1 SUBMITTED 13 FEB 23 1 REVISIONS REQ. 26 MAR 23; REVISIONS RECD. 1 APR 23 2 ACCEPTED 3 MAY 23 3 ONLINE-FIRST: MAY 2023 4 DOI: https://doi.org/10.18295/squmj.5.2023.026 5 6 Is Forced Coughing Effective in Reducing Pain During Cervical Biopsy? 7 A systematic review and meta-analysis 8 Yassamine Ouerdane,1 Aya Abd Elmegeed,2 Mohammed Tarek,3 Imane 9 Bakhtaoui,4 Ahmed K. Awad,5 *Nihal Al Riyami,6 Ahmed Samy7 10 11 Departments of 1Medicine and 4Pediatric Surgery, Saad Dahlab University, Blida, Algeria; 12 2Department of Zoology, Menofia University, Menofia, Egypt; 3Department of Medicine, Al-13 Azhar University, Cairo, Egypt; 5Department of Medicine, Ain-Shams University, Cairo, Egypt; 14 6Department of Obstetrics and Gynecology, Sultan Qaboos University, Muscat, Oman; 15 7Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt. 16 *Corresponding Author’s e-mail: drriyami@hotmail.com 17 18 Abstract 19 Our objective was to compare potential analgesic effect of forced coughing (FC) technique 20 versus local anesthetics (LA) or placebo during cervical biopsy. We systematically searched five 21 electronic databases from inception till March 2021; Scopus, PubMed, Web of Science, 22 Cochrane Library, Google Scholar. The data was extracted from six RCTs and analyzed them 23 using Review Manager Software. During cervical biopsy, the overall effect estimate favored LA 24 over FC group (MD =1.06; 95% CI [0.58 to 1.54]; p < 0.0001). On the other hand, when 25 compared to no pain management pooled data were comparable between the two groups (MD = -26 1.2; 95% CI [-3.35 to 0.94]; p = 0.27). Procedure duration was significantly longer in LA than 27 FC group (MD = -1.94; 95% CI [-2.47 to - 1.41]; p < 0.00001). FC and LA seemed to useful 28 pain-lowering modalities during the cervical biopsy according to settings and availability. 29 Further studies are recommended. 30 2 Keywords: Cervical Biopsy; Colposcopy; Forced Coughing; Pain. 31 32 Introduction 33 Colposcopic-guided biopsy (CGB) is an easily performed outpatient procedure and is generally 34 done without anesthesia to diagnose and follow up precancerous and cancerous cervical 35 diseases.1 Nevertheless, procedural discomfort and pain could exacerbate patients' anxiety and 36 fear during the procedure, the speculum insertion, or solution application.2 Furthermore, women 37 with known with pre-invasive cervical disease or human papillomavirus (HPV) infection have a 38 higher risk for experiencing pain during the procedures thus needing additional analgesia.3 39 40 In the past two decades, various pharmacological and nonpharmacological methods have been 41 evaluated to reduce pain with CGB. These include benzocaine gel and its spray forms, lidocaine 42 injections, ibuprofen, topical lignocaine gel, and prilocaine anesthesia; however, their results 43 were mixed and non-conclusive.4-6 Injection of 1% lidocaine decreased pain during procedures 44 compared with no anesthetics.7,8 However, it has several disadvantages, such as painful 45 injections, difficulty accessing the injection site, the possibility of tissue damage by needles, thus 46 interfering with the pathological diagnosis, risk of accidental intravascular injection, and allergic 47 reactions.9 In addition, the use of benzocaine spray or topical xylocaine before cervical biopsy 48 showed no benefit in reducing procedural pain.10,11 Oral delivery of pain medication, e.g., 49 ibuprofen, also did not provide an advantage over a placebo in decreasing pain associated with 50 colposcopic-guided cervical biopsy.4 51 52 Similarly, trials of nonpharmacological methods such as coughing, simple visual distraction, 53 hypnosis, and music reported non-conclusive results.12,13 Among all nonpharmacological 54 approaches, forced coughing (FC) has the most significant contribution to pain relief during 55 CGBs, while among pharmacological approaches, local anesthetic agents such as prilocaine and 56 lidocaine have the most significant potential as pain-relieving medication. However, local 57 anesthetic agents have adverse effects that do not exist with forced coughing.9 58 Consequently, this systematic review and meta-analysis was performed to synthesize evidence 59 from published RCTs and compare the efficacy and safety of forced coughing versus local 60 3 anesthetics compared with no analgesia in reducing pain associated with colposcopic-guided 61 biopsy. 62 63 Methods 64 All phases of this study was performed according to the Cochrane handbook for systematic 65 reviews of treatments.14 We also followed the PRISMA statement requirements during reporting 66 of this systematic review and meta-analysis.14 Because this study was a systematic review and 67 meta-analysis, formal ethical approval was not required. 68 69 Literature Search Strategy 70 A comprehensive search was conducted including the following electronic databases: PubMed, 71 Cochrane Central, Scopus, and Web of Science from inception till March 2021. The combination 72 of the following terms were used in our search strategy; (forced and cough or coughing and 73 cervical or cone or cervix and biopsy or colposcopic). No restrictions by language or publication 74 period were employed. We manually screened the references of included studies to retrieve those 75 not identified by database searching. 76 77 Eligibility criteria and study selection 78 All clinical trials that met the following criteria were included in the study:(1) population: 79 patients undergoing colposcopic guided cervical biopsy; (2) intervention: forced coughing; (3) 80 comparator: local anesthetics or control (without any intervention); (4) outcomes: our primary 81 outcome was VAS pain score during cervical biopsy while secondary outcomes were VAS pain 82 score during speculum insertion, immediately and five minutes after the procedure, and duration 83 of the cervical biopsy for both the groups; (5) study design: randomized controlled trials. There 84 was no restriction regarding age, ethnicity, location, and publication date. 85 86 We excluded in vitro and animal studies; studies whose data were unreliable for extraction and 87 analysis overlapped datasets; non-English studies; and conferences, books, review articles, 88 posters, thesis, editorial, notes, letters, case series, and case reports. Two authors independently 89 screened the titles and abstracts of retrieved records for eligibility. In case of disagreement, the 90 full text was retrieved and reviewed independently by a senior author for a final decision. 91 4 92 Data extraction 93 Two authors extracted the studies data independently using an offline data extraction form. The 94 extracted data were study design, population characteristics; risk of bias domains; and study 95 outcomes. Two investigators scored the studies and collected the information independently. In 96 case of discrepancies in scoring, a consensus was reached after discussion. The primary outcome 97 was pain score during cervical biopsy measured by visual analog scale (VAS), while secondary 98 outcomes were VAS pain score during speculum insertion, immediately after the procedure, Five 99 minutes after the procedure, and duration of the cervical biopsy. 100 101 Risk of bias assessment 102 Two independent reviewers used the Cochrane risk of bias (ROB) assessment tool to assess the 103 quality of retrieved RCTs, as described in Chap. 8.5 of the Cochrane handbook of systematic 104 reviews of interventions 5.1.0.14 The Cochrane collaboration risk of bias tool includes six 105 domains, namely random sequence generation (selection bias), allocation sequence concealment 106 (selection bias), blinding of participants and personnel (performance bias), blinding of outcome 107 assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting 108 (reporting bias), and other potential sources of bias. The authors classified studies in each 109 domain as low, high, or unclear risk of bias. 110 111 Data synthesis 112 Changes in VAS scores were calculated as mean difference (MD) and 95% confidence interval 113 (CI) in a fixed-effect model using the Mantel–Haenszel (M–H) method. The fixed-effect model 114 was used, assuming that the included studies were homogeneous and comparable in terms of 115 study design, quality, and measures of treatment effect. Review Manager 5.3 was used for 116 windows during data synthesis and a sensitivity analysis was performed to ensure that none of 117 the included studies affected the results and whether the overall effect size was statistically 118 robust. This resulted in excluding two studies. 119 120 Assessment of heterogeneity 121 5 Heterogeneity was assessed by visual inspection of the forest plots and measured statistically by 122 I2 statistics and chi-square tests. The chi-square test measures significant heterogeneity, while 123 the I2 statistics quantify the magnitude of heterogeneity in the effect size. We assessed and 124 interpreted heterogeneity according to the Cochrane handbook of systematic reviews and meta-125 analysis (chapter 9).14 In this handbook, an alpha level (for chi-square test) below 0.1 is 126 indicative of significant heterogeneity, and the I2 statistic is interpreted as follows: (0–40 %: 127 might not be important; 30–60 %: may represent moderate heterogeneity; 50–90 %: may 128 represent substantial heterogeneity). In the case of significant heterogeneity, the random-effects 129 model was used. Otherwise, the fixed-effect model was employed. 130 131 Publication bias 132 The number of included studies in the analysis was less than 10. Therefore, we cannot assess the 133 publication bias using the Egger test.15 134 135 Results 136 Search results 137 We searched databases for randomized controlled trials matching our eligibility criteria and 138 found a total of 501 records. Only 12 articles were eligible for full-text screening after the title 139 and abstract screening. Of them, only six articles (N=532 patients) were included in our meta-140 analysis, as shown in the PRISMA flow diagram (supplementary fig.1); three studies compared 141 FC with LA (1.0–2.0 mL of 1% lidocaine), two studies compared FC with no pain management, 142 and only one study reported the results of FC compared with LA and no pain treatment. The 143 baseline characteristics of patients and a summary of included studies are shown in Table 1 and 144 supplementary Table 1. 145 146 Risk of bias assessment 147 Using the Cochrane risk-of-bias tool (Version 2) for randomized trials (ROB 2), we found that 148 the quality of included studies was low in most criteria except for bias due to missing outcome 149 data and bias in the selection of reported results. The summary of quality bias assessment 150 domains of included studies is shown in (supplementary fig.2). 151 152 6 Pain during cervical biopsy 153 Pooled data from four studies2,5,16,17 with 378 patients showed a lower pain score in LA group 154 than FC group (MD =1.06; 95% CI [0.58to 1.54]; p ˂ 0. 0001; supplementary fig.3). Pooled 155 studies were homogenous (p =0.27). 156 157 The effect size of a subgroup analysis that compared FC and no pain management showed no 158 statistically significant difference between the two groups (MD = -1.2; 95% CI [-3.35 to 0.94]; p 159 = 0.27; Fig.1). Significant heterogeneity was observed in subgroup analysis that compared FC 160 versus no pain management (p =0.05, I2 = 67%), best resolved by excluding Goldesteinakavia et 161 al. study,18 as shown in Fig.1. 162 163 Pain during speculum insertion 164 Pooled data from four studies2,5,16,17 showed a statistically significant difference between the FC 165 and LA groups with a reduction in the pain score in the FC group (MD = -0.33; 95% CI [-0.64 to 166 -0.01]; p =0.04; Fig.2). Pooled studies were homogenous (p =0.2). 167 168 On the other hand, the overall effect from Kuhn et al.19 and Nakiet al.5 showed no statistically 169 significant difference in pain score during speculum insertion between FC and no pain 170 management group (MD = -0.06; 95% CI [-0.25 to 0.13]; p = 0.53; Fig.2). Pooled studies were 171 homogenous (p =0.91). 172 173 Overall pain score immediately post-procedure 174 The overall effect size showed no significant difference between FC and LA (MD = 075; 95% CI 175 [-0.27 to 1.78]; p = 0.15). Pooled data were homogenous (P=0.45). 176 177 There was no significant difference in overall pain score immediately post-procedure between 178 FC and no pain management group (MD = -2.10; 95% CI [-5.81 to 1.61]; p = 0.27) (Fig.3). 179 Pooled studies were heterogeneous (p ˂ 0. 0001; I2 = 90%). Heterogeneity was best resolved by 180 excluding Goldesteinakavia et al. study,18 as shown in Fig.3. 181 182 Overall score 5 minutes post procedure 183 7 The overall effect size showed no significant difference between FC and LA (MD = - 0.20; 95% 184 CI [-0.89 to -0.58]; p = 0.62; supplementary Fig.4). The results were heterogeneous under a 185 random effect model (p ˂ 0. 00001; I2 = 96%). 186 187 Duration of procedure 188 Pooled data from four studies2,5,16,17 showed a statistically significant difference between FC and 189 LA with longer procedure duration in LA group than FC group (MD=-1.94; 95% CI [-2.47 to -190 1.41]; p ˂ 0. 00001; supplementary Fig.5). Pooled studies were heterogeneous under a random-191 effect model (p =0.0003; I2 =84 %; supplementary Fig.5). Heterogeneity was best resolved by 192 excluding Naki et al. study,5 as shown in supplementary Fig.5. 193 194 Discussion 195 To the best of our knowledge and based on a literature search, this is the first systematic review 196 and meta-analysis to investigate the efficacy of FC in relieving pain during the colposcopic-197 guided biopsy. Our systematic review and meta-analysis showed that FC was better than local 198 anesthesia in reducing pain during speculum insertion; however, no significant differences were 199 found compared to the non-pain management. On the other hand, our analysis favored the LA 200 group with more reduction in pain scores during cervical biopsy compared to the FC group; 201 however, pain scores were comparable in the LA group compared with the non-pain 202 management group. There was no significant difference in the overall pain score post- procedure 203 in the FC group compared to the LA and no pain management. Moreover, the duration of the 204 procedure was shorter in the FC group than in the LA group due to time spent to inject the drug, 205 however this did not affect the amount of tissue obtained. 206 207 Colposcopic-guided biopsy (CGB) has great value in modern gynecology; it is used to examine 208 patients with abnormal cytology and can be used to diagnose changes in cervical or vaginal 209 epithelium. However, many patients remain reluctant to undergo a CGB due to procedure-related 210 pain, anxiety, and discomfort. The fear of pain seems to be the main obstacle to proper 211 gynecological examination.20 The LA injection, such as lidocaine, was painful, and many women 212 were afraid of needles and refused to have those injections. An alternative nonpharmacological 213 pain management technique is FC which can replace LA injections.18 The published literature 214 8 reported no adverse effects or other reactions or costs in the FC group.2,5,16-19 Conversely, 215 injecting a local anesthetic might cause tissue damage that interferes with the pathological 216 diagnosis.16 217 218 Pain is a highly subjective, complex phenomenon, and its perception can be influenced by 219 several factors such as race/ethnicity, gender, previous experience, number of vaginal births, and 220 psychological state.21,22 Several pharmacological and nonpharmacological interventions could 221 help minimize pain sensation,23 and FC is one of the effective pain-relieving measures.16 Forced 222 coughing proved effective during speculum insertion and post-procedure.24 Based on our 223 analysis, the procedure duration in the FC group was shorter than the LA group; the latter might 224 be considered time-consuming due to the inclusion of injection as an additional step in the entire 225 surgical procedure. 226 227 In numerous cases, FC and other methods such as cognitive tasks, music cartoons in children, 228 humor, and imagining pleasant scenes work as distraction methods and could reduce procedural 229 pain.25-27 However, the mechanisms are not fully understood. The gate control theory of pain 230 may explain it.28,29 Moreover, FC results in a sudden rise in blood pressure, which could be a 231 source of pain relief.30,31 232 233 In terms of cervical biopsies, LA was more effective in reducing pain than FC. This was also 234 demonstrated in a recent study by Naki et al.,5 in which they conducted a randomized study 235 comparing local lidocaine injection vs. FC as a distracting method. They found that the FC 236 method may not be a potent distractor, and LA provided significant pain relief during the 237 cervical biopsy. On the other hand, another study by Schmid et al.16 reported that FC during 238 cervical biopsies reduced patients' discomfort to a comparable extent to local anesthesia. So, 239 these conflicting results were evaluated in our analysis, and we also found no differences 240 between the two methods in the overall pain score post-procedure. Pain associated with the 241 injection is missing during forced coughing; however, this advantage did not reduce pain 242 sensation during CGB. 243 244 9 The colposcopic procedure is performed as an outpatient clinical practice, and physicians give 245 attention to doing this procedure at an appropriate time. FC cuts down the costs associated with 246 the biopsy, and we show here that FC is time-saving compared with LA, in which its use would 247 be an important issue for clinics with low resources and a high volume of patients when choosing 248 their pain relief methods. 249 250 However, the use of LA is encouraged due to its significant effect in reducing pain sensation 251 during cervical biopsy compared with the nonpharmacological forced coughing method. 252 253 Strengths and weaknesses 254 We included six RCTs in the quantitative analysis constituting a strong evidence level. The 255 included studies range from moderate to high quality. The main limitation of our study is related 256 to the evaluation of pain with a VAS score which is not an objective method and can be 257 influenced by several factors, such as social and cultural status. 258 259 Conclusion 260 The forced coughing technique and local anesthetics are useful as pain-lowering modalities 261 during the colposcopy-guided biopsy, however local anesthetics seemed to be more beneficial 262 but this was not statistically significantaccording to settings and availability.We advise using 263 local anesthetics as potentially effective pain lowering modality during colposcopy and cervical 264 biopsy. If not available, forced coughing technique would be an appropriate, simple and practical 265 alternative to lower pain during colposcopy. Further studies with larger sample size are 266 recommended to support this recommendation. 267 268 Conflict of Interest 269 The authors have no conflicts of interest. 270 271 Authors’ Contribution 272 AS conceptualized the idea. YO validated the idea and formulated the search strategy. YO, AAE, 273 IB, MT and AKA collected the data. AAE, IB, MT and AKA assessed the quality of the data and 274 prepared the graphs. IB prepared the summary and baseline tables. YO and AAE analyzed the 275 10 data. YO, AAE, MT and AKA drafted the manuscript. NAR and AS reviewed and edited the 276 manuscript. All authors approved the final version of the manuscript. 277 278 References 279 1. Escobar PF, Rojas-Espaillat L, Tisci S, Enerson C, Brainard J, Smith J, et al. Optical 280 coherence tomography as a diagnostic aid to visual inspection and colposcopy for preinvasive 281 and invasive cancer of the uterine cervix. Int J Gynecol Cancer [Internet]. 2006 Sep;16(5):1815–282 22. Available from: https://ijgc.bmj.com/lookup/doi/10.1111/j.1525-1438.2006.00665.x. DOI: 283 10.1111/j.1525-1438.2006.00665.x 284 2. Bogani G, Serati M, Cromi A, Di Naro E, Casarin J, Pinelli C, et al. Local anesthetic 285 versus forced coughing at colposcopic-guided biopsy: a prospective study. Eur J Obstet Gynecol 286 Reprod Biol [Internet]. 2014 Oct;181:15–9. Available from: 287 https://linkinghub.elsevier.com/retrieve/pii/S0301211514003947. DOI: 288 10.1016/j.ejogrb.2014.07.022 289 3. Mercier RJ, Zerden ML. Intrauterine Anesthesia for Gynecologic Procedures. Obstet 290 Gynecol [Internet]. 2012 Sep;120(3):669–77. Available from: 291 http://journals.lww.com/00006250-201209000-00027. DOI: 10.1097/AOG.0b013e3182639ab5 292 4. Church L. Analgesia for colposcopy: double-masked, randomized comparison of 293 ibuprofen and benzocaine gel. Obstet Gynecol [Internet]. 2001 Jan;97(1):5–10. Available from: 294 http://linkinghub.elsevier.com/retrieve/pii/S002978440001084X. DOI: 10.1016/s0029-295 7844(00)01084-x 296 5. Naki MM, Api O, Acioglu HC, Uzun MG, Kars B, Unal O. Analgesic Efficacy of Forced 297 Coughing versus Local Anesthesia during Cervical Punch Biopsy. Gynecol Obstet Invest 298 [Internet]. 2011;72(1):5–9. Available from: https://www.karger.com/Article/FullText/320842. 299 DOI: 10.1159/000320842 300 6. Wong G, Li R, Wong T, Fan S. The effect of topical lignocaine gel in pain relief for 301 colposcopic assessment and biopsy: is it useful? BJOG An Int J Obstet Gynaecol [Internet]. 2008 302 Jul;115(8):1057–60. Available from: http://doi.wiley.com/10.1111/j.1471-303 0528.2008.01780.xDoi: 10.1111/j.1471-0528.2008.01780.x 304 7. Oyama IA, Wakabayashi MT, Frattarelli LC, Kessel B. Local anesthetic reduces the pain 305 of colposcopic biopsies: A randomized trial. Am J Obstet Gynecol [Internet]. 2003 306 https://ijgc.bmj.com/lookup/doi/10.1111/j.1525-1438.2006.00665.x https://linkinghub.elsevier.com/retrieve/pii/S0301211514003947 http://journals.lww.com/00006250-201209000-00027 http://linkinghub.elsevier.com/retrieve/pii/S002978440001084X https://www.karger.com/Article/FullText/320842 11 May;188(5):1164–5. Available from: 307 https://linkinghub.elsevier.com/retrieve/pii/S0002937803001200. DOI: 10.1067/mob.2003.290. 308 8. Duncan ID, McKinley CA, Pinion SB, Wilson SM. A Double-Blind, Randomized, 309 Placebo-Controlled Trial of Prilocaine and Felypressin (Citanest and Octapressin) for the Relief 310 of Pain Associated with Cervical Biopsy and Treatment with the Semm Coagulator. J Low Genit 311 Tract Dis [Internet]. 2005 Jul;9(3):171–5. Available from: https://journals.lww.com/00128360-312 200507000-00008. DOI:10.1097/01.LGT.0000171663.86847.45 313 9. Speca SJ, Boynes SG, Cuddy MA. Allergic Reactions to Local Anesthetic Formulations. 314 Dent Clin North Am [Internet]. 2010 Oct;54(4):655–64. Available from: 315 https://linkinghub.elsevier.com/retrieve/pii/S0011853210000649. Doi: 316 10.1016/j.cden.2010.06.006 317 10. Clifton PA, Shaughnessy AF, Andrews S. Ineffectiveness of topical benzocaine spray 318 during colposcopy. J Fam Pract [Internet]. 1998 Mar;46(3):242–6. Available from: 319 http://www.ncbi.nlm.nih.gov/pubmed/9519022 320 11. Prefontaine M, Fung-Kee-Fung M, Moher D. Comparison of topical Xylocaine with 321 placebo as a local anesthetic in colposcopic biopsies. Can J Surg [Internet]. 1991 Apr;34(2):163–322 5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2025805 323 12. Carwile JL, Feldman S, Johnson NR. Use of a Simple Visual Distraction to Reduce Pain 324 and Anxiety in Patients Undergoing Colposcopy. J Low Genit Tract Dis 325 [Internet]. 2014 Oct;18(4):317–21. Available from: https://journals.lww.com/00128360-326 201410000-00008. DOI:10.1097/LGT.0000000000000024 327 13. Chan Y., Lee PW., Ng T., Ngan HY., Wong L. The use of music to reduce anxiety for 328 patients undergoing colposcopy: a randomized trial. Gynecol Oncol [Internet]. 2003 329 Oct;91(1):213–7. Available from: 330 https://linkinghub.elsevier.com/retrieve/pii/S0090825803004128. DOI: 10.1016/s0090-331 8258(03)00412-8 332 14. Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of 333 Interventions. Chichester, UK: John Wiley & Sons, Ltd; 2008. 334 15. Stuck AE, Rubenstein LZ, Wieland D, Vandenbroucke JP, Irwig L, Macaskill P, et al. 335 Bias in meta-analysis detected by a simple, graphical. BMJ. 1998 Feb;316(7129):469–469. 336 https://linkinghub.elsevier.com/retrieve/pii/S0002937803001200 https://journals.lww.com/00128360-200507000-00008 https://journals.lww.com/00128360-200507000-00008 https://linkinghub.elsevier.com/retrieve/pii/S0011853210000649 https://journals.lww.com/00128360-201410000-00008 https://journals.lww.com/00128360-201410000-00008 https://linkinghub.elsevier.com/retrieve/pii/S0090825803004128 12 16. Schmid BC, Pils S, Heinze G, Hefler L, Reinthaller A, Speiser P. Forced coughing versus 337 local anesthesia and pain associated with cervical biopsy: a randomized trial. Am J Obstet 338 Gynecol [Internet]. 2008 Dec;199(6):641.e1-641.e3. Available from: 339 https://linkinghub.elsevier.com/retrieve/pii/S0002937808008016. DOI: 340 10.1016/j.ajog.2008.07.017 341 17. Karaman E, Kolusarı A, Alkış İ, Çetin O. Comparison of topical lidocaine spray with 342 forced coughing in pain relief during colposcopic biopsy procedure: a randomised trial. J Obstet 343 Gynaecol (Lahore) [Internet]. 2019 May 19;39(4):534–8. Available from: 344 https://www.tandfonline.com/doi/full/10.1080/01443615.2018.1538329 DOI: 345 10.1080/01443615.2018.1538329 346 18. Goldstein Akavia T, Segev Y, Balan E, Siegler E. The analgesic efficacy of forced 347 coughing during cervical punch biopsy: A prospective randomised controlled study. Aust New 348 Zeal J Obstet Gynaecol [Internet]. 2018 Dec 7;58(6):681–5. Available from: 349 https://onlinelibrary.wiley.com/doi/abs/10.1111/ajo.12784. DOI: 10.1111/ajo.12784 350 19. Kuhn T, Ukazu A, Strickland PO, Roche N, Taveras Y, Kovalenko O, et al. 351 The Effect of Forced Cough to Minimize Pain and Discomfort at the Time of Colposcopy-352 Guided Cervical Biopsy. J Low Genit Tract Dis [Internet]. 2020 Apr;24(2):211–4. Available 353 from: http://journals.lww.com/10.1097/LGT.0000000000000517. DOI: 354 10.1097/LGT.0000000000000517 355 20. Stafl A. Colposcopy. Cancer [Internet]. 1976 Jul;38(1):432–5. Available from: 356 https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(197607)38:1%3C432::AID- 357 CNCR2820380167%3E3.0.CO;2-Q 358 21. Linton SJ, Shaw WS. Impact of Psychological Factors in the Experience of Pain. Phys 359 Ther [Internet]. 2011 May 1;91(5):700–11. Available from: https://academic.oup.com/ptj/article-360 lookup/doi/10.2522/ptj.20100330. Doi: 10.2522/ptj.20100330 361 22. Wandner LD, Scipio CD, Hirsh AT, Torres CA, Robinson ME. The Perception of Pain in 362 Others: How Gender, Race, and Age Influence Pain Expectations. J Pain [Internet]. 2012 363 Mar;13(3):220–7. Available from: 364 https://linkinghub.elsevier.com/retrieve/pii/S152659001100873X. Doi: 365 10.1016/j.jpain.2011.10.014 366 https://linkinghub.elsevier.com/retrieve/pii/S0002937808008016 https://onlinelibrary.wiley.com/doi/abs/10.1111/ajo.12784 http://journals.lww.com/10.1097/LGT.0000000000000517 https://academic.oup.com/ptj/article-lookup/doi/10.2522/ptj.20100330 https://academic.oup.com/ptj/article-lookup/doi/10.2522/ptj.20100330 https://linkinghub.elsevier.com/retrieve/pii/S152659001100873X 13 23. Bukola IM, Paula D. The Effectiveness of Distraction as Procedural Pain Management 367 Technique in Pediatric Oncology Patients: A Meta-analysis and Systematic Review. J Pain 368 Symptom Manage [Internet]. 2017 Oct;54(4):589-600.e1. Available from: 369 https://linkinghub.elsevier.com/retrieve/pii/S0885392417302695. Doi: 370 10.1016/j.jpainsymman.2017.07.006 371 24. Kiviharju M, Kalliala I, Nieminen P, Dyba T, Riska A, Jakobsson M. Pain Sensation 372 During Colposcopy and Cervical Biopsy, With or Without Local Anesthesia: A Randomized 373 Trial. J Low Genit Tract Dis [Internet]. 2017 Apr;21(2):102–7. Available from: 374 https://journals.lww.com/00128360-201704000- 00004. DOI: 10.1097/LGT.0000000000000292 375 25. Tsao JCI, Fanurik D, Zeltzer LK. Long-Term Effects of a Brief Distraction Intervention 376 on Children’s Laboratory Pain Reactivity. Behav Modif [Internet]. 2003 Apr 26;27(2):217–32. 377 Available from: http://journals.sagepub.com/doi/10.1177/0145445503251583. 378 Doi.org/10.1177/0145445503251583 379 26. Fowler-Kerry S, Lander JR. Management of injection pain in children. Pain [Internet]. 380 1987 Aug;30(2):169–75. Available from: https://journals.lww.com/00006396-198708000-00003. 381 Doi: 10.1016/0304-3959(87)91072-4. 382 27. Weisenberg M, Tepper I, Schwarzwald J. Humor as a cognitive technique for increasing 383 pain tolerance. Pain [Internet]. 1995 Nov;63(2):207–12. Available from: 384 https://journals.lww.com/00006396-199511000-00009. Doi: 10.1016/0304-3959(95)00046-U 385 28. Melzack R, Wall PD. Pain Mechanisms: A New Theory. Science (80- ) [Internet]. 1965 386 Nov 19;150(3699):971–8. Available from: 387 https://www.sciencemag.org/lookup/doi/10.1126/science.150.3699.971. DOI: 388 10.1126/science.150.3699.971 389 29. Bruehl S, Chung OY, Ward P, Johnson B, McCubbin JA. The relationship between 390 resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain 391 sufferers: the effects of opioid blockade. Pain [Internet]. 2002 Nov;100(1):191–201. Available 392 from: https://journals.lww.com/00006396- 200211000-00020. DOI: 10.1016/S0304-393 3959(02)00295-6 394 30. Kern MJ, Gudipati C, Tatineni S, Aguirre F, Serota H, Deligonul U. Effect of abruptly 395 increased intrathoracic pressure on coronary blood flow velocity in patients. Am Heart J 396 [Internet]. 1990 Apr;119(4):863–70. Available from: 397 https://linkinghub.elsevier.com/retrieve/pii/S0885392417302695 http://journals.sagepub.com/doi/10.1177/0145445503251583 https://journals.lww.com/00006396-198708000-00003 https://journals.lww.com/00006396-199511000-00009 https://www.sciencemag.org/lookup/doi/10.1126/science.150.3699.971 14 https://linkinghub.elsevier.com/retrieve/pii/S0002870305803242. DOI: 10.1016/S0002-398 8703(05)80324-2 399 400 https://linkinghub.elsevier.com/retrieve/pii/S0002870305803242 15 Table 1: Baseline characteristics of included studies 401 Study ID Arms Total number Age M±SD BMI M±S D Obstetric history Indication for biopsy Vagina l birth numbe r (%) Cesarean birth number (%) Curettage number (%) H-SIL number (%) L-SIL number (%) Bogani 2014 (2) Forced coughing 49 34±11.25 7 (14%) 2 (4%) 11 (22%) 32(66%) Local anesthetic 51 38±11.5 14 (27%) 1(2%) 8 (16%) 40 (78%) Goldstein akavia 2018 (17) Forced coughing 45 33.02±3.7 8 1 (2.2%) 11 (24.4%) no pain management 45 31.23±3.4 1 4 (8.8%) 11 (24.4%) Karaman 2019 (20) Forced coughing 42 41.6± 10.9 26.9 ± 4.2 30 (71.4%) 5 (12.5%) 6 (14.2%) 20 (47.6%) Lidocaine spray 44 42.1 ± 11.4 27.62 ± 3.2 32 (72.7%) 6 (14.2%) 6 (13.6%) 20(45.4%) Kuhn 2020 (18) Forced coughing 56 36.8± 11.1 29.1 (6.5) 14 (25) 46 (82.1) no pain management 54 37.9±10.3 28.5 (4.9) 22 (40.7) 40 (74.1) Naki 2011 (5) Forced coughing 39 37.3±9.9 Local anesthetic 39 40.4±9.1 no pain management 36 38.9±7.6 Schmid 2008 (21) Forced coughing 34 Local anesthetic 34 * SD: Standard deviation; BMI: body mass index, H-SIL: high grade squamous intraepithelial 402 lesion; L-SIL: low grade squamous intraepithelial lesion; ASCUS: atypical squamous cell of 403 undetermined significance. 404 16 405 Figure 1: VAS pain score during cervical biopsy in the forced coughing group compared with 406 LA and no pain management group respectively after resolving heterogeneity. 407 408 409 Figure 2: VAS pain score during speculum insertion in forced coughing group compared with 410 LA and no pain management group respectively 411 412 413 17 414 Figure 3: Overall VAS pain score immediately after the procedure in the forced coughing group 415 compared with LA and no pain management group respectively, after removing heterogeneity. 416 417 418