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Abstract

PURPOSE:

To evaluate variables that modulate pain during intramuscular botulinum toxin A injections in children.

METHODS:

As part of a Quality Improvement project, this retrospective analysis compared reported pain during and five minutes post injections with patient and procedural variables using subgroup and regression analyses ( $N=$ 593 procedures with 249 unique patients).

RESULTS:

Mean procedural pain for all procedures ( $n=$ 563) was 3.8 $\pm$ 3.0. Most children reported no pain (83.8%) or mild pain (12.1%) five minutes after the procedure. Provider, previous patient experience, and dose did not significantly impact pain. Linear regression analysis (R ${}^{2}=$ 0.64) demonstrated that younger age ( $p<$ 0.05), use of vapo-coolant spray or topical anesthetic ( $p<$ 0.01), and body region injected ( $p<$ 0.01) were significantly associated with increased procedural pain. Logistic regression (R ${}^{2}=$ 0.14) demonstrated that pain during the procedure ( $p<$ 0.001) and older age ( $p<$ 0.01) increased the likelihood of pain post-procedure. Utilization of personnel for distraction did not significantly predict pain ratings at either time point.

CONCLUSION:

Age, topical anesthesia, and injected region impact procedural pain and in nearly 96% of cases, patients report mild or no pain within five minutes. Additional research into these predictors is necessary, but short-lived procedural pain may suggest that frequent use of sedation/anesthesia is unnecessary.

Keywords

Botulinum toxin pain spasticity pediatrics chemoneurolysis

1. Introduction

Since the initial report of successful use in 1993, intramuscular botulinum toxin injections have become common and effective procedures for management of limb and axial spasticity in children [1]. The typical therapeutic effect of the botulinum toxin A (BoNT-A) is 3–6 months, therefore patients often undergo repeated procedures [2]. Clinical practice includes wide variations of injection style, procedural sedation/general anesthesia (which carries risks for increased morbidity and adds cost), topical anesthetic, and distraction techniques [3, 4, 5, 6]. No information is published analyzing the impact that procedural factors have on pain in this population. The goal of this retrospective analysis was to identify factors that could be targeted to reduce procedural pain as part of a larger quality improvement project.

2. Methods

A retrospective chart review was conducted of patients who received BoNT-A injections during a two-and-a-half-year period between 2014 and 2016 ( $N=$ 593 procedures with 249 unique patients). The population underwent first time and repeat procedures under the care of five different attending physicians in a designated procedure room with guardians present. EMG and anatomic landmarks were the primary means of localization. One provider (44% of procedures) has a technique utilizing local intramuscular redirection at each cutaneous site. Procedures completed concurrently with salivary gland BoNT-A injections, imaging, or other invasive procedures while under general anesthesia ( $n=$ 30) were excluded from the final analysis. In 2014, it became standard practice of the department to record peri-procedural pain ratings as part of the division’s quality improvement project to reduce pain associated with in-office procedures. If the patient was cognitively capable, a clinical nurse obtained a rating of pain experienced during the procedure and five minutes post-procedure using a 1–10 numerical rating scale with faces. If the patient was unable to give a report, the parent was asked to provide a proxy rating of the patient’s pain at these time points. Data were examined at both the patient and procedure level to determine the appropriate analytical approach.

Average and median pain ratings during the procedure and post-procedure were calculated. In addition, changes in pain between during- and post- procedures were examined. Pre-existing differences in pain ratings and age between subgroups of patients were compared using t-tests (alpha $=$ 0.05). Subgroups of interest included: age, attending physician versus trainees performing procedure, repeat versus first procedure for the patient, use of vapo-coolant spray/topical anesthetics, and presence of Child Life specialists for distraction.

Exploratory regression models were calculated to determine potential predictors of pain, which included age, repeat procedure, presence of Child Life, use of either vapo-coolant spray or topical lidocaine/prilocaine cream, number of injection sites and region(s) of the body injected (leg, thigh, arm, hand and axial). Pain during the procedure was treated as a continuous variable and a multiple linear regression was conducted [7]. Pain was further classified as absent (rating of 0), mild (ratings of 1–3), moderate (ratings 4–7) and severe (ratings 8–10) [8, 9]. Post-procedural pain scores were dichotomized into pain (any score $\geqslant$ 1) versus no pain (a score of 0), due to the small frequency of patients experiencing mild/moderate/severe pain, and a logistic regression was employed.

3. Results

All procedures undergoing final analysis ( $n=$ 563) were treated as unique data points, as there was more variability at the procedure level than at the subject level (design effect $=$ 1.4). Most of these children were diagnosed with cerebral palsy ( $n=$ 189), while the remaining 60 had a variety of other neurological and musculoskeletal conditions. Patient demographics and procedural characteristics are outlined in Table 1.

Table 1
Patient demographics and procedural characteristics

Total procedures	563
Unique patients	249
Gender
Male	305 (54.2%)
Female	258 (45.8%)
Age, years
Median	8
Mean	9.2 $\pm$ 5.6
Repeat procedures	362 (64.3%)
Unique diagnoses of cerebral palsy	189 (75.9%)
Child Life	376 (66.8%)
Any anesthetic	509 (90.4%)
Dose
Total units, mean	170.3 $\pm$ 119.9
Units per kg, mean	6.8 $\pm$ 4.3
Units per kg, range	0.3–21.3
Total number of injections	1021
Mean injections per procedure	4 $\pm$ 2.3
Site of injections
Leg	370 (36.2%)
Thigh	322 (31.5%)
Arm	180 (17.6%)
Hand	73 (7.1%)
Axial	76 (7.4%)

Procedural pain ratings were reported in the moderate range for 33% of cases and severe for 12% of cases (Fig. 1). However, the vast majority of children had either no pain (83.8%) or mild pain (12.1%) five minutes after the procedure. For all procedures, mean pain during the procedure was 3.8 (sd $=$ 3) while mean post-procedure pain was 0.5 (sd $=$ 1.3). Subgroup analysis is shown in Table 2. There were no significant differences in pain when a trainee (resident or fellow) performed the injections compared with an attending physician. There also were no differences in pain for novel versus repeat procedural experiences. Children who had Child Life specialists present had similar pain ratings during injection compared to children who did not have Child Life specialists present, and were significantly younger, 8.1 compared to 11.3 years old. When Child Life specialists were present, post-procedure pain ratings were significantly lower and the decrement in pain ratings from during- to post- procedure was significantly greater.

Table 2

Procedural pain ratings across intervention subgroups

	N	Pain during	Pain after	Change in pain ( $\Delta$ )	Age (yrs)
		Mean $\pm$ SD	Mean $\pm$ SD	Mean $\pm$ SD	Mean $\pm$ SD
Total	563	3.8 $\pm$ 3.0	0.5 $\pm$ 1.3	3 $\pm$ 2.8	9.2 $\pm$ 5.5
Trainee injected	105	4.0 $\pm$ 2.8	0.6 $\pm$ 1.4	3.4 $\pm$ 2.7	9.3 $\pm$ 5.4
No trainee	458	3.8 $\pm$ 3.0	0.4 $\pm$ 1.3	3.3 $\pm$ 2.8	9.2 $\pm$ 5.6
First time injection	201	3.7 $\pm$ 2.8	0.4 $\pm$ 1.2	3.2 $\pm$ 2.7	9.2 $\pm$ 5.8
Repeat injection	362	3.9 $\pm$ 3.0	0.5 $\pm$ 1.4	3.4 $\pm$ 2.9	9.2 $\pm$ 5.4
Child Life	377	3.9 $\pm$ 3.0	0.4 $\pm$ 1.0*	3.6 $\pm$ 2.8**	8.1 $\pm$ 4.9**
No Child Life	187	3.6 $\pm$ 2.9	0.7 $\pm$ 1.8	2.9 $\pm$ 2.7	11.3 $\pm$ 6.1
Vapo-coolant	503	3.9 $\pm$ 3.0*	0.5 $\pm$ 1.3	3.4 $\pm$ 2.8*	9.2 $\pm$ 5.5
No vapo-coolant	60	3.1 $\pm$ 2.7	0.3 $\pm$ 1.3	2.8 $\pm$ 2.5	9.4 $\pm$ 6.2
Topical anesthetic	11	4.8 $\pm$ 3.2	1.1 $\pm$ 2.4	3.7 $\pm$ 2.5	9.6 $\pm$ 6.9
Oral sedative	6	5.5 $\pm$ 3.8	0 $\pm$ 0	5.5 $\pm$ 3.8	8.7 $\pm$ 5.3

${}^{*}$ significant at the 0.05 level, ${}^{**}$ significant at the 0.001 level. Average reported pain values by subgroup. P-values represent comparison of means between the variable groups using Student’s T-test.

Figure 1.

Change in pain ratings following injection. Distribution of pain ratings during and post-procedure. Graphs B-D represent the distribution of post-procedure pain for each respective subgroup of absent, mild, moderate, and severe procedural pain.

Regression analyses of procedural pain ratings at both time points are shown in Table 3. The model explained about 64% of overall variance in pain scores. Injections into the leg, thigh and hand were positively associated with procedural pain, as was the use of any topical anesthetic. Age was negatively related such that reports of pain were lower among older children. A logistic regression was performed to determine significant predictors of the likelihood of post-procedural pain (no pain versus any pain $\geqslant$ 1). The logistic regression model was statistically significant, $\chi^{2}(12)=$ 90.3, $p<$ 0.001, explained 25.3% (Nagelkerke r-square) of the variance in post-procedural pain, and correctly predicted approximately 84% of the sample. Increasing pain during the procedure was associated with an increase in likelihood of reporting pain post-procedure. Age was also positively associated with the likelihood of experiencing pain after the procedure, which was opposite of the relationship found between age and pain during the procedure (Table 3). The remaining variables were not significantly associated with pain ratings.

Table 3

Factors predicting pain during and after BoNT-A injections

Predictors of pain during procedure	Coefficients		95% CI
Gender	0.	05	( $-$ 0.42, 0.52)
Age	$-$ 0.	05 ${}^{*}$	( $-$ 0.10, $-$ 0.004)
Repeat procedure	0.	46	( $-$ 0.04, 0.96)
Child Life	0.	10	( $-$ 0.41, 0.61)
Any anesthetic	2.	42 ${}^{**}$	(1.70, 3.13)
Number of sites	0.	08	( $-$ 0.08, 0.24)
Leg	1.	60 ${}^{**}$	(1.03, 2.17)
Thigh	0.	83 ${}^{*}$	(0.20, 1.46)
Arm	0.	37	( $-$ 0.37, 1.11)
Hand	1.	85 ${}^{**}$	(1.02, 2.68)
Axial	0.	53	( $-$ 0.29, 1.34)
Predictors of post-procedure pain	Odds ratio		95% CI
Pain score during botox	1.	43 ${}^{**}$	(1.31, 1.57)
Gender	0.	83	(0.50, 1.39)
Age	1.	12 ${}^{**}$	(1.07, 1.19)
Repeat procedure	1.	18	(0.67, 2.03)
Child Life	0.	73	(0.42, 1.26)
Any anesthetic	1.	57	(0.55, 4.50)
Number of sites	0.	91	(0.77, 1.07)
Leg	1.	19	(0.60, 2.35)
Thigh	1.	05	(0.55, 2.00)
Arm	0.	70	(0.33, 1.47)
Hand	0.	78	(0.31, 1.98)
Axial	1.	21	(0.50, 2.91)

${}^{*}$ significant at the 0.05 level, ${}^{**}$ significant at the 0.001 level. Regression and logistic regression analyses of variables affecting reported pain during and post intramuscular botulinum toxin A injections.

4. Discussion

Intramuscular botulinum toxin A injections have been shown to be effective at reducing muscular tone, which is commonly utilized to improve function, range of motion, positioning, and hygiene in patients with spasticity [10]. Peri-procedural pain ratings are a simplification of a broader experience that also includes efficacy, anxiety, and guardian satisfaction [11]. Minimization of pain is important because pain with injection has been shown to impact discontinuation of the intervention [12]. This study demonstrated that without the use of general anesthesia, inhaled sedation, or enteral sedation, the vast majority of patients (roughly 84%) were pain free with only 4% reporting greater than mild pain at five minutes. This data set is similar to unpublished data from an alternate institution, in which 98% of a small cohort ( $n=$ 50) reported “minimal” pain at 10 minutes post injection [5].

Two modifiable risk factors, topical anesthetic use and utilization of Child Life specialists for distraction, were examined because they are both potential means for improving patient experience. Distraction was associated with lower post-procedural pain scores. However, it is likely that clinical selection bias and age as a confounder limited the ability to draw impactful conclusions. This selection bias was clinically observed as a tendency to utilize more “pain relieving” and distraction techniques in children known to have a greater expression of pain. This bias may explain, in part, the finding that any topical anesthetic use was associated with significantly higher procedural pain ratings. A prospective, randomized evaluation of patients receiving sham versus topical anesthetics would provide more definitive information regarding the impact of topical anesthetics in this population. The patients’ novel versus repeat procedure status was not associated with changes in pain ratings in this population, which is not aligned with research in pediatric cancer patients demonstrating a potentiation of pain during subsequent visits [13]. The results of the exploratory regressions suggest that receiving injections in the leg, thigh, and hand were more painful for children than arm or axial sites. Therefore, pain reducing interventions may be more useful for those children.

Another potential limitation of the study was the inability to analyze differences between parent proxy and patient pain ratings. Younger children may have a higher frequency of proxy reports and as such, this limitation may have impacted the findings that showed an association between increased age and less procedural pain but increased likelihood of post-procedure pain. It has been shown that when using numerical scales, parents tend to assign higher pain ratings than children report [14]. Observational tools minimize the variance of patient vs. parent/guardian proxy ratings and have been shown to be a reliable and valid measure in children with cognitive impairment [15]. Anxiety may have a stronger impact on younger children’s procedural pain response. Resolution of the anxiety following the procedure could explain more complete resolution of pain than in older children. It would be useful to thoroughly examine anxiety states pre- and during- procedure in this population as it has been shown to be highly correlated to the experience of pain in children without disability [16, 17].

5. Conclusion

Pain was reported as absent or mild shortly after the procedure in at least 95% of cases. Exploratory findings suggest that younger age, use of any topical anesthetic, and location of injections significantly increase acute pain during a procedure. Acute pain during the procedure and older age increase the presence of pain 5 minutes after the procedure. Any efforts to improve patient experience should address short term pain reduction. Further exploration of these variables is required to reduce morbidity, avoid unnecessary costs, and determine ideal pain-relief practices.

Footnotes

Conflict of interest

The authors have no conflicts of interest to report.

References

Koman

, Mooney

, Smith

, Goodman

, Mulvaney

. Management of cerebral palsy with botulinum-A toxin: preliminary investigation. J Pediatr Orthop. 1993; 13: 489-95. doi: 10.1097/01241398-199307000-00013

Lukban

, Rosales

, Dressler

. Effectiveness of botulinum toxin A for upper and lower limb spasticity in cerebral palsy: a summary of evidence. J Neural Transm. 2009 116(3): 319-31. doi: 10.1007/s00702-008-0175-8

Bakheit

. Botulinum toxin in the management of childhood muscle spasticity: comparison of clinical practice of 17 treatment centres. Eur J Neurol. 2003 10(4): 415-9. doi: 10.1046/j.1468-1331.2003.00619.x

Kinnett

. Botulinum toxin A injections in children. Am J Phys Med Rehabil. 2004 83(Supplement): S59-S64. doi: 10.1097/01.phm.0000141131.66648.e9

Koman

, Paterson Smith

, Balkrishnan

. Spasticity associated with cerebral palsy in children. Paediatr Drugs. 2003; 5(1): 11-23. doi: 10.2165/00148581-200305010-00002

Roback

, Carlson

, Babl

, Kennedy

. Update on pharmacological management of procedural sedation for children. Curr Opin Anaesthesiol [Internet]. 2016 29: S21-S35. doi: 10.1097/aco.0000000000000316

Sinatra

, de Leon-Casasola

, Ginsberg

, Viscusi

editors. Acute Pain Management. New York, NY: Cambridge University Press; 2009. p. 649.

Hirschfeld

, Zernikow

. Variability of “optimal” cut points for mild, moderate, and severe pain: neglected problems when comparing groups. Pain. 2013 154(1): 154-9. doi: 10.1016/j.pain.2012.10.008

Tsze

, Hirschfeld

, Dayan

, Bulloch

, von Baeyer

. Defining no pain, mild, moderate, and severe pain based on the Faces Pain Scale – Revised and Color Analog Scale in children with acute pain. Pediatr Emerg Care [Internet]. 2016; 1. Available from: http://dx.doi.org/10.1097/pec.0000000000000791

10.

Bjornson

, Hays

, Graubert

, Price

, Won

, McLaughlin

, et al. Botulinum toxin for spasticity in children with cerebral palsy: a comprehensive evaluation. Pediatrics. 2007 1; 120(1): 49-58. doi: 10.1542/peds.2007-0016

11.

Symons

, Rivard

, Nugent

, Tervo

. Parent evaluation of spasticity treatment in cerebral palsy using botulinum toxin type A. Arch Phys Med Rehabil. 2006; 87(12): 1658-60. doi: 10.1016/j.apmr.2006.08.343

12.

Linder-Lucht

, Kirschner

, Herrmann

, Geth

, Korinthenberg

, Berweck

, et al. Why do children with cerebral palsy discontinue therapy with botulinum toxin A? Dev Med Child Neurol. 2006; 48(4): 319. doi: 10.1017/s0012162206000697

13.

Chen

, Zeltzer

, Craske

, Katz

. Children’s memories for painful cancer treatment procedures: implications for distress. Child Dev. 2000; 71(4): 933-47. doi: 10.1111/1467-8624.00200

14.

Voepel-Lewis

, Malvivya

, Tait

. Validity of parent ratings as proxy measures of pain in children with cognitive impairment. Pain Manag Nurs. 2005; 6(4): 168-74. doi: 10.1016/j.pmn.2005.08.004

15.

Voepel-Lewis

, Merkel

, Tait

, Trzcinka

, Malviya

. The reliability and validity of the Face, Legs, Activity, Cry, Consolability Observational Tool as a measure of pain in children with cognitive impairment. Anesth Analg. 2002; 95(5): 1224-9. doi: 10.1097/00000539-200211000-00020

16.

Cohen

, Blount

, Cohen

, Johnson

. Dimensions of pediatric procedural distress: children’s anxiety and pain during immunizations. J Clin Psychol Med Settings. 2004; 11(1): 41-47. doi: 10.1023/b:jocs.0000016268.40662.ed

17.

Ersig

, Kleiber

, McCarthy

, Hanrahan

. Validation of a clinically useful measure of children’s state anxiety before medical procedures. J Spec Pediatr Nurs. 2013; 18(4): 311-19. doi: 10.1111/jspn.12042.

Factors affecting procedural pain in children during and immediately after intramuscular botulinum toxin injections for spasticity