Effectiveness of cold application on postoperative pain following Botulinum toxin injections type A in the orofacial region: a systematic review of randomized controlled studies Cold and Injections

Main Article Content

Maryam Altuhafy
Ruqaya Lilo
Luay Jabr
Olga Korczeniewska
Junad Khan


Botulinum, neurotoxin, topical, EMLA, pain


Objective: This systematic review aims to evaluate self-perceived pain levels in patients undergoing a BoNT/A injection in the orofacial region with a cold application compared to other types of treatments. Methods: An electronic search was performed of indexed databases including PubMed, EMBASE, Scopus, ISI web of knowledge and Cochrane library up to and including April 2023. A Risk of Bias (RoB) assessment was conducted using the Cochrane tool for assessment. Due to a high heterogeneity of the included studies, a meta-analysis was not conducted. This study was registered in the PROSPERO database (CRD42023407290). Results: An initial electronic and manual search revealed a total of 496 and 5 manuscripts, respectively. After removing duplicates, 170 studies remained. Following the eligibility criteria, five randomized controlled trials (RCTs) were included. Four RCTs used the visual analog scale (VAS), and one used the numerical rating score (NRS) to assess post-operative pain. Three RCTs had a high, whereas two RCTs had a moderate ROB. Conclusions: the present review proves it inconclusive to identify the best cold modality protocol to alleviate pain in patients undergoing BoNT/A injections. However, 80% of the studies showed significant reduction in pain following injections and a positive outcome overall. Future standardized and power adjusted clinical studies are needed to identify cost effective and standardized cold treatment protocols in patients undergoing injections.

Abstract 174 | PDF Downloads 131


1. Mittal SO, Machado D, Richardson D, Dubey D, Jabbari B. Botulinum toxin in restless legs syndrome - A randomized double-blind placebo-controlled crossover study. Toxins (Basel). 2018; 108(10):401.
2. Altuhafy MR, Yadav R, Talluri S, Jabr L, Kalladka M, Khan J. The Efficacy of Botulinum Toxin in the Management of Restless Leg Syndrome: A Systematic Review of Randomized Control Trials. Indian J Sleep Med. 2022; 17(1):15-21.
3. Field M, Splevins A, Picaut P, et al. AbobotulinumtoxinA (Dysport®), OnabotulinumtoxinA (Botox®), and IncobotulinumtoxinA (Xeomin®) neurotoxin content and potential implications for duration of response in patients. Toxins (Basel). 2018; 10(12):535.
4. Mittal SO, Safarpour D, Jabbari B. Botulinum Toxin Treatment of Neuropathic Pain. Semin Neurol. 2016; 36(1):73-83.
5. Pucks N, Thomas A, Hallam MJ, Venables V, Neville C, Nduka C. Cutaneous cooling to manage botulinum toxin injection-associated pain in patients with facial palsy: A randomised controlled trial. J Plas Reconstr Aesthet Surg. 2015; 68(12):1701-1705.
6. Irkoren S, Ozkan HS, Karaca H. A clinical comparison of EMLA cream and ethyl chloride spray application for pain relief of forehead botulinum toxin injection. Ann Plast Surg. 2015; 75(3):272-274.
7. Richards RN. Ethyl chloride spray for sensory relief for botulinum toxin injections of the hands and feet. J Cutan Med Surg. 2009; 13(5):253-6.
8. Kassir M, Gupta M, Galadari H, et al. Complications of botulinum toxin and fillers: A narrative review. J Cosmet Dermatol. 2020; 19(3):570-573.
9. Elibol O, Ozkan B, Hekimhan PK, Cağlar Y. Efficacy of skin cooling and EMLA cream application for pain relief of periocular botulinum toxin injection. Ophthalmic Plast Reconstr Surg. 2007; 23(2):130-3.
10. Dutton JJ. Botulinum-A toxin in the treatment of craniocervical muscle spasms: short-and long-term, local and systemic effects. Surv Ophthalmol. 1996; 41(1):51-65.
11. Grandas F, Elston J, Quinn N, Marsden C. Blepharospasm: a review of 264 patients. J Neurol, Neurosurg Psychiatry. 1988; 51(6):767-772.
12. Beer KR, Wilson F. Skin cooling provides minimal relief of patient discomfort during periocular botulinum toxin type A injection. Dermatol Surg. 2011; 37(6):870-872.
13. Saeliw P, Preechawai P, Aui-aree N. Evaluating the effects of ice application on patient comfort before and after botulinum toxin type A injections. J Med Assoc Thai. 2010; 93(10):1200-4
14. Weiss RA, Lavin PT. Reduction of pain and anxiety prior to botulinum toxin injections with a new topical anesthetic method. Ophthalmic Plast Reconstr Surg. 2009; 25(3):173-177.
15. Chorney SR, Villwock JA, Suryadevara AC. Vibration versus ice to reduce cosmetic Botulinum toxin injection pain—a randomized controlled trial. Ear Nose Throat J. 2019; 98(6):351-355.
16. Yavuzer R, Demirtas Y. Painful injections with Botox. Plast Reconstr Surg. 2003; 111(1):509.
17. Flynn TC, Carruthers A, Carruthers J. Surgical pearl: the use of the Ultra-Fine II short needle 0.3-cc insulin syringe for botulinum toxin injections. J Am Acad Dermatol. 2002; 46(6):931-933.
18. Engel SJ, Afifi AM, Zins JE. Botulinum toxin injection pain relief using a topical anesthetic skin refrigerant. J Plast Reconstr Aesthet Surg. 2010; 63(9):1443-1446.
19. Sarifakioglu N, Sarifakioglu E. Evaluating the effects of ice application on the pain felt during botulinum toxin type-a injections: a prospective, randomized, single-blind controlled trial. Ann Plast Surg. 2004; 53(6):543-546.
20. Airaksinen OV, Kyrklund N, Latvala K, Kouri JP, Gronblad M, Kolari P. Efficacy of cold gel for soft tissue injuries: a prospective randomized double-blinded trial. Am J Sports Med. 2003; 31(5):680-684.
21. Richman PB, Singer AJ, Flanagan M, Thode Jr HC. The effectiveness of ice as a topical anesthetic for the insertion of intravenous catheters. Am J Emerg Med. 1999; 17(3):255-257.
22. Waters BL, Raisler J. Ice massage for the reduction of labor pain. J Midwifery Womens Health. 2003; 48(5):317-321.
23. Lehmann JF, Warren GC, Sham SM. Therapeutic Heat and Cold. Clin Orthop Relat Res.1974; 99:207-245.
24. Kuzu N, Ucar H. The effect of cold on the occurrence of bruising, haematoma and pain at the injection site in subcutaneous low molecular weight heparin. Int J Nurs Stud. 2001; 38(1):51-9.
25. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015; 350:g7647.
26. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessin0g risk of bias in randomised trials. BMJ. 2011; 343:d5928.
27. Richards RN. Ethyl chloride spray for sensory relief for botulinum toxin injections of the hands and feet. J Cutan Med Surg. 2009; 13(5):253-256.
28. Söylev MF, Koçak N, Kuvaki B, Özkan SB, Kir E. Anesthesia with EMLA® cream for botulinum A toxin injection into eyelids. Ophthalmologica. 2002; 216(5):355-358.
29. Dong H, Kerl H, Cerroni L. EMLA® cream‐induced irritant contact dermatitis. J Cutan Pathol. 2002; 29(3):190-192.
30. Wahlgren CF, Quiding H. Depth of cutaneous analgesia after application of a eutectic mixture of the local anesthetics lidocaine and prilocaine (EMLA cream). J Am Acad Dermatol. ; 2000; 42(4):584-588.
31. Linder JS, Edmonson BC, Laquis SJ, Drewry Jr RD, Fleming JC. Skin cooling before periocular botulinum toxin A injection. Ophthalmic Plast Reconstr Surg. 2002; 18(6):441-442.
32. Özucer B, Cam OH. A clinical comparison of EMLA cream and vibratory anesthetic device application for alleviation of pain associated with botulinum toxin injection for the masseter muscle hypertrophy. KBB-Forum 2020; 19(2):231-236.
33. Strazar AR, Leynes PG, Lalonde DH. Minimizing the pain of local anesthesia injection. Plast Reconstr Surg. 2013; 132(3):675-684.
34. van Laborde S, Dover JS, Moore M, Stewart B, Arndt KA, Murad A. Reduction in injection pain with botulinum toxin type B further diluted using saline with preservative: a double-blind, randomized controlled trial. J Am Acad Dermatol. 2003; 48(6):875-7.
35. Bechara FG, Sand M, Altmeyer P, Sand D, Hoffmann K. Skin cooling for botulinum toxin A injection in patients with focal axillary hyperhidrosis: a prospective, randomized, controlled study. Ann Plast Surg. 2007; 58(3):299-302.
36. do Nascimento-Junior EM, Dos Santos GMS, Mendes MLT, et al. Cryotherapy in reducing pain, trismus, and facial swelling after third-molar surgery: systematic review and meta-analysis of randomized clinical trials. J Am Dent Assoc. 2019; 150(4):269-277.
37. Wang H, Guan J, Zhang X, et al. Effect of cold application on pain and bruising in patients with subcutaneous injection of low-molecular-weight heparin: A meta-analysis. Clin Appl Thromb Hemost. 2020; 26:1076029620905349.
38. Chen CT, Tung HH, Chen YC, et al. Cold application for pain and anxiety reduction following chest tube removal: A systematic review and meta‐analysis. J Clin Nurs. 2023; 32(3-4):574-583.
39. Poulain B, de Paiva A, Dolly JO, Weller U, Tauc L. Differences in the temperature dependencies of uptake of botulinum and tetanus toxins in Aplysia neurons. Neurosci Lett. 1992; 139(2):289-92.