Utility of lidocaine in reducing pain of intramuscular benzathine penicillin G in children with rheumatic heart disease: A randomized, double-blind crossover study

ABSTRACT

Background:

The current recommended secondary prevention of rheumatic fever (RF)/rheumatic heart disease (RHD) includes every 21–28 days injection of benzathine penicillin G (BPG), which causes pain. We evaluated the effect of the coadministration of lidocaine on reducing the pain of BPG injections in children with RF/RHD.

Patients and Methods:

Children aged 7–18 years who received BPG were eligible for a randomized crossover study. Participants received a secondary prophylaxis dose of intramuscular (IM) BPG with and without additional lidocaine as a diluent (0.2–0.4 mg/kg) and were randomized to the intervention (as a sequence). Participants and staff completing the evaluation were blinded to the sequence. Pain scales were assessed by participants using a Visual Analog Scale (VAS) and staff using the Wong–Baker Faces Pain Scale (WBFPS) at 5 and 60 min after injection.

Results:

Forty-two children were included in the study. Both lidocaine and aquadest sterile water groups were well matched in baseline characteristics. The pain scores at 5 min after BPG injection were lower when lidocaine was coadministrated: 2 (min–max 1–9) in lidocaine versus 5 (min–max 1–9) in sterile water (P = 0.001) using VAS score and 2 (min–max 0–10) in lidocaine versus 4 (1–8) in sterile water (P = 0.002) using WBFPS. Scores at 60 min after BPG injection showed no differences between treatments with P = 0.551 and P = 0.167, respectively, using VAS and WBFPS. No adverse event was observed.

Conclusion:

The coadministration of lidocaine as diluent resulted in reduced pain 5 min after IM injection of BPG.

INTRODUCTION

Lack of compliance with secondary prevention is a risk factor for recurrent attacks of rheumatic fever (RF) or rheumatic heart disease (RHD).[1] The mortality risk is higher in patients with recurrent attacks. Secondary prevention using penicillin prophylaxis and managing streptococcal pharyngitis play an important role. RF and/or RHD as secondary prophylaxis in children using intramuscular (IM) injection of benzathine penicillin G (BPG) presents a significant challenge due to the pain caused during IM injection every 3 or 4 weeks. Patient compliance and comfort are needed for the success of secondary prophylaxis therapy.[2]

The pain induced by IM injection causes both physical and psychological problems. Patients experience significant discomfort and pain during and after an IM injection, with approximately 40% of patients reporting severe pain.[3] The mean pain intensity of patients receiving BPG IM injections was interpreted as severe using the Visual Analog Scale (VAS) with a score of 7.4 from 10.[4] Reducing pain during BPG can also be done in various ways, including the use of 23-size needle, warming the syringe to room temperature, waiting for the alcohol to dry before injection, applying pressure with the thumb for 10 s before inserting the needle to prevent drug leakage so that the drug does not enter the subcutaneous tissue which can cause pain, giving injections slowly at a rate of 10 s/mL (over 2–3 min), distracting the patient during injection and an injection angle of 90°,[5] and lidocaine hydrochloride 1% as a diluent.[4,6] About 71% of patients preferred to use local anesthesia to reduce pain in IM BPG; fear before IM BPG injection was reduced by 50% after using local anesthesia, and fear of seeking medical help was reduced by 30% of lidocaine as a diluent does not affect the pharmacokinetic effects of BPG, penicillin, or cephalosporins.[4,7,8,9] Our study aims to investigate the efficacy and safety of lidocaine as a diluent for BPG injection to reduce pain in patients with RF or RHD.

PATIENTS AND METHODS

Study design

This study was conducted as a randomized, double-blind clinical trial crossover design at Prof. Dr. I G.N.G. Ngoerah General Hospital, Bali, Indonesia, over 7-month periods from April to December 2023. Three weeks later, the crossover was done as a standard BPG injection after the washout period. The protocol for this study was approved by the ethical committee of the Medical Faculty of Universitas Udayana (Number: 1309/UN14.2.2.VII.14/LT/2023) and approved by Prof. Dr. I G.N.G. Ngoerah Denpasar Review Board (No: DP. 04.03/D.XVII.22.2/28458/2023).

Participants

The patients were recruited from an outpatient cardiology clinic with the diagnosis of RF or RHD based on clinical, echocardiography, and serology, consistent with local and international guidelines. The inclusion criteria were patients on regular BPG injection and those aged ≥7–18 years old. Exclusion criteria were penicillin allergy, lidocaine allergy, mental retardation to avoid wrong pain assessment, and a pain scale ≥4 in the beginning. Informed consent was obtained from all patients, parents, or relatives. Patients developing allergic reactions after BPG injection, stopping the intervention before reporting VAS and WBPFS or dying, were considered to have dropped out of the study. A sample size of 42 is primarily based on the expected number.

The 42 participants were randomized using block randomization with a block size of six. A research assistant used a computer system to do the randomization, and the random code was stored in an envelope and opened after the study was completed. Both clinicians and participants were blinded to the contents of the syringe; only the nursing staff would know which syringe contained lidocaine and which contained sterile water. The consort flow diagram of the study is presented in Figure 1.

Figure 1.

Flow diagram of the study with crossover after 3 weeks of the first sequel. VAS: Visual Analog Scale, WBFPS: Wong–Baker Faces Pain Scale

Intervention

Each participant received two treatments, each on a single occasion, and then, after 3 weeks, received another arm of intervention. In treatment A, BPG was administered without lidocaine; in treatment B, BPG was administered with lidocaine. Participants were randomly allocated 1:1 to receive treatment A or B first (sequence 1 or sequence 2, respectively). The treatment received 600,000 U or 1,200,000 U of BPG (according to body weight) diluted in sterile water until 7 mL in a 10 mL syringe for the first treatment and then draw up 0.25 mL of lidocaine hydrochloride 2% into the tip of 10 mL syringe for next 3 weeks on the second treatment. The injections were given intramuscularly in the gluteus muscle. The other group received the same regimen, syringe, 21 Gauge, pressure, and technique injection, and only one nurse in charge who was responsible for the injection was aware of this randomization.

Outcomes

The primary objective of the study was to determine whether IM injection affected local pain 5 min and 60 min after injection; patients indicated the intensity of pain on a VAS [Figure 2] reported by them, and an investigator evaluated the WBPFS [Figure 3], enumerated from 0 (no pain) to 10 (maximum pain) just after IM injection.

Figure 2.

Visual Analog Scale

Figure 3.

Wong–Baker Faces Pain Scale

Statistical analysis

The data were analyzed using Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL, USA) version 18. Categorical data are reported as numbers and percentages, and continuous data are reported as mean plus/minus standard deviation (SD). The Wilcoxon test was used to compare the pain score between two diluent formulations and 5 and 60 min after IM BPG injection. Multivariate analysis of covariance test was used for multivariate analysis. P < 0.05 was considered statistically significant for all tests. The suitability test between VAS and Wong–Baker Faces Pain Scale (WBFPS) using the Bland–Altman test. The frequency distribution summarized the safety profile of lidocaine.

RESULTS

Forty-three patients were recruited, and 42 participated in the study. One patient was excluded because of mental retardation [Figure 1], but no dropout was reported. Patient characteristics are shown in Table 1. In summary, treatment duration and body weight between groups were different.

Table 1.

Baseline clinical characteristics of the study population before conducting the crossover

Variables	Lidocaine diluent (n=21), n (%)	Sterile water diluent (n=21), n (%)
Age (years), mean (SD)	12.4 (3.4)	12.3 (2.8)
Sex (boys)	13 (46.4)	15 (53.6)
Body weight (kg), median (minimum–maximum)	45 (20–128)	39.5 (26–92)
History BPG injection (yes)	20 (57.1)	15 (42.9)
Duration of previous BPG injection (months), median (minimum–maximum)	24 (0–72)	5 (0–55)
Nutrition status
Normal-weight	12 (52.2)	11 (47.8)
Underweight	2 (40)	3 (60)
Overweight/obese	7 (50)	7 (50)
Baseline VAS, mean (SD)	0	0
Baseline Wong–Baker score, mean (SD)	0	0

VAS: Visual Analog Scale, SD: Standard deviation, BPG: Benzathine penicillin G

The Bland–Altman test, between the VAS, conducted by patients, and WBFPC, which the investigator conducted, was not significantly different, with a mean difference of 0.310 (SD 1.448) confidence interval 95% −2.528–3.147. The normality test was performed, and VAS and WBFPS scores were not normally distributed; hence, the score was displayed as the median. Wilcoxon analysis was carried out in the lidocaine and sterile water diluent groups. The administration of lidocaine diluent was associated with a significant immediate reduction of pain in 5 min after BPG injection (VAS P = 0.001 and WBPFS P = 0.002). Meanwhile, the pain at 60 min showed no significant difference (VAS and WBFPS were P > 0.05), as shown in Table 2.

Table 2.

Analysis bivariate analysis of Visual Analog Scale and Wong-Baker Faces Pain Scale score after benzathine penicillin G injection

Scores	Lidocaine diluent	Sterile water diluent	P
VAS after 5-min, median (minimum–maximum)	2 (1–9)	5 (1–9)	0.001
WBFPS after 5-min, median (minimum–maximum)	2 (0–10)	4 (1–8)	0.002
VAS after 60-min, median (minimum–maximum)	0 (0–6)	0 (0–9)	0.551
WBFPS after 60-min, median (minimum–maximum)	0 (0–6)	0 (0–6)	0.167

VAS: Visual Analog Scale, WBFPS: Wong–Baker Faces Pain Scale

A multivariate analysis was conducted using the multivariate analysis of covariance test; lidocaine, as the diluent after being controlled, was found to reduce pain at 5 min significantly (VAS P < 0.001 and WBFPS P = 0.003), whereas body weight and duration of previous BPG injection had P > 0.05 for both VAS and WBPFS, the results are shown in Table 3.

Table 3.

Multivariate analysis of pain score after 5-min injection

Variables	VAS (P)	WBFPS (P)
Lidocaine	<0.001	0.003
Body weight	0.560	0.074
Duration of previous BPG injection	0.394	0.178

VAS: Visual Analog Scale, WBFPS: Wong-Baker Faces Pain Scale, BPG: Benzathine penicillin G

Side effects were assessed immediately up to 1 h after injection. There were no side effects, including redness, itching, bleeding, swelling, burning at the injection site, or allergic reactions.

DISCUSSION

Long-term treatment with penicillin is recommended to prevent infection with Group A Streptococcus. Therefore, adherence to 3- or 4-weekly BPG injections is critical to prevent rapid disease progression. Noncompliance to IM BPG injections is often due to painful injections and associated allergic reactions.[10] The mean pain intensity of patients receiving BPG IM injection was classified as severe using a VAS with a score of 7.4/10.[4] Similarly, our study found moderate-intensity pain in the group that received only sterile water diluent with a median VAS score of 5 (range 1–9) and WBFPS of 4 (range 1–8).

We identified that there was no difference in several factors that influence pain between the two groups, which were the proportion of age, sex, and previous pain experience; these characteristics are similar to other studies.[11,12,13] In this study, we performed identical methods to reduce pain during BPG injection in two groups which were the use of 21 gauge needles, warming the syringe to room temperature, waiting for alcohol to dry before injection, applying pressure with the thumb for 10 s before inserting the needle, giving injections slowly at a rate of 10 s/mL (over 2–3 min), distracting the patient during injection (with conversation) and the angle of injection when making IM injections, an angle of 90° while injection.[5] In this study, we used the abovementioned techniques in addition to lidocaine solvent. Meanwhile, our research found a significant difference in the duration of previous treatment between the two groups, and these findings were analyzed.

The severity of pain after the administration of BPG IM injection may reduce compliance with treatment; thus, improvements in tolerability might reduce the recurrent attacks. Our study showed differences in pain perception in the coadministration lidocaine and sterile water diluent groups based on VAS and WBFPS scores 5 min after BPG injection. Factors affecting pain perception, such as body weight and previous duration of BPG injection, were analyzed, and it was shown that only coadministration of lidocaine 2% diluent reduced the pain severity after BPG injection. Several studies have been conducted to reduce pain by stimulating nonnociceptive nerves. Research using 1% lidocaine hydrochloride as a solvent was shown to reduce the pain scale in BPG IM injection. There was no significant difference in serum penicillin levels using lidocaine solvent.[4,6] Research conducted to reduce pain in BPG injections in RF suggested that about 71% of patients preferred to use local anesthesia to reduce pain in IM BPG therapy; fear before IM BPG injection was reduced by 50% after using local anesthesia and fear of seeking medical help, was reduced by 30%.[7]

Lidocaine is physically or chemically similar to penicillin. The effect of lidocaine as a diluent does not affect the pharmacokinetic impact of BPG or other cephalosporins. Still, relatively, the intensity and frequency of pain at the injection site are reduced by lidocaine administration.[4,6,8,9] Lidocaine is physically and chemically compatible with penicillin.[4] We found no local side effects and toxicity of lidocaine related to coadministration of lidocaine, including redness of the skin at the injection site, itching, bleeding, and swelling at the injection site. The lidocaine used was 0.25 mL of lidocaine hydrochloride 2%, which is equivalent to 32 mg of lidocaine, which is lower than the maximum dose.[14] However, a limitation of our study is that it did not evaluate the pharmacokinetics of BPG in coadministration with lidocaine 2%.

CONCLUSIONS

The coadministration of lidocaine as diluent resulted in reduced pain intensity 5 min after injection of BPG IM without adverse events.

Conflicts of interest

The authors declare no competing interests. The drugs used (lidocaine, BPG, sterile water) were generic and standard from the hospital.

Funding Statement

This work received internal funding from Prof. Dr. I G.N.G. Ngoerah Hospital.