Effects of botulinum toxin dilution with isolated lidocaine (without epinephrine) on injection pain and post-operative complications: pilot randomized clinical trial

Abstract

Introduction

Pain and complications of botulinum toxin injection are important deterrents that may reduce patient satisfaction. Toxin attenuation via lidocaine (with or without epinephrine) might alleviate pain. Except a recent study, no study has assessed the effects of the incorporation of lidocaine alone (without epinephrine/additives) to botulinum toxin.

Methods

This pilot multicenter double-blind randomized placebo-controlled clinical trial was performed on 102 patients randomly divided into two groups of experimental (lidocaine without epinephrine) or control (normal saline). Patients received 100 units of botulinum toxin. In the experimental group, botulinum toxin was diluted with 1 ml of 2 % lidocaine without adrenalin; in the placebo group, botulinum toxin was diluted with 1 ml of normal saline. Pain was assessed after injection using a 11-point numerical rating scale ‘0–10’. Post-injection complications were assessed 24 h later based on patients' reports and surgeons' observations. Data were analyzed using Student t-test and Fisher exact test (α = 0.05).

Results

The groups were balanced in terms of age and gender (P > 0.05). The mean (SD) pain levels in the placebo and lidocaine groups were 3.70 ± 2.05 and 3.39 ± 1.78, respectively (P = 0.310, t-test). Ptosis and diplopia were not observed in any groups. Asymmetry existed in 4 control subjects (8.7 %) and 5 experimental subjects (8.9 %) (P = 1.0, Fisher). In the control group, 12 patients needed retouch treatment (26.1 %); in the lidocaine group, 11 patients needed retouch therapy (19.6 %) (Fisher, P = 0.482).

Conclusions

Dilution of botulinum toxin with lidocaine might not reduce injection pain or alter the incidence of the assessed complications after 24 h.

1. Introduction

Given its nerve blocking effects, botulinum neurotoxin has been broadly used for treating several conditions such as blepharospasm, various pains, paralysis-induced facial asymmetry, strabismus, or temporomandibular disorders, among others.1, 2, 3, 4, 5 Botulinum toxin type A (BTX-A) has become relatively widespread in the world of cosmetics, because it has a low risk of consequences and it is minimally invasive.4, 5, 6 Botulinum toxin A is among the most used cosmetic treatments.^4,5,7

Nevertheless, there are issues with using botulinum toxin.⁸ Pain is the most frequent side effect that patients describe; it may discourage some patients from treatment.^4,9 Additionally, occasionally the neurotoxin may disseminate and inadvertently paralyze undesired muscles, leading to issues like ptosis.^4,5,8 The high vascularization of the often-injected regions —forehead, glabella, and the eyes—presents another difficulty, since the vascularization raises the possibility of neurotoxin washout at the regions being injected and unintentional toxin diffusion into other muscles.^4,5,10

Some researchers have proposed combining adrenalin-incorporated lidocaine with in the botulinum toxin to solve these issues.^5,10 After diluting BTX with lidocaine-adrenalin, the vasoconstrictor adrenalin may lessen the neurotoxin's propagation to undesirable muscles while also decreasing the washout of lidocaine and neurotoxin, while lidocaine may lessen the neurotoxin's pain.⁴ In this regard, a few very small studies exist with only one regarding pain; these include a clinical trial with 10 patients, a clinical trial with 15 patients, and two clinical series without control groups: The clinical studies generated controversy; one of them argued that neither the injection results nor the pain would be less predictable with this strategy; the other reported that by adding lidocaine and epinephrine, the impact would be felt right away, increasing predictability (they did not measure pain).^10,11 Only one of them studied pain.¹¹

Another significant clinical dilemma, nevertheless, is raised by the fact that if the vasoconstrictor adrenaline promotes predictability, then epinephrine's removal from lidocaine¹² may decrease predictability and cause the botulinum toxin to spread more widely than it should within the injection site.⁴ Clinical significance arises from the present suggestion by some dermatologists and surgeons that the integration of lidocaine may improve the duration or effectiveness of the effects of botulinum neurotoxin.^4,5 If so, would it be at the cost of less predictable results caused by the vasoactive effect of lidocaine without epinephrine? Without adrenaline, can iatrogenic effects appear? Furthermore, it's probable that in the absence of epinephrine, lidocaine rapidly leaves the region, attenuates below the effective dose, and loses its anesthetic properties. This is worth assessing since it has major clinical implications.⁴

This has not been assessed at all except our group's recent study.⁴ We investigated for the first time the effect of the dilution of BTX with lidocaine excluding epinephrine on pain intensity and post-operative complications.⁴ But there is no more study in this regard. Besides that, the literature on other aspects of botulinum pain is scarce as well. For example, the literature on the pain intensity of botulinum toxin diluted with lidocaine (either with or without epinephrine) is as well limited to our recent study only.⁴ The rest of the scarce literature is merely about attenuating BTX using epinephrine-included lidocaine, with two clinical trials as small as n = 10 or n = 15.^10,11

Due to the lack of any studies on isolated lidocaine (without epinephrine) at the time of conducting this study (2019–2020), and also due to the scarcity of the literature on lidocaine attenuation in general, and also because of the importance of the subject, this study was conducted. We aimed to test whether the addition of lidocaine excluding adrenalin to BTX-A can reduce the pain and post-operative complications. The null hypotheses were the absence of any pain-alleviating impact from lidocaine on injection pain or post-operative complications after the injection.

2. Materials and methods

This preliminary multicenter double-blind randomized placebo-controlled clinical trial was performed on 102 patients randomly divided into two groups of experiment (lidocaine without adrenalin) or placebo control (normal saline). It was a 2-arm trial with parallel arms and with a 1:1 allocation ratio. Included were all patients who had indications for botulinum toxin injection in the forehead area and had been referred to BouAli Hospital and a Tehran private clinic at the time of the examination (2019) and who did not have a previous unpleasant history and who had announced their written consent after explaining the study. All patients signed informed consent forms. The ethics of this study have been approved by the ethics committee and research committee (ethics code: IR.IAU.DENTAL.REC.1399.039). The sample of this preliminary study is not overlapped with any other studies. This article is prepared in accordance with CONSORT. The method was not changed after commencement.

2.1. Sample size

At the time of conducting this preliminary study, there was no study on pain intensity after botulinum injection without lidocaine. Thus, it was not possible to calculate any effect sizes. We aimed for about 100 patients as 6 to 10 times the only available clinical trials on botulinum plus lidocaine pain (with epinephrine, as there was no study on botulinum pain without epinephrine).^10,11 This size was split into 50 controls and 50 experimental subjects. In the case of drop-outs, we would add new randomly selected new patients (if available) to partially compensate for the loss of subjects. The final sample was 102 subjects: 46 controls and 56 lidocaine experiments.

2.2. Eligibility criteria and the sample

All patients who met the criteria for BTX-A injection in the forehead region, who were not previously known to have had an uncomfortable side effect after injection, and who had been sent to BouAli Hospital in Tehran and a private clinic at the time of the visit were included. Every individual required symmetric mimetic function of the forehead muscles. Individuals having a history of neuromuscular disorders or allergies to lidocaine or botulinum toxin type A would be excluded. Initially, all individuals with an unpleasant past (including allergies), eyelid ptosis, asymmetry in injection sites, or diplopia were excluded after filling out the patient file and obtaining a medical history. A specialized physician saw the patient to make the diagnosis of ptosis and asymmetry, while the patient's words were used to make the diagnosis of diplopia. To get the required sample size, new patients would take the place of the patients who were lost to follow-up.⁴

2.3. Randomization and blinding

Patients were randomly assigned to one of two groups. Computer software was used to randomly assign the participants. Because the trial was triple-blind, none of the participants, the surgeon, or the observer knew the materials' identity or grouping: The botulinum toxin's delivering surgeon was unaware of the experimental and placebo assignments. The grouping was also hidden from the observers and patients. Every document was coded and stored in a sealed envelope. The concealing was done by the same individual that carried out the randomization. She did not participate in any of the tests. Without being aware of the categorization, the blinded surgeon —who was the same for both groups— performed the injection and filled out the form.⁴ The contents of the vials in both groups were similar to each other.

2.4. Interventions

In both groups, all patients received the botulinum toxin type A manufactured by the Ipsen factory (France) under the brand name Dysport in vials of 500 units each. Each vial was used for 5 patients (100 units of BTX per patient), according to the manufacturer's instructions. In the experimental group, botulinum toxin dilution in each vial was carried out with 5 ml of 2 % lidocaine; in the control group, botulinum toxin within each vial was diluted with 5 ml of normal saline. Standardized method: An experienced technician diluted the botulinum toxin. A skilled surgeon administered injections while standing. This was deemed safe because, for the dilution with regular saline, we adhered precisely to the manufacturer's instructions, and because lidocaine has been shown to be safe in multiple prior studies when used alone or in combination with other materials.¹³ In every subgroup, a 29-gauge needle was utilized. A 9 % injectable solution of sodium chloride without any preservatives was used as normal saline in the placebo group, where botulinum toxin was diluted with it. The experimental group used a 2 % lidocaine solution with a preservative in order to dilute the botulinum toxin. At 20 sites, a skilled surgeon gave each patient a precise injection (5 units per site per individual, totaling 100 units in each person). These were common points that were safe and effective since they were advised in textbooks.¹⁴ They were: 1. The edge of the corrugator muscle; 2. The middle of the distance between the previous two points on the nose; 3. About 1 cm above the supraorbital notch; 4. About 1 cm above point #3 on each side, two new points were selected with equal distances on the frontal muscle; 5. About 1 cm above points #4 and between these points, three new points were selected with equal distances on the frontal muscle; 6. The eyebrow's tail; 7. The temporal line; 8. Two points were selected around the eye at the location of the orbicularis oculi muscle on the lateral rim of the eye (Fig. 1).⁴

Fig. 1.

A schematic figure showing the injection sites on the left side of the face. Except the points 2 and 5 which are located on the midline, the rest of points repeat on the right side. Injections points were: 1. The edge of the corrugator muscle; 2. The middle of the distance between the previous two points on the nose; 3. About 1 cm above the supraorbital notch; 4. About 1 cm above point #3 on each side, two new points were selected with equal distances on the frontal muscle; 5. About 1 cm above points #4 and between these points, three new points were selected with equal distances on the frontal muscle; 6. The eyebrow's tail; 7. The temporal line; 8. Two points were selected around the eye at the location of the orbicularis oculi muscle on the lateral rim of the eye.

2.5. Outcomes

The pain level was assessed by asking the patient immediately after injection (using 11-point numeric rating scale [0 as no pain to 10 as unbearable pain]). After 24 h, the following items were evaluated: ptosis (assessed by observation), asymmetry (examined by observation), diplopia (assessed by questioning the patient), and the need for retouch (expressed by patients as a need to revise, touch up, and repeat a part of the injections). Ptosis, which can affect one or both eyelids, is the term for drooping of the top eyelid. In the less severe type, drooping eyelids cover a portion of the pupil, lowering the upper visual amplitude. In the more severe version, drooping eyelids are above the pupil.¹⁵ Another eye complication linked to botulinum toxin injection is diplopia. When the lateral rectus muscle is paralyzed, extraocular muscular dysfunction occurs, leading to diplopia.¹⁵ After a frontalis muscle injection to address hyperkinetic forehead lines, eyebrow asymmetry can occasionally be observed in the upper face third near the tail of the eyebrows.^4,15

2.6. Statistical analysis

Descriptive statistics and 95 % confidence intervals (CI) were calculated for the groups. Data normality was checked and confirmed using the Kolmogorov-Smirnov test. The difference between pain levels of the groups was assessed using an independent-samples t-test, as this test is used to compare continuous variables between two groups. The groups were compared using a Fisher exact test in terms of the complications; this test is appropriate for comparing two groups in terms of dichotomous variables. The post hoc power was calculated for the tests. The programs in use were QuickCalcs (Graphpad, USA), and ClinCalc (ClinCalc LLC by Sean Kane, USA). The level of significance was set at 0.05.

3. Results

There was no missing data. There were 93 females and 9 males in the study: in the placebo group, there were 46 patients, i.e., 4 men and 42 women, while in the lidocaine group there were 56 patients, i.e., 5 men and 51 women (Fig. 2). According to the Fisher exact test, proportions of genders were similar in both groups (P = 1.0). Patients’ mean (SD) age in the control group was 42.86 ± 11.6; it was 45.39 ± 12.87 in the experimental group. According to the t-test, the difference between ages was not significant (P = 0.304). No harm was identified with this research. The trial ended when it reached the desired sample size. The experiments were done in 2019–2020. All randomized patients were included in the final analysis.

Fig. 2.

The flow diagram of patients.

The mean (SD) pain levels in the control and lidocaine groups were 3.70 ± 2.05 (95 % CI: 3.108–4.292) and 3.39 ± 1.78 (95 % CI: 2.924–3.856), respectively (Table 1). The difference between the groups was insignificant (P = 0.310, t-test, post hoc power = 12.5 %). Ptosis was not observed in any groups. Similarly, diplopia was not seen in any patients in either group. Asymmetry existed in 4 control subjects (8.7 %) and 5 experimental subjects (8.9 %). The difference was not significant (P = 1.0, Fisher exact test, post hoc power = 4.1 %). In the control group, 12 patients needed retouch treatment (26.1 %) and in the lidocaine group, 11 patients needed retouch therapy (19.6 %). The difference between the groups was not significant (Fisher exact test, P = 0.482, post hoc power = 3.6 %, Table 1).

Table 1.

Descriptive statistics for study outcomes. The P values are calculated using the t-test and Fisher test.

Group	N	Pain	Asymmetry	Retouch	Ptosis	Diplopia
BTX	56	3.39 ± 1.78	5	11	0	0
Placebo	46	3.70 ± 2.05	4	12	0	0
	P value	0.310	1.0	0.482	–	–

4. Discussion

The findings of this study might indicate that the addition of lidocaine to botulinum toxin might not significantly reduce pain or any complications of injection. This should be approached with caution due to the observed low post hoc power. Nevertheless, it should be noted that such a low post hoc power may not be necessarily and always due to methodological shortcomings like small samples. In the present study, the sample was rather large; it seems that the low post hoc power stemmed from a very close similarity of pain levels in both groups. The computed confidence intervals confirmed this by showing a high degree of overlap between the groups, suggesting some degree of certainty in the result. In any case, even if a difference was to be detected statistically, for instance by increasing the sample size, that difference might still be clinically negligible. In 2023, Sarkarat et al.⁴ compared epinephrine-less lidocaine versus placebo and observed a significant reduction in pain. According to them, the overall difference between the groups was about 6.4 %, as the pain level perceived by the lidocaine group was 3.51 ± 2.04, while it was 4.15 ± 2.35 in the placebo group.⁴ The reason might root in methodological differences as the sample size of the study by Sarkarat et al.⁴ was larger than the current study (which is large as well), allowing the other study to detect smaller differences. Not to mention that in their study as well, the extent of the statistically significant difference was clinically negligible and rather similar to that observed in the present study, which was 3.1 %. It should be noted that statistical significance aside, the extent of pain reduction was clinically negligible in both studies, because the minimum clinically important difference for pain relief is about 20 %, i.e., about 20 % reduction in pain is necessary for the pain alleviation to be perceived as beneficial.¹⁶ A recent retrospective study evaluated the effects of BTX and its dilution (with lidocaine [without epinephrine] versus normal saline) on injection pain and also on the reduction of myofascial pain by BTX.¹⁷ During injection, the average pain level was 4.59 ± 1.64 in the lidocaine group, while it was 3.15 ± 2.32 in the normal saline group. In other words, BTX diluted with normal saline reduced pain more than lidocaine.¹⁷ Although the difference between the pains in their 2 groups was significant, that difference was clinically negligible as well, because it was way below a minimum of 20 % pain reduction necessary for being clinically meaningful.¹⁶

There is almost no other study in this regard. Therefore, we are limited to discussing more general aspects of our findings. There are 2 clinical series and 2 controversial clinical trial studies on the effects of dilution of botulinum toxin with the combination of lidocaine and epinephrine.^5,10,11,18 There were two clinical series with no control groups, a clinical study with 10 patients focused just on complications and not pain, and a clinical trial with 15 patients focused exclusively on pain occurrence and not its intensity.^5,10,11,18 Only one clinical investigation¹¹ had looked at pain occurrence (but not severity), and the trials included as few as 10 or 15 people.^10,11 Both before-after case series that lacked control groups came to the same conclusion: using this strategy would yield adequate outcomes.^5,18 However, the absence of a control group made their results questionable in terms of placebo effects or the extent of efficacy of lidocaine-epinephrine administration. As for the randomized clinical trials, de Quadros et al.¹¹ randomly assigned the facial sides of 15 patients to receive BTX attenuated with adrenalin and lidocaine or diluted with normal saline. In their research, 8 patients (53.3 %) reported pain on the placebo side, while 3 patients (20.0 %) mentioned pain on the adrenalin-lidocaine side.⁴

According to Ravso and Bove¹⁸ who did not include any control groups in their series of cases involving the injection of lidocaine with epinephrine and botulinum toxin, the addition of lidocaine may help to prevent unsatisfactory outcomes after the injection of botulinum toxin. Another case series research by Kim et al.⁵ suggested that dilution of botulinum toxin with adrenaline and lidocaine might enhance patient satisfaction with facial rejuvenation injections because of longer duration of benefits, quicker outcomes, less discomfort and bruising, and enhanced appearance. Additionally, despite a noticeable difference observed in the first 48 h by de Quadros et al.,¹¹ they were unable to demonstrate any statistically significant differences in the frequency of muscle paralysis or symmetry between the placebo side versus the adrenalin-lidocaine side.¹¹ The effects of adding adrenaline and lidocaine to BTX on the predictability of BTX injection in ten individuals were evaluated by Gassner and Sherris.¹⁰ According to their findings, adding lidocaine together with adrenalin might enhance the safety and predictability of BTX by giving the doctor instant feedback on the degree of paralysis.¹⁰ Sarkarat et al.⁴ evaluated post-injection complications and reported BTX might does not influence the postinjection complications examined 2 weeks after injection.⁴ Their results were in line with the present study.

Pain is experienced at two stages of BTX injection: initially, when the needle perforates the skin and surrounding tissues, and then again once the neurotoxin is delivered into the tissue. By topically anesthetizing the area with cold packs or eutectic combination of local anesthetics (EMLA) cream,¹⁹ needle discomfort can be reduced.⁴ Anesthetics like lidocaine can lessen the discomfort brought on by the neurotoxin's release into the tissues. Nevertheless, the incorporation of lidocaine does not lessen the discomfort of the needle.⁴ Consequently, it is advised to lessen discomfort throughout both the early and late stages in therapeutic settings.⁴ Since pain appears to be localized largely on the skin, injection method and needle gauge may have an impact. This may explain why pain may be identical when administered by the same individual using the same technique. However, further research is required to validate this theorem.⁴ There's also the proposal that lidocaine may exacerbate pain by causing burning sensations.²⁰ Such an effect may confound the results and also correspond to the small difference observed between groups that did not pass the level of significance within the current study, possibly needing larger samples and more powerful analyses to capture the difference, like in our previous study.⁴ However, However, by numbing the muscle and boosting blood flow, lidocaine is thought to hasten the effect of botulinum by enabling the muscle to take in more of the substance.⁴ Further investigation is also required to test this hypothesis.

This pilot study had some strengths: it had a relatively large sample size, benefited from a triple-blind multi-center randomized trial design, and evaluated a novel question. Further, the design aligns with routine clinical practice or cosmetic protocols because the BTX application protocol used in the current study was similar to the protocol routinely followed clinically.

There were limitations as well. The sample size was not based on power calculations. Still, this sample size of 102 patients was about 6–10 times larger than the clinical trials on botulinum pain (with sizes of 10 or 15 patients) that were conducted before it, not to mention that this study was novel because those previous ones were merely on lidocaine plus epinephrine. The post hoc powers were low, necessitating the interpretation of the findings with caution. Nevertheless, based on the observed 95 % CIs, these low powers seemed to be primarily due to the close similarities of outcomes in both groups and not because of methodological shortcomings. This implies that the findings might be trusted as a small and perhaps clinically negligible differences between the groups.

An important limitation was not excluding participants with a previous history of BTX injection (or any other injection for that matter), which might act as a confounding factor. Although we did check their history for such injections, a history of previous BTX injections was not an exclusion criterion. This was done to improve the sample size. Nevertheless, it can also confound the results because patients with a previous history of injections, especially BTX injections, can expect some level of pain and/or complications, and such expectations may introduce bias to the study. Nonetheless, randomizing the patients might have reduce this confounding factor to some extent. As another limitation, it might be argued that pain assessment could have been repeated over time, for example once immediately after injection and once again after 24 h. Nevertheless, injection pain wanes off after a short time, and therefore, it was not very practical or useful to measure it in multiple sessions over time. The 24h follow-up window was too short for the assessment of complications. Another limitation was the lack of a positive control group. Future studies should also include a third group, a positive control which should be the dilution of BTX with lidocaine together with epinephrine.

The generalizability of our findings was limited to the ethnicity of the patients as well as the brand of BTX in use and the number of women enrolled which was much larger than the number of men. Women outnumbered men in this study, since our sample reflected the real population in which women are much more prone than men to seek BTX treatment. Another factor that can affect generalizability is the chief complaints of patients; we enrolled patients regardless of their chief complaints being cosmetic or therapeutic reasons.

5. Conclusions

Within the limitations of this pilot study, it might be concluded that the addition of lidocaine without epinephrine to botulinum toxin might not significantly reduce BTX injection pain or alter the incidence of any of the post-injection complications assessed after 24 h: ptosis, asymmetry, diplopia, and the need for retouch.

Patient consent

All patients signed informed consent forms. The ethics of this study have been approved by the ethics committee and research committee (ethics code: IR.IAU.DENTAL.REC.1399.039).

Ethics approval and consent to participate

The participants were briefed completely before the study and signed written informed consents. The ethics of this study were approved by the research committee of the Islamic Azad University (ethics code: IR.IAU.DENTAL.REC.1399.039) in accordance with the Helsinki declaration.

Consent for publication

This paper does not include any images of participants.

Availability of data

The data are not available.

Author contributions

Farzin Sarkarat searched the literature, conceived and designed the study, collected the sample and performed all the injections and post-operative assessments, interpreted the findings, and supervised the thesis. Marzie Naeini searched the literature, performed the evaluations, interpreted the findings, and wrote the thesis. Roozbeh Kahali and Mehdi Sezavar searched the literature, supervised the thesis, interpreted the findings, and critically reviewed the thesis. Vahid Rakhshan searched the literature, performed the statistics, interpreted the findings, prepared the figures, drafted and revised the article, and responded to the reviewers. All authors reviewed the final version and agreed to submit the paper to this journal.

Funding

The study was self-funded by the authors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.