Single-centre, randomized, clinical trial of opioid-free analgesia versus routine opioid-based analgesia regimen for the management of acute post-operative pain following caesarean section: study protocol
Background: Pain management post-caesarean section is a common source of exposure to opioids in women. To address the rising opioid addiction associated with peri-operative administration, trend in operative analgesia is moving towards opioid-free, multimodal analgesia. We present our protocol for this study so that it may be replicated in other settings and possibly modified for future studies.
Methods: In a Single-centre, non-inferiority, parallel, randomized, controlled, clinical trial with balanced allocation [1:1] into two arms, we compared a peri-operative opioid-free analgesia regimen with a routine post-operative opioid-based analgesia regimen in women undergoing caesarean section under spinal anaesthesia. Primary outcome measures were post-operative pain intensity at 4, 8 and 24 hours (using Numerical Rating Scale) and post-operative pentazocine use. Secondary outcome measures were the incidence of adverse events and Apgar score. Results will be published in a peer-reviewed, open access journal.
Conclusions: This protocol adopted the use of intravenous paracetamol and intravenous NSAID as baseline analgesics. Magnesium sulphate was introduced peri-operatively as part of our opioid-free multimodal analgesia regimen because of its established effect in decreasing post-operative pain and opioid use. We also relied on the preventive analgesic effect of administration of intravenous paracetamol and intravenous magnesium sulphate before surgical incision, continued intraoperatively and post-operatively. In addition, magnesium sulphate is a familiar drug to the obstetrician, readily available and affordable in most settings where comprehensive emergency obstetric care is offered, easy to administer and it has been well tolerated clinically.
Trial registration: This protocol was registered with clinicaltrials.gov (Identifier: NCT04539249) on September 3, 2020, prospectively.
Yim N, Parsa FD. From the Origins of the opioid use (and misuse) to the challenge of opioid-free pain management in surgery. In: Cascella M, ed. From conventional to innovative approaches for pain treatment. London, UK: IntechOpen; 2018. Available at: http://dx.doi.org/10.5772/intechopen. 82675. Accessed on 7 November, 2020.
Schaefer CP, Tome ME, Davis TP. The opioid epidemic: a central role for the blood brain barrier in opioid analgesia and abuse. Fluids Barriers CNS. 2017;14:32.
Koekpe EJ, Manning EL, Miller TE, Ganesh A, Williams DGA, Manning MW. The rising tide of opioid use and abuse: the role of anaesthesiologist. Perioper Med. 2018;7:16. Available at: https://dx.doi.org/10.1186/s13741-018-0097-4. Accessed on January 24, 2020.
Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77(5):1048-56.
Kehlet H. Surgical stress: the role of pain and analgesia. Br J Anaesth. 1989;63(2):189-95.
Malek J, Sevcik P, Bejsovec D, Gabrhelik T, Hnilicova M, Krikava I, et al. Postoperative pain management. 3rd ed. Prague, Czech Republic: Mlada fronta a.s.; 2017. Available at: https://www.wfsahq.org/components/com_virtual_library/media/125136f77e1b7daf7565bd6653026c35-Postoperative-Pain-Management-170518.pdf. Accessed on 24 January, 2020.
Zukowski M, Kotfis K. The use of opioid adjuvants in perioperative multimodal analgesia. Anestezjol Intens Ter. 2012;44(1):42-6.
Wick EC, Grant MC, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: a review. JAMA Surg. 2017;152(7):691-7.
Bateman BT, Franklin JM, Bykov K, Avorn J, Shrank WH, Brennan TA, et al. Persistent opioid use following Cesarean delivery: patterns and predictors among opioid naive women. Am J Obstet Gynecol. 2016;215(3):353-18.
Brummett CM, Waljee JF, Goesling J, Moser S, Lin P, Englesbe MJ, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152(6):e170504.
Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of and risk factors for chronic opioid use among opioid-naive patients in the postoperative period. JAMA Intern Med. 2016;176(9):1286-93.
Zhao S, Chen F, Feng A, Han W, Zhang Y. Risk factors and prevention strategies for postoperative opioid abuse. Pain Res Manag. 2019;2019:7490801.
Klimas J, Gorfinkel L, Fairbairn N, Amato L, Ahamad K, Nolan S, et al. Strategies to identify patient risks of prescription opioid addiction when initiating opioids for pain: a systematic review. JAMA Netw. Open. 2019;2(5):e193365.
Centers for Disease Control and Prevention. Drug overdose deaths. Washington, D.C, U.S. Department of Health & Human Services; 2019. Available at: https://www.cdc.gov/drugoverdose/ data/statedeaths.html. Accessed on 1 November, 2019.
Moghe S. Opioid history: from ‘wonder drug’ to abuse epidemic. Atlanta, Georgia: Cable News Network; 2016. Available at: www.cnn.com/2016/05/12/health/opioid-addiction-history/. Accessed on 1 November, 2019.
Adeosun AA. Opioid crisis: a public health concern in Colorado, United States. J Glob Health Rep. 2019;3:e2019056.
Belzak L, Halverson J. Evidence synthesis – The opioid crisis in Canada: a national perspective. Health Promot Chronic Dis Prev Can. 2018;38(6):224-33.
National Drug & Alcohol Research Centre (AU). Majority of opioid overdose deaths in Australia are related to pharmaceutical opioids. Sydney, AU: University of New South Wales; 2019. Available at: http://connections.edu.au/news/majority-opioid-overdose-deaths-australia-are-related-pharmaceutical-opioids. Accessed on 24 January, 2020.
Royal Pharmaceutical Society. Opioid overdose deaths ‘rising sharply’ in England and Wales OECD says. London, UK: Royal Pharmaceutical Society; 2019. Available at: https://doi.org/10.1211/PJ.2019. 20206561. Accessed on 24 January, 2020.
Federal Ministry of Health, Government of Nigeria; National Bureau of Statistics, Government of Nigeria; Centre for Research and Information on Substance Abuse (CRISA); United Nations office on Drugs and Crime (UNODC). Drug use in Nigeria. Vienna, Austria: United Nations office on Drugs and Crime. 2018:57.
Loewenstein A, Zalk N. West Africa’s opioid crisis. Doha, Qatar: Al Jazeera Media Network; 2019. Available at: https://www.aljazeera. com/programmes/peopleandpower/2019/08/west-africa-opioid-crisis-190827135612104.html. Accessed on 4 November, 2020.
Kazeem Y. A national survey has confirmed the massive scale of Nigeria’s drug problem. New York: Quartz Media, Inc.; 2019. Available at: https://qz.com/africa/1538843/nigeria-drug-abuse-14-million-adults-use-drugs/amp/. Accessed November 4, 2020.
Lee B, Schug SA, Joshi GP, Kehlet H. Prospect Working Group. Procedure-specific pain management (PROSPECT) – an update. Best Pract Res Clin Anaesthesiol. 2018;32(2):101-11.
Kamdar NV, Hoftman N, Rahman S, Cannesson M. Opioid-free analgesia in the era of enhanced recovery after surgery and the surgical home: implications for postoperative outcomes and population health. Anesth. Analg. 2017;125(4):1089-91.
Fiore Jr. JF, Olleik G, Charbel EAK, Alldrit A, Figueiredo AG, Marquez-Gdev SA, et al. Preventing opioid prescription after major surgery: a scoping review of opioid-free analgesia. Br. J. Anaesth. 2019;123(5):627-36.
Vadivelu N, Mitra S, Schermer E, Kodumudi V, Kaye AD, Urman RD. Preventive analgesia for postoperative pain control: a broader concept. Local Reg Anesth. 2014;7:17-22.
Kim M. An opioid success story: efforts to minimize painkillers after surgery appear to be working. Johannesburg, South Africa: The Conversation Africa, Inc.; 2019. Available at: https://www.google.com/amp/s/theconversation.com/amp/an-opioid-success-story-efforts-to-minimize-painkillers-after-surgery-appear-to-be-working-119148. Accessed on 5 November, 2019.
Johnson SR. Hospitals look to cut opioids from surgery and beyond. Detroit, Michigan: Crain communications, Inc.; 2019. Available at: https://www.modernhealthcare.com/care-delivery/hospitals-look-cut-opioids-surgery-and-beyond. Accessed on 24 January, 2020.
Dennis J, Soto E, Chauhan SP, Sibai B. Non-opioid versus opioid analgesia after hospital discharge from a caesarean delivery: a randomized clinical trial. Am J Obstet Gynecol. 2019;220(1):S34.
Egede JO, Ajah LO, Umeora OU, Ozumba BC, Onoh RC, Obuna JA, et al. Pentazocine alone versus pentazocine plus diclofenac for pain relief in the first 24 hours after Caesarean section: a randomized controlled study. J Clin Diagn Res. 2017;11(4):1-5.
Bakhsha F, Niaki AS, Jafari SY, Yousefi Z, Aryaie M. The effects of diclofenac suppository and intravenous paracetamol and their combination on the severity of postoperative pain in patients undergoing spinal anaesthesia during caesarean section. J Clin Diagn Res. 2016;10(7):UC09-12.
European Society of Regional Anaesthesia & Pain Therapy. Overall recommendations: pain management for elective caesarean section surgery. Geneva, Switzerland: European Society of Regional Anaesthesia & Pain Therapy; 2020. Available at: https://esraeurope.org/prospect/procedures/c-section/prospect-recommendations/. Accessed on 5 November, 2019.
Sravani P, Indrani C, Rajanna SP. Efficacy of Surgical Transversus Abdominis Plane Block in Patients Undergoing Cesarean Delivery. J South Asian Feder Obst Gynae. 2020;12(5):302-6.
Wehbe SA, Ghulmiyyah LM, Dominique EH, Hosford SL, Ehleben CM, Saltzman SL, et al. Prospective randomized trial of iliohypogastric-ilioinguinal nerve block on post-operativbe morphine use after inpatient surgery of the female reproductive tract. J Negat Results Biomed. 2008;7:11.
Kahraman F, Eroglu A. The effect of intravenous magnesium sulphate infusion on sensory spinal block and postoperative pain score in abdominal hysterectomy. Biomed Res Int. 2014;2014:236024.
McKeown A, Seppi V, Hodgson R. Intravenous magnesium sulphate for analgesia after caesarean section: a systematic review. Anesthesiol Res Pract. 2017;2017:9186374.
Shin HJ, Kim EY, Na HS, Kim TK, Kim MH, Do SH. Magnesium sulphate attenuates acute postoperative pain and increased pain intensity after surgical injury in staged bilateral total knee arthroplasty: a randomized, double-blinded, placebo-controlled trial. Br J Anaesth. 2016;117(4):497-503.
Kalani N, Sanie MS, Zabetian H, Radmehr M, Sahraei R, Jahromi HK, et al. Comparison of the analgesic effect of paracetamol and magnesium sulphate during surgeries. World J Plast Surg. 2016;5(3):280-6.
Murphy JD, Paskaradevan J, Eisler LL, Ouanes JP, Tomas VA, Freck EA, et al. Analgesic efficacy of continuous intravenous magnesium infusion as an adjunct to morphine for postoperative analgesia: a systematic review and meta-analysis. Middle East J Anesthesiol. 2013;22(11);11-20.
Albrecht E, Kirkham KR, Liu SS, Brull R. Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013;68(1):79-90.
Alam W, Yaqub KM, Saeed MA. Fixed dose vs height and weight adjusted dose of bupivacaine for caesarean section: A randomised controlled trial. J Pak Med Assoc. 2018;68(9):1345-9.
Flight L, Julious SA. Practical guide to sample size calculations: non-inferiority and equivalence trials. Pharm Stat. 2016;15(1):80-9.
Borges NC, Silva BC, Pedroso CF, Silva TC, Tatagiba BSF, Pereira LV. Postoperative pain in women undergoing caesarean section. Enferm. Glob. 2017;16(4):374-83.
Cepeda MS, Africano JM, Polo R, Alcala R, Carr DB. What decline in pain intensity is meaningful to patients with acute pain? Pain. 2003;105(1-2):151-7.
European Society of Regional Anaesthesia & Pain Therapy. Evidence review process: procedure specific pain management for elective caesarean section surgery 2020. Geneva, Switzerland: European Society of Regional Anaesthesia & Pain Therapy; 2020. Available at: https://esraeurope.org/prospect/procedures/caesarean-section-2020/evidence-review-process-16/. Accessed on 5 April, 2021.
European Society of Regional Anaesthesia & Pain Therapy. Summary recommendations: procedure specific pain management for elective caesarean section surgery 2020. Geneva, Switzerland: European Society of Regional Anaesthesia & Pain Therapy; 2020. Available at: https://esraeurope.org/prospect/procedures/caesarean-section-2020/summary-recommendations-20/. Accessed on 5 April, 2021.
European Society of Regional Anaesthesia & Pain Therapy. Prospect Methodology: procedure specific pain management for elective caesarean section surgery. Geneva, Switzerland: European Society of Regional Anaesthesia & Pain Therapy; 2020. Available at: https://esraeurope.org/prospect-methodology/. Accessed on 5 April, 2021.