Effect of Topical Anesthetics on Needle Insertion Pain During Botulinum Toxin Type A Injections for Limb Spasticity

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1 ORIGINAL ARTICLE Effect of Topical Anesthetics on Needle Insertion Pain During Botulinum Toxin Type A Injections for Limb Spasticity Sharon Fung, MD, Chetan P. Phadke, PhD, Alice Kam, MD, Farooq Ismail, MD, Chris Boulias, MD, PhD 1643 ABSTRACT. Fung S, Phadke CP, Kam A, Ismail F, Boulias C. Effect of topical anesthetics on needle insertion pain during botulinum toxin type A injections for limb spasticity. Arch Phys Med Rehabil 2012;93: Objective: To compare pain perception using 3 anesthetics (eutectic mixture of local anesthetics [EMLA], vapocoolant spray, and ice) compared with a control (no anesthetic) during botulinum toxin type A (BTX-A) injections for lower limb spasticity. Design: A placebo-controlled, single-blinded study where each study patient served as their own control. Setting: Spasticity clinic. Participants: Subjects (N 30) with ankle spasticity who visited the clinic for BTX-A injections in the gastrocnemius muscle were consecutively sampled. Intervention: The gastrocnemius muscle was divided into 4 quadrants and 1 of the 3 different anesthetic agents was applied to each quadrant with 1 quadrant using no anesthetic, control. Main Outcome Measures: Numerical Rating Scale (NRS) and the Wong-Baker FACES scale. Results: Pain perception using the NRS and FACES scale was significantly lower using ice and EMLA compared with control and spray conditions (P.05). Pain perception using EMLA and ice was similar. These results indicate that patients experience minimal to moderate pain during BTX-A injections. Conclusions: Pain relief offered by EMLA and ice was comparable, suggesting that ice is a more convenient option because of brief application time (compared with EMLA). Spray may have made the patients more sensitive to pain and alternative approaches for using vapocoolant should be considered. Key Words: Anesthetics, local; Botulinum toxins; Muscle spasticity; Pain perception; Rehabilitation by the American Congress of Rehabilitation Medicine CLINICAL EXPERIENCE indicates that botulinum toxin type A (BTX-A) focal chemodenervation injection for spasticity is a procedure that can be perceived as uncomfortable by some patients. One of the reasons for potential discomfort during BTX-A injections is that injections may be required in several muscles and a number of sites per muscle, which can increase the skin puncture related discomfort. Various topical From the Division of Physiatry, Department of Medicine (Fung, Kam, Ismail, Boulias) and the Department of Physical Therapy (Phadke), University of Toronto, Toronto; and Spasticity Research Program, West Park Healthcare Centre, Toronto (Phadke, Ismail, Boulias), ON, Canada. Supported by the West Park Foundation, Toronto, ON, Canada. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Chris Boulias, MD, PhD, West Park Healthcare Centre, 82 Buttonwood Ave, Toronto, ON, Canada M6M 2J5, chris.boulias@westpark.org. In-press corrected proof published online on May 5, 2012, at /12/ $36.00/0 agents can be used to provide preprocedural anesthesia to minimize pain during needle puncture, including ice, eutectic mixture of lidocaine and prilocaine (EMLA) (a mixture of 2.5% lidocaine and 2.5% prilocaine), and vapocoolant spray. Currently, in our clinic most patients are not provided with any local anesthetic agents unless the clinician notices excessive signs of discomfort or if the patient specifically requests local anesthesia. There is no evidence for recommending one anesthetic agent over another based on patients perceived level of pain during injection of BTX-A for limb spasticity. There are key differences between various anesthetic agents with respect to method of application, time course required, and cost parameters. EMLA cream is a common topical anesthetic agent; however, the application process can be quite cumbersome. Because it is gel, it needs to be applied evenly over the skin and then the area needs to be covered with an adhesive tape, but it can still inadvertently drip and ooze onto clothing and other areas. Alternatively, EMLA cream can also be purchased in a self-impregnated patch adherent dressing, which is meant to be more user friendly, albeit more costly. In practice, where several areas and multiple muscle sites are to be injected, such patches may be impractical. Additionally, the recommended 60-minute activation time can significantly extend the patient visit duration. 1 However, in cases where patients have allodynia, or are unable to position themselves for use of other topical agents, lidocaine/prilocaine cream is ideal. Ice is a nonpharmacologic anesthetic alternative that has been used in pain management for thousands of years. 2 Furthermore, it is inexpensive and readily available in a clinic or hospital setting. Because it requires a short period of time (45 60s) to exert a temporary anesthetic effect on the skin, it can be applied while the patient is on the procedure table, over the specific injection point. It also allows for flexibility, specifically, if during the procedure another needle entry point is required, an alternate point can be quickly anesthetized. However, where there is allodynia of the area to be injected, ice may exacerbate pain and thus using ice would not be appropriate. Another nonpharmacologic product that is used in clinical settings to ease injection pain is skin refrigerant (vapocoolant). Clinical applications have included preprocedural anesthesia prior to minor procedures, such as intravenous cannulation, intradermal vaccination, prior to BTX-A for hyperhydrosis, blepharospasm, as well as cosmetic procedures. Vapocoolant spray quickly evaporates, and acts in a matter of seconds to temporarily interrupt nociceptive input. 3 The spray is made of halogenated hydrocarbons (1,1,1,3,3-Pentafluoropropane and ANOVA BAI BDI BTX-A EMLA NRS List of Abbreviations analysis of variance Beck Anxiety Inventory Beck Depression Inventory botulinum toxin type A eutectic mixture of lidocaine and prilocaine Numerical Rating Scale

2 1644 EFFECT OF TOPICAL AGENTS ON NEEDLE INSERTION PAIN, Fung 1,1,1,2-Tetrafluroethane), classified as a class 2 medical device, has been deemed to be nonflammable, environmentally friendly, and has no systemic effects. Vapocoolant sprays are extremely quick, taking effect after 15 to 30 seconds of spraying, 4 and bring the skin s temperature down to 4 C when sprayed from the recommended cm (4-in) target distance. The anesthesia lasts up to 60 seconds. When economical considerations are factored into the scheme, a spray can consisting of 40 applications costs $60 (average $1.50 per site), which may be too expensive if multiple injection sites are required. Advantages for using anesthetic agents, such as ice and spray, include short application time, which is unlikely to extend the patient visit duration and can be easily integrated into current clinical practice. There have been previous studies comparing various topical pharmacologic anesthetics, but few compare the effects to ice and fewer are in the context of BTX-A injections. 1 In a previous study, 5 topical anesthetics, such as EMLA cream, lignocaine subcutaneous injection, and vapocoolant, were compared before venous cannulation procedure. It was reported that both lignocaine injection and vapocoolant were effective in strong pain relief, but EMLA was not. The lack of anesthetic effect with EMLA was attributed to the application time in this study, which was only 5 minutes instead of the recommended 60 minutes. Similarly, Weiss and Lavin 6 also recently reported the effectiveness of vapocoolant in decreasing pain of injection procedure compared with no anesthetic. However, neither of the above studies compared the effect of vapocoolant and EMLA with the effect of ice. Yoon et al 7 compared ice to vapocoolant and found that ice applied for 1 minute prior to an intradermal skin test was significantly more effective than vapocoolant spray. In a similar study by Kuwahara and Skinner, 8 60% of patients were found to perceive no difference in pain perception using ice and EMLA. In this study, it was noted that EMLA was left in place for less than 60 minutes in some cases, which is considered suboptimal, and may account for the lack of difference between the 2 groups. It is clear from the above studies that a systematic comparison of various types of topical anesthetics is needed in order to investigate the best option in terms of pain relief, activation time, and cost. Another reason warranting such a comparison is that the benefit of using local anesthesia for BTX-A injections specifically for the treatment of focal limb spasticity is not known. Pain perception during needle puncture with BTX-A injections has been studied for conditions such as hyperhydrosis, 9 blepharospasm, 10 or wrinkle reduction. 10,11 Elibol et al 10 compared vapocoolant to EMLA and found that both are effective at relieving pain associated with periocular BTX-A injections, with no significant difference in pain scores. Where lidocaine cream was used in cosmetic injection of BTX-A for treatment of crow s feet, 11 it was found that there was a statistically significant reduction in pain with topical anesthetic compared with controls. Although, there is evidence suggesting effective pain relief provided by both EMLA and vapocoolants, none of the above studies testing the effectiveness of local anesthesia during BTX-A injections have tested the effect of ice. Moreover, most of these studies involved injections in the face and neck area, which is very sensitive to pain; in contrast, the majority of injections for focal limb spasticity are in the arms and legs where pain perception can be different than the facial region. It is, thus, important to study the effects of local anesthetics in arms and legs in order to understand the magnitude of pain relief that can be gained using a variety of local anesthetics. The availability of multiple products requires a careful comparison of these products. The purpose of this study was to compare topical anesthetic effects of EMLA, vapocoolant, and ice in a placebo-controlled, single-blinded design in order to inform treating physicians of the most effective modality available for pain relief during BTX-A focal chemodenervation for spasticity. METHODS Thirty patients (mean age SD, 55 16y) with clinical signs of ankle spasticity were recruited from the West Park Healthcare Centre Spasticity Clinic. Patients were included in the study if they were already patients of the clinic receiving ongoing BTX-A injections, had no sensory impairment, no allodynia, and no rash or open skin over the calf. Patients were excluded if they could not communicate with the clinic staff, specifically if they were unable to express themselves and read English. This was determined by a study physician. All participants provided a signed written consent approved by the hospital research ethics board. Depression and anxiety of our patient cohort was assessed using the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI). The BDI is the most used self-rating scale for assessing depression. 12 Its alpha-coefficients are higher than It reflects 6 of the 9 Diagnostic and Statistical Manual of Mental Disorders criteria well. 14 A review from Richter et al concluded that the BDI has high internal consistency, high content validity, validity in differentiating between depressed and non-depressed subjects, sensitivity to change, and international propagation. 12(p160) The BAI is a commonly used scale for measuring anxiety symptoms, and it has been successfully translated to a few other languages. It is known to have good psychometric properties, with a high level of internal consistency. 15(p477) This scale was selected for this study because of its simplicity. The pain assessments were performed only on 1 leg of each participant. Prior to BTX-A focal chemodenervation injection, the calf area was marked into 4 quadrants and each quadrant was assigned 1 of the following 4 study conditions (fig 1): control, EMLA, ice, and Gebauer Pain Ease vapocoolant spray. a EMLA cream was applied over the skin of the gastrocnemius to be injected, 60 minutes prior to the injection. An ice pack was applied to a different quadrant for 60 seconds prior to the injection. The vapocoolant spray (Gebauer Pain Ease), was dispensed according to the manufacturer s instructions: the spray was held at a distance of 10cm from the skin and sprayed continuously for 10 seconds, just prior to the physician entering the room. A cardboard shield was used to protect against contamination and exposure of the other 3 quadrants. The control quadrant did not receive anesthetic. In this way, each study patient served as their own control. The type of anesthetic in each quadrant and the order that each quadrant was to be injected were randomized. After application of EMLA in 1 quadrant, a self-adhering dressing was placed over the posterior calf covering the gastrocnemius muscle for 60 minutes. After 60 minutes of EMLA application, the adhesive and cream was removed from the quadrant. The patient was placed inside the treatment room in a prone or side lying position so that they were unable to visually determine the order of needle injections. The physician was positioned outside the treatment room, and when he indicated that he was ready, ice was applied for 60 seconds, and vapocoolant was sprayed over the predesignated quadrant on the patient s gastrocnemius immediately before the physician entered the room. The treating physician was blinded to the order and type of anesthetic used in each quadrant. The BTX-A was prepared in advance, and the skin was sterilized in advance for injection, thus allowing the treating physician to immediately proceed to inject the calf muscle. This procedure ensured almost immedi-

3 EFFECT OF TOPICAL AGENTS ON NEEDLE INSERTION PAIN, Fung 1645 value of 0.90 and a 95% confidence interval between 0.86 and 0.93, 16 the FACES pain scale was considered an easier tool for our neurologic population. A one-way analysis of variance (ANOVA) was used to test the differences in pain scores between the 4 conditions. A separate ANOVA was used for the NRS and the Wong-Baker FACES Pain Rating Scale. If the ANOVA was significant, then we performed post hoc tests (Bonferroni-Holm) to test which pairs of conditions showed significant differences in pain scores. We ran Pearson correlation coefficient tests to examine the association between the BDI and BAI and the 2 pain scales. We also ran a regression analysis to check if the baseline BDI and BAI scores could predict pain outcomes. Statistical tests were performed using Microsoft Excel (version 2003) b and an Excel add-in, Daniel s Toolbox. c P.05 was considered statistically significant. RESULTS Two subjects in this study received incobotulinum toxin A, and the rest of the subjects received onabotulinum toxin A. Mean anxiety scores SD in our subjects on the BAI were (range, 0 26), indicating borderline minimal to mild level of anxiety; and mean depression scores SD on the BDI were (range, 0 32), indicating no depression to minimal depression in our patient group. For the mean pain perception SD for the control condition, the pain perception using the NRS was (range, 0 7) and for the FACES scale was (range, 0 6). For the EMLA condition, the pain perception using the NRS was (range, 0 6) and for the FACES scale was (range, 0 6). For the spray condition, the pain perception using the NRS was (range, 0 10) and for the FACES scale was (range, 0 10). For the ice condition, the pain perception using the NRS was (range, 0 7) and for the FACES scale was (range, 0 8). EMLA and ice produced a mean 43% and 53% decrease in NRS pain scores, respectively, and a 28% and 57% decrease in the FACES scale pain scores, respectively, compared with the control condition. Spray induced a mean decrease of 3% in the NRS pain scores and a paradoxical mean increase of 12% in the FACES pain score compared with the control condition (fig 2). Fig 1. Sites on the gastrocnemius muscle chosen for local anesthetic application. The numbers represent the quadrants used for different types of anesthetic; each quadrant was randomly assigned to 1 of 4 anesthetic conditions. ate injection after the vapocoolant spray was applied. The physician was given a randomized order to inject the quadrants, which was different for each study patient, the whole process requiring about a minute to complete. The Wong-Baker FACES pain rating scale 16 and the Numerical Rating Scale (NRS) were briefly explained to each participant prior to the injection. The participants were asked to rank their pain corresponding to a number on a pain scale at the time of skin puncture by a standard 27-gauge needle used for all injections. All participants were instructed to rank the pain perceived when the needle pierced the skin. The Wong-Baker FACES pain scale was used for this study in order to accommodate participants with mild cognitive impairment. The facial expression drawings were originally developed to assess pain severity in pediatric populations; however, because there is excellent agreement between the Wong-Baker FACES Pain Rating Scale and the visual analog scale with a P Effect of Anesthetic Type Numerical Rating Scale. One-way ANOVA for NRS scores showed significant difference between different types of anesthetics (P.004). Subsequent post hoc tests revealed that both EMLA and ice were significantly more effective in pain Fig 2. Mean percent change in pain perception compared with the control condition (no anesthetic). Error bars represent SE of the mean. *Significantly different (P<.05); **P.057.

4 1646 EFFECT OF TOPICAL AGENTS ON NEEDLE INSERTION PAIN, Fung relief than the control condition (P.007). The spray condition was not significantly different than control (P.953). Both the EMLA and ice induced significantly greater pain relief compared with the spray condition (P.013). FACES scale. One-way ANOVA for the FACES scale scores showed significant difference between different types of anesthetics (P.006). Subsequent post hoc tests revealed that the ice condition was significantly more effective in pain relief than the spray condition (P.007). There was a strong trend for EMLA being more effective than the spray and control conditions (P.015 and P.057, respectively). There was also a strong trend for ice being more effective than control (P.02). Correlation The NRS and FACES scale scores were significantly associated and the Pearson correlation coefficient ranged from.87 to.96 for all 4 conditions. Additionally, in the EMLA condition, pain and BDI scores showed a moderate inverse relationship with each other (Pearson correlation coefficient.39 and.42 for the NRS and FACES scale, respectively; P.05). Thus, patients with greater depression were more likely to feel greater relief with EMLA. There was poor association for other conditions between pain and BDI and all conditions and BAI scores. DISCUSSION Preprocedural anesthesia, when used to make a patient more comfortable, should be effective, easy to administer, economical, and not interfere with patient flow in the clinic. We report here that patients experience pain ranging from mild to moderate during BTX-A injections in their leg. Our study shows that there is a significant decrease in pain perception compared with the control condition when either EMLA or ice is used as a topical anesthetic prior to needle puncture in BTX-A injections for spasticity. These findings are similar to Kuwahara and Skinner, 8 who found that there was no difference in ice or EMLA as topical anesthetics. In our study, both the NRS and FACES pain scales showed comparable decrease in pain perception. Interestingly, the vapocoolant spray did not offer pain relief, and in fact, was no better than using no anesthesia. This is similar to the results by Yoon et al, 7 who found ice to be a better preprocedural anesthetic than vapocoolant in the context of upper extremity intradermal injection. Effectiveness of the Local Analgesics The EMLA significantly decreased pain perceived during injection using both the NRS and FACES scale. Previous studies show conflicting evidence for the use of EMLA prior to injections. 5,11 It was reported that EMLA did not induce greater analgesia than vapocoolant spray, and it was suggested that the application time for EMLA may not have been sufficient, 5 because the cream must be applied for at least 60 minutes prior to injection in order to achieve optimal transdermal absorption. 1 To avoid this problem, EMLA was applied to all subjects in our study for at least 60 minutes prior to injection. Thus it is clear that if less than manufacturer recommended application times are used, it can adversely affect the amount of analgesia experienced by the patients. Ice also significantly decreased the pain perception using both the NRS and the Wong-Baker FACES scale. The fact that ice provided significant pain relief was in keeping with previous studies that explored the use of ice. 7,8 Our result of a similar analgesic effect achieved by ice and EMLA is important, because ice is a nonpharmacologic agent that is both economical and easily available. In terms of application time and convenience, vapocoolant spray appears most effective, because it requires only a press of a valve, followed by 15 to 30 seconds to activate. However, our results show that the spray did not significantly decrease pain perception and appears to be in contradiction with previous studies. 6,10,17 In the studies by Elibol, 10 Weiss, 6 and colleagues, the spray was used for facial BTX-A injections. It is difficult to compare our results with these 2 studies, because the spray may work differently on facial skin, which is more perceptive than skin overlying gastrocnemius tested in our study. It is also possible that the lack of blinding and placebo control may have affected the results of Weiss and Lavin. 6 However, in the study by Farion et al, 17 subjects were blinded as to whether they were receiving vapocoolant or sham spray in the context of cannulation. Their results showed a modest reduction in pain with the use of vapocoolant spray in children. Again, it is difficult to compare studies done in children and on patients with facial injections 18 with our study done in adults with leg injections. To our knowledge, ours is the first study that has tested pain perception during BTX-A injections for focal spasticity, and future studies need to test the effect of local anesthetics on various areas in the arms and legs. NRS Versus FACES Scale Our results show that both scales are comparable, because both the NRS and FACES scales were able to distinguish the main differences in pain perception; however, the NRS scale appears to be more sensitive, because the post hoc tests using the NRS showed significant differences, whereas when using the FACES scale, there were little differences found in the post hoc tests. Based on these findings, it appears that the NRS scale is the scale of choice in future studies examining pain perception during BTX-A injections. Association With Depression Our subject population in this study was heterogeneous with conditions such as cerebral palsy, stroke, spinal cord injury, brain injury, and multiple sclerosis. Most of the above are chronic and can be associated with depression, which is known to influence pain thresholds. 19 We administered both the BAI and the BDI to screen for mood disorders in our population. Our subject population had borderline minimal to mild anxiety and none to minimal depression. Thus, it is unlikely that the mood disorders of our patients influenced our results. We did, however, find that EMLA was more effective if the subjects had greater depression. These results suggest that the amount of depression should be taken into account when choosing a topical anesthetic, because EMLA appears to be more likely to induce significant pain relief compared with other local anesthetics in patients with higher levels of depression. Study Limitations We did not test upper limb areas, which are generally more sensitive than legs, and it is possible that analgesic effects of the various agents may be different in arms. We did not measure the pain experienced during repositioning of the needle after the initial skin penetration, or the pain caused by any tissue expansion during injection subsequent to needle insertion. It is possible that patients may have experienced pain during the repositioning of the needle within the muscle belly. In any case, the local anesthetic is unlikely to influence intramuscular pain. Furthermore, the difference between patients receiving incobotulinum toxin A instead of onabotulinum toxin A is not an issue in our study, because patients were asked to rank their pain during needle puncture, not on infusion of medication. Pain experience would be identical with any kind

5 EFFECT OF TOPICAL AGENTS ON NEEDLE INSERTION PAIN, Fung 1647 of drug, because the needle gauge was identical. We did not measure the time taken to inject each quadrant, and hence in cases where the vapocoolant anesthetized quadrant was injected last, it can be conceivable that the effects had worn off. However, it would be expected that the pain rankings would approach that of the placebo rankings. Comparing the NRS pain rankings of study patients who received injections to the vapocoolant anesthetized quadrant first compared with fourth resulted in averages of 3.5 compared with 3.2, respectively. The difference between these groups is 0.3, which is not statistically or clinically significant. The lack of pain relief and increase in pain in the spray condition in our study and others 7 suggests that vapocoolant spray may cause hypersensitivity. 1 It has been suggested that an alternate mode of delivery is to spray the vapocoolant on to a cotton ball and transfer the chemical to the skin to be injected. 1 We sprayed the vapocoolant directly over the skin and it is possible that the alternate method of using a cotton ball may prove to be more effective. CONCLUSIONS Although patient comfort is an essential consideration when performing BTX-A focal chemodenervation for spasticity, clinicians must also take into account the ease of administration of a topical anesthetic, activation time, cost, and impact on clinic flow. Even though vapocoolant spray was the easiest to apply with minimal impact on prolonging appointment times, it had little effect on patient perceived pain. These results differ from studies using vapocoolant as a topical anesthetic agent over the face. 6,10 Our study results are in keeping with previous studies, which found ice and EMLA to be effective preprocedural anesthetic agents, and that using a topical anesthetic results in reduced pain compared with a control condition. 7,8,11 Among the anesthetic agents we tested, EMLA required the greatest efforts in terms of application of the cream to a specific area followed by application of an adhesive dressing over it. Although these steps could be avoided by using more expensive adhesive EMLA patches, they would still require 60- minute activation time and the removal of the adhesive dressing and cream residue as the area is cleaned and prepared prior to injection. Factors, such as cost of EMLA cream, can significantly diminish its utility in a clinical setting where BTX-A is injected in multiple sites and using EMLA could become cost-prohibitive. Additionally, in terms of facilitating efficient patient flow in the clinic, the 60-minute transdermal absorption time may adversely affect both the number of patients that can be seen per hour and the duration of patient s clinic visit. Most clinics are equipped with refrigerators, and making ice is a negligible cost over that of the operating costs of the fridge. The advantage of using ice over EMLA is the short application time (45 60s). Should another needle entry point or multiple injection sites be required, multiple areas can be quickly anesthetized without a significant prolongation of the procedure, and thus minimally impacting the clinic flow and timing. Additionally, the anesthesia induced by ice is of a very short duration, which minimizes precautions required to prevent inadvertent injury to the anesthetized area. Ice is naturally the most economical product of the 3 we tested and appears to be a superior local anesthetic for temporary pain relief during BTX-A injections for limb spasticity. References 1. Reis EC, Jacobson RM, Tarbell S, Weniger BG. Taking the sting out of shots: control of vaccination-associated pain and adverse reactions. Pediatr Ann 1998;27: Trescot AM. Cryoanalgesia in interventional pain management. Pain Physician 2003;6: Lehmann JF, Boswell S, Price R, et al. Quantitative evaluation of sway as an indicator of functional balance in post-traumatic brain injury. Arch Phys Med Rehabil 1990;71: Dzubow LM. Histologic and temperature alterations induced by skin refrigerants. J Am Acad Dermatol 1985;12: Selby IR, Bowles BJ. Analgesia for venous cannulation: a comparison of EMLA (5 minutes application), lignocaine, ethyl chloride, and nothing. J R Soc Med 1995;88: Weiss RA, Lavin PT. Reduction of pain and anxiety prior to botulinum toxin injections with a new topical anesthetic method. Ophthal Plast Reconstr Surg 2009;25: Yoon WY, Chung SP, Lee HS, Park YS. Analgesic pretreatment for antibiotic skin test: vapocoolant spray vs ice cube. Am J Emerg Med 2008;26: Kuwahara RT, Skinner RB. EMLA versus ice as a topical anesthetic. Dermatol Surg 2001;27: Baumann L, Frankel S, Welsh E, Halem M. Cryoanalgesia with dichlorotetrafluoroethane lessens the pain of botulinum toxin injections for the treatment of palmar hyperhidrosis. Dermatol Surg 2003;29:1057-9; discussion Elibol O, Ozkan B, Hekimhan PK, Cağlar Y. Efficacy of skin cooling and EMLA cream application for pain relief of periocular botulinum toxin injection. Ophthal Plast Reconstr Surg 2007;23: Carruthers A, Carruthers J. Single-center, double-blind, randomized study to evaluate the efficacy of 4% lidocaine cream versus vehicle cream during botulinum toxin type A treatments. Dermatol Surg 2005;31: Richter P, Werner J, Heerlein A, Kraus A, Sauer H. On the validity of the Beck Depression Inventory. A review. Psychopathology 1998;31: Beck AT, Steer RA, Carbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 1988;8: Moran PW, Lambert MJ, editors. A review of current assessment tools for monitoring changes in depression. New York: Wiley; Creamer M, Foran J, Bell R. The Beck Anxiety Inventory in a non-clinical sample. Behav Res Ther 1995;33: Garra G, Singer AJ, Taira BR, et al. Validation of the Wong-Baker FACES Pain Rating Scale in pediatric emergency department patients. Acad Emerg Med 2010;17: Farion KJ, Splinter KL, Newhook K, Gaboury I, Splinter WM. The effect of vapocoolant spray on pain due to intravenous cannulation in children: a randomized controlled trial. CMAJ 2008; 179: Engel SJ, Afifi AM, Zins JE. Botulinum toxin injection pain relief using a topical anesthetic skin refrigerant. 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