicillin G and to assess use of other pain medications 24 hours post injection.

Dose Rationale and Risk/Benefits Use of 0.5 ml 1% lidocaine was decided upon based off the size of the prefilled BPG syringe and the room for additional liquid within the syringe. 1% lidocaine is commonly used as a pain relief measure in clinical settings for injections and other procedures.

Overview or Design Summary This study is a double blinded randomized placebo control trial of addition of the effect on pain of the addition of 0.5ml 1% lidocaine solution to prepackaged benzathine Penicillin G injection, compared to addition of 0.5 ml normal saline solution, in adults being treated for syphilis (Treponema pallidum) infections, within the Infectious Diseases Clinic at Washington University in St. Louis.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Joseph Cherabie, MD; Phone Number: 7202858096; Email: jcherabie@wustl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Adults 18 years of age or above
• Confirmed syphilis diagnosis (reactive RPR with confirmatory treponemal testing)
• Receiving first injection in series if patient requires 3x weekly injections for syphilis treatment

Exclusion Criteria:

• Penicillin allergy (anaphylaxis)
• Lidocaine allergy (anaphylaxis)
• Second or third injection in series if patient requires 3x weekly injections for syphilis treatment
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lidocaine + Benzathine Penicillin G Arm; 0.5ml 1% lidocaine solution added to prefilled 1.2 million units Benzathine Pencillin G syringe which will be injected once into the gluteal muscle of the study participant, the side (left or right) to be randomly assigned with the control assigned to the other gluteal muscle.	Drug: Lidocaine; 0.5ml 1% lidocaine solution added to prefilled 1.2 million units Benzathine Pencillin G syringe
Placebo Comparator: Normal Saline + Benzthine Penicillin G Arm; 0.5ml normal saline solution added to prefilled 1.2 million units Benzathine Pencillin G syringe which will be injected once into the gluteal muscle of the study participant, the side (left or right) to be randomly assigned with the study arm assigned to the other gluteal muscle.	Drug: normal Saline; 0.5ml normal saline solution added to prefilled 1.2 million units Benzathine Pencillin G syringe

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Pain Score (0-10) of Benzathine Penicillin G + Lidocaine Injection 10 minutes post injection	The average rating of participants' injection site pain with added lidocaine from 0 (no pain) to 10 (extreme pain) at 10 minutes post injection	10 minutes
Mean Pain Score (0-10) of Benzathine Penicillin G + Saline Injection 10 minutes post injection	The average rating of participants' injection site pain with added lidocaine from 0 (no pain) to 10 (extreme pain) at 10 minutes post injection	10 minutes
Relative difference of mean pain scores between injection types 10 minutes post injection	Comparative t-test of means of pain scores at injections sites at 10 minutes post injection	10 minutes
Mean Pain Score (0-10) of Benzathine Penicillin G + Lidocaine Injection 24 hours post injection	The average rating of participants' injection site pain with added lidocaine from 0 (no pain) to 10 (extreme pain) at 24 hourspost injection	24 hours
Mean Pain Score (0-10) of Benzathine Penicillin G + Saline Injection 24 hours post injection	The average rating of participants' injection site pain with added lidocaine from 0 (no pain) to 10 (extreme pain) at 24 hours post injection	24 hours
Relative difference of mean pain scores between injection types at 24 hours post injection	Comparative t-test of means of pain scores at injections sites at 24 hours post injection	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Adverse reactions	To see if there are any adverse effects of adding 0.5 ml 1% lidocaine to prepackaged Benzathine Penicillin G	7 days
Rate of Use of other pain medications	To assess use of other pain medications 24 hours post injection.	24 hours

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

General Publications

• Amir J, Ginat S, Cohen YH, Marcus TE, Keller N, Varsano I. Lidocaine as a diluent for administration of benzathine penicillin G. Pediatr Infect Dis J. 1998 Oct;17(10):890-3. doi: 10.1097/00006454-199810000-00008.
• Janier M, Hegyi V, Dupin N, Unemo M, Tiplica GS, Potocnik M, French P, Patel R. 2014 European guideline on the management of syphilis. J Eur Acad Dermatol Venereol. 2014 Dec;28(12):1581-93. doi: 10.1111/jdv.12734. Epub 2014 Oct 27. Erratum In: J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1248. J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1248.
• Estrada V, Santiago E, Cabezas I, Cotano JL, Carrio JC, Fuentes-Ferrer M, Vera M, Ayerdi O, Rodriguez C, Lopez L, Cabello N, Nunez MJ, Puerta T, Sagastagoitia I, Del Romero J. Tolerability of IM penicillin G benzathine diluted or not with local anesthetics, or different gauge needles for syphilis treatment: a randomized clinical trial. BMC Infect Dis. 2019 Oct 23;19(1):883. doi: 10.1186/s12879-019-4490-5.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: March 20, 2024
• First Submitted That Met QC Criteria: April 27, 2024
• First Posted (Actual): April 30, 2024

Study Record Updates

• Last Update Posted (Actual): April 30, 2024
• Last Update Submitted That Met QC Criteria: April 27, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Lidocaine; Syphilis; Syphilis Treatment; Benzathine Penicillin G
• Additional Relevant MeSH Terms: Infections; Communicable Diseases; Sexually Transmitted Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Sexually Transmitted Diseases, Bacterial; Spirochaetales Infections; Urogenital Diseases; Genital Diseases; Syphilis; Treponemal Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Lidocaine
• Other Study ID Numbers: 202401099

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