Brazilian Journal of Anesthesiology
https://bjan-sba.org/article/doi/10.1016/j.bjane.2021.10.010
Brazilian Journal of Anesthesiology
Systematic Review

Safety and effectiveness of adding fentanyl or sufentanil to spinal anesthesia: systematic review and meta-analysis of randomized controlled trials

Neuber Martins Fonseca, Gabriel Magalhães Nunes Guimarães, João Paulo Jordão Pontes, Liana Maria Tores de Araujo Azi, Ricardo de Ávila Oliveira

Downloads: 0
Views: 219

Abstract

Introduction: Spinal infusions of either fentanyl or sufentanil have been reported in international reports, articles, and scientific events worldwide. This study aimed to determine whether intrathecal fentanyl or sufentanil offers safety in mortality and perioperative adverse events.
Methods: MEDLINE (via PubMed), EMBASE, CENTRAL (Cochrane library databases), gray literature, hand-searching, and clinicaltrials.gov were systematically searched. Randomized controlled trials with no language, data, or status restrictions were included, comparing the effectiveness and safety of adding spinal lipophilic opioid to local anesthetics (LAs). Data were pooled using the random-effects models or fixed-effect models based on heterogeneity.
Results: The initial search retrieved 4469 records; 3241 records were eligible, and 3152 articles were excluded after reading titles and abstracts, with a high agreement rate (98.6%). After reading the full texts, 76 articles remained. Spinal fentanyl and sufentanil significantly reduced postoperative pain and opioid consumption, increased analgesia and pruritus. Fentanyl, but not sufentanil, significantly reduced both postoperative nausea and vomiting, and postoperative shivering; compared to LAs alone. The analyzed studies did not report any case of in-hospital mortality related to spinal lipophilic opioids. The rate of respiratory depression was 0.7% and 0.8% when spinal fentanyl or sufentanil was added and when it was not, respectively. Episodes of respiratory depression were rare, uneventful, occurred intraoperatively, and were easily manageable.
Conclusion: There is moderate to high quality certainty that there is evidence regarding the safety and effectiveness of adding lipophilic opioids to LAs in spinal anesthesia.

Keywords

Anesthesia, spinal; Fentanyl; Sufentanil; Safety; Drug-related side effects and adverse reactions

References

1. Finch JS, DeKornfeld TJ. Clinical investigation of the analgesic potency and respiratory depressant activity of fentanyl, a new narcotic analgesic. J Clin Pharmacol J New Drugs. 1967;7:46 −51.
2. Chen SW, Maguire PA, Davies MF, et al. Evidence for mu1-opioid receptor involvement in fentanyl-mediated respiratory depression. Eur J Pharmacol. 1996;312:241−4.
3. Willette RN, Doorley BM, Sapru HN. Activation of cholinergic mechanisms in the medulla oblongata reverse intravenous opioid-induced respiratory depression. J Pharmacol Exp Ther. 1987;240:352−8.
4. Gehling M, Tryba M. Risks and side-effects of intrathecal morphine combined with spinal anaesthesia: a meta-analysis. Anaesthesia. 2009;64:643−51.
5. Wang J, Sun H, Sun W-T, et al. Efficacy and safety of intrathecal morphine for pain control after spinal surgery: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25:2674−84.
6. Uppal V, Retter S, Casey M, et al. Efficacy of intrathecal fentanyl for cesarean delivery: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis. Anesth Analg. 2020;130:111−25.
7. Popping DM, Elia N, Marret E, et al. Opioids added to local anesthetics for single-shot intrathecal anesthesia in patients undergoing minor surgery: a meta-analysis of randomized trials. Pain. 2012;153:784−93.
8. Higgins JPT, Thomas J, Chandler J, et al., Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. 2020 at <https://doi.org/10.1002/9781119536604>
9. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
10. Guyatt GH, Oxman AD, Vist GE, et al. GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924−6. 
11. Agrawal A, Asthana V, Sharma J, et al. Efficacy of lipophilic vs lipophobic opioids in addition to hyperbaric bupivacaine for patients undergoing lower segment caeserean section. Anesth Essays Res. 2016;10:420.
12. Akan B, Yagan O, Bilal B, et al. Comparison of levobupivacaine alone and in combination with fentanyl and sufentanil in patients undergoing transurethral resection of the prostate. J Res Med Sci Off J Isfahan Univ Med Sci. 2013;18:378−82.
13. Asokumar B, Newman LM, McCarthy RJ, et al. Intrathecal bupivacaine reduces pruritus and prolongs duration of fentanyl analgesia  during labor: a prospective, randomized controlled trial. Anesth Analg. 1998;87:1309−15.
14. Atallah MM, Shorrab AA, Abdel Mageed YM, et al. Low-dose bupivacaine spinal anaesthesia for percutaneous nephrolithotomy: the suitability and impact of adding intrathecal fentanyl. Acta Anaesthesiol Scand. 2006;50:798−803.
15. Atallah MM, Helal MA, Shorrab AA. Hypobaric bupivacaine spinal anesthesia for cystoscopic intervention: the impact of adding fentanyl. Middle East J Anaesthesiol. 2003;17:415−26.
16. Attri J, Kaur G, Kaur S, et al. Comparison of levobupivacaine and levobupivacaine with fentanyl in infraumbilical surgeries under spinal anaesthesia. Anesth Essays Res. 2015;9:178−84.

17. Ben-David B, Solomon E, Levin H, et al. Intrathecal fentanyl with small-dose dilute bupivacaine: better anesthesia without prolonging recovery. Anesth Analg. 1997;85:560−5.
18. Ben-David B, Frankel R, Arzumonov T, et al. Minidose bupivacaine- fentanyl spinal anesthesia for surgical repair of hip fracture in the aged. Anesthesiology. 2000;92:6−10.
19. Bidikar M, Mudakanagoudar M, Santhosh MCB. Comparison of intrathecal levobupivacaine and levobupivacaine plus fentanyl for cesarean section. Anesth Essays Res. 2017;11:495−8.
20. Biswas B, Rudra A, Bose B, et al. Intrathecal fentanyl with hyperbaric bupivacaine improves analgesia during caesarean delivery and in early postoperative period. Indian J Anaesth. 2002;46:469.
21. Chandra BJ, Kusum MB, Anurup P, et al. Intrathecal bupivacaine with 5mg of sufentanil or 25mg fentanyl for caesarean delivery in pregnancy induced hypertension. J Anaesthesiol Clin Pharmacol. 2008;24:420.
22. Chilvers CR, Vaghadia H, Mitchell GW, et al. Small-dose hypobaric lidocaine-fentanyl spinal anesthesia for short duration outpatient laparoscopy. II. Optimal fentanyl dose. Anesth Analg. 1997;84:65−70.
23. Cowan CM, Kendall JB, Barclay PM, et al. Comparison of intrathecal fentanyl and diamorphine in addition to bupivacaine for caesarean section under spinal anaesthesia. Br J Anaesth. 2002;89:452−8.
24. Dahlgren G, Hultstrand C, Jakobsson J, et al. Intrathecal sufentanil, fentanyl, or placebo added to bupivacaine for cesarean section. Anesth Analg. 1997;85:1288−93.
25. Desai D, Bumiya P, Upadhyay M. Spinal anesthesia with low dose bupivacaine and fentanyl for femur surgeries in elderly patients. J Anes Cri Open Access. 2019;11:60−4.
26. Farzi F, Mirmansouri A, Naderi Nabi B, et al. Comparing the effect of adding fentanyl, sufentanil, and placebo with intrathecal bupivacaine on duration of analgesia and complications of spinal anesthesia in patients undergoing cesarean section. Anesthesiol Pain Med. 2017;7:e12738.
27. Gauchan S, Thapa C, Prasai A, et al. Effects of intrathecal fentanyl as an adjunct to hyperbaric bupivacaine in spinal anesthesia for elective caesarean section. Nepal Med Coll J NMCJ. 2014;16:5−8.
28. Girgin NK, Gurbet A, Turker G, et al. The combination of lowdose levobupivacaine and fentanyl for spinal anaesthesia in ambulatory inguinal herniorrhaphy. J Int Med Res. 2008;36:1287 −92.
29. Gupta S, Sampley S, Kathuria S, et al. Intrathecal sufentanil or fentanyl as adjuvants to low dose bupivacaine in endoscopic urological procedures. J Anaesthesiol Clin Pharmacol. 2013;29:509−15.
30. Gurbet A, Turker G, Girgin NK, et al. Combination of ultra-low dose bupivacaine and fentanyl for spinal anaesthesia in outpatient anorectal surgery. J Int Med Res. 2008;36:964−70.
31. Hassani V, Movassaghi G, Safaian R, et al. Bupivacaine-sufentanil versus bupivacaine-fentanyl in spinal anesthesia of patients undergoing lower extremity surgery. Anesthesiol Pain Med. 2014;4:e12091.
32. Hoda MQ, Saeed S, Afshan G, et al. Haemodynamic effects of intrathecal bupivacaine for surgical repair of hip fracture. J Pak Med Assoc. 2007;57:245−8.
33. Hunt CO, Naulty JS, Bader AM, et al. Perioperative analgesia with subarachnoid fentanyl-bupivacaine for cesarean delivery. Anesthesiology. 1989;71:535−40.
34. Jain K, Grover VK, Mahajan R, et al. Effect of varying doses of fentanyl with low dose spinal bupivacaine for caesarean delivery in patients with pregnancy-induced hypertension. Int J Obstet Anesth. 2004;13:215−20.
35. Kararmaz A, Kaya S, Turhanoglu S, et al. Low-dose bupivacainefentanyl spinal anaesthesia for transurethral prostatectomy. Anaesthesia. 2003;58:526−30.

36. Khezri MB, Rezaei M, Delkhosh Reihany M, et al. Comparison of postoperative analgesic effect of intrathecal clonidine and fentanyl added to bupivacaine in patients undergoing cesarean section: a prospective randomized double-blind study. Pain Res Treat. 2014;2014:513628.
37. Korhonen AM, Valanne JV, Jokela RM, et al. Intrathecal hyperbaric bupivacaine 3 mg + fentanyl 10 mg for outpatient knee arthroscopy with tourniquet. Acta Anaesthesiol Scand. 2003;47:342−6.
38. Kuberan A, Jain K, Bagga R, et al. The effect of spinal hyperbaric bupivacaine-fentanyl or hyperbaric bupivacaine on uterine tone and fetal heart rate in labouring women: a randomised controlled study. Anaesthesia. 2018;73:832−8.
39. Kuusniemi KS, Pihlajam€aki KK, Pitk€anen MT, et al. The use of bupivacaine and fentanyl for spinal anesthesia for urologic surgery. Anesth Analg. 2000;91:1452−6.
40. Lauretti GR, Mattos AL, Reis MP, et al. Combined intrathecal fentanyl and neostigmine: therapy for postoperative abdominal hysterectomy pain relief. J Clin Anesth. 1998;10:291−6.
41. Lee YY, Muchhal K, Chan CK, et al. Levobupivacaine and fentanyl for spinal anaesthesia: a randomized trial. Eur J Anaesthesiol. 2005;22:899−903.
42. Lee SJ, Kim SH, Jung JD, et al. The effects of intrathecal fentanyl for spinal anesthesia in lower extremity surgery. Korean J Anesthesiol. 2009;56:280−3.
43. Lee JH, Chung KH, Lee JY, et al. Comparison of fentanyl and sufentanil added to 0.5% hyperbaric bupivacaine for spinal anesthesia in patients undergoing cesarean section. Korean J Anesthesiol. 2011;60:103−8.
44. Mahajan R, Grover V, Jain K, et al. Intrathecal fentanyl with low dose hyperbaric bupivacaine for caesarean delivery in patients with pregnancy induced hypertension. J Anaesthesiol Clin Pharmacol. 2005;21:51−8.
45. Makwana J, Tn S, Khande A, et al. Comparison between hyperbaric Bupivacaine and hyperbaric Bupivacaine plus Fentanyl intrathecally in major gynaecological surgeries. Int J Med Sci Public Health. 2014;3:319.
46. Martin R, Tsen LC, Tzeng G, et al. Anesthesia for in vitro fertilization: the addition of fentanyl to 1.5% lidocaine. Anesth Analg. 1999;88:523−6.
47. Martyr JW, Clark MX. Hypotension in elderly patients undergoing spinal anaesthesia for repair of fractured neck of femur. A comparison of two different spinal solutions. Anaesth Intensive Care. 2001;29:501−5.
48. Neeta S, Upadya M, Gosain A, et al. A prospective randomized controlled study comparing intrathecal bupivacaine combined with fentanyl and sufentanil in abdominal and lower limb surgeries. Anesth Essays Res. 2015;9:149−54.
49. Bozdogan Ozyilkan N, Kocum A, Sener M, et al. Comparison of intrathecal levobupivacaine combined with sufentanil, fentanyl, or placebo for elective caesarean section: A prospective, randomized, double-blind, controlled study. Curr Ther Res - Clin Exp. 2013;75:64−70.
50. Palmer CM, Voulgaropoulos D, Alves D. Subarachnoid fentanyl augments lidocaine spinal anesthesia for cesarean delivery. Reg Anesth. 1995;20:389−94.
51. Rajbhandari D, Mahato MP, Dahal P, et al. The comparison of effectiveness of different doses of fentanyl added to hyperbaric bupivacaine for spinal anaesthesia in emergency appendectomy: the comparison of effectiveness of different doses of fentanyl added to hyperbaric bupivacaine for spinal anaesthesia in emergency appendectomy. Medico Res Chron. 2020;7:240−9.
52. Randalls B, Broadway JW, Browne DA, et al. Comparison of four subarachnoid solutions in a needle-through-needle technique for elective caesarean section. Br J Anaesth. 1991;66:314−8. 
53. Sadegh A, Tazeh-kand NF, Eslami B. Intrathecal fentanyl for prevention of shivering in spinal anesthesia in cesarean section. Med J Islam Repub Iran. 2012;26:85−9.

54. Shahriari A, Khooshideh M. Intrathecal fentanyl added to lidocaine for cesarean delivery under spinal anesthesia - A randomised clinical trial. Middle East J Anesthesiol. 2007;19:397 −406.
55. Shim SM, Park JH, Hyun DM, et al. The effects of adjuvant intrathecal fentanyl on postoperative pain and rebound pain for anorectal surgery under saddle anesthesia. Korean J Anesthesiol. 2018;71:213−9.
56. Singh H, Yang J, Thornton K, et al. Intrathecal fentanyl prolongs sensory bupivacaine spinal block. Can J Anaesth J Can Anesth. 1995;42:987−91.
57. Sung TY, Kim MS, Cho CK, et al. Clinical effects of intrathecal fentanyl on shoulder tip pain in laparoscopic total intraperitoneal inguinal hernia repair under spinal anaesthesia: a double-blind, prospective, randomized controlled trial. J Int Med Res. 2013;41:1160−70.
58. Techanivate A, Urusopone P, Kiatgungwanglia P, et al. Intrathecal fentanyl in spinal anesthesia for appendectomy. J Med Assoc Thail Chotmaihet Thangphaet. 2004;87:525−30.
59. Tyagi P, Srivastava A. Comparision of bupivacaine alone and its combination with different doses of fentanyl in spinal anesthesia for cesarean section: a prospective randomized study. Indian J Public Health Res Dev. 2013;4:19.
60. Unal D, Ozdogan L, Ornek HD, et al. Selective spinal anaesthesia with low-dose bupivacaine and bupivacaine + fentanyl in ambulatory arthroscopic knee surgery. J Pak Med Assoc. 2012;62:313 −8.
61. Venkata HG, Pasupuleti S, Pabba UG, et al. A randomized controlled prospective study comparing a low dose bupivacaine and fentanyl mixture to a conventional dose of hyperbaric bupivacaine for cesarean section. Saudi J Anaesth. 2015;9:122−7.
62. Wang H, Peng X, Zhan L, et al. Effects of intrathecal bupivacaine and bupivacaine plus fentanyl in elderly patients undergoing total hip arthroplasty. J Coll Physicians Surg Pak. 2019;29:1133−7.
63. Weigl W, Bierylo A, Wielgus M, et al. Analgesic efficacy of intrathecal fentanyl during the period of highest analgesic demand after cesarean section A randomized controlled study. Med U S. 2016;95:e3827.
64. Wang Y, Guo Q, Wang E, et al. Spinal anesthesia with low dose sufentanil-bupivacaine in transurethral resection of the prostate. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2006;31:925−8.
65. Zohar E, Noga Y, Rislick U, et al. Intrathecal anesthesia for elderly patients undergoing short transurethral procedures: a dose-finding study. Anesth Analg. 2007;104:552−4. 
66. Shende D, Cooper GM, Bowden MI. The influence of intrathecal fentanyl on the characteristics of subarachnoid block for caesarean section. Anaesthesia. 1998;53:706−10.
67. Seewal R, Shende D, Kashyap L, et al. Effect of addition of various doses of fentanyl intrathecally to 0.5% hyperbaric bupivacaine on perioperative analgesia and subarachnoid-block characteristics in lower abdominal surgery: a dose-response study. Reg Anesth Pain Med. 2007;32:20−6.
68. Seyhan T€O, ¸Senturk E, ¸Senbecerir N, et al. Spinal anesthesia in cesarean section with different combinations of bupivacaine and fentanyl. Agri. 2006;18:37−43.
69. Sert€oz N, Aysel I, Uyar M. The effects of sufentanil added to low-dose hyperbaric bupivacaine in unilateral spinal anaesthesia for outpatients undergoing knee arthroscopy. Agri. 2014;26:158−64.
70. Abdollahpour A, Azadi R, Bandari R, et al. Effects of adding midazolam and sufentanil to intrathecal bupivacaine on analgesia quality and postoperative complications in elective cesarean section. Anesthesiol Pain Med. 2015;5:e23565.
71. Aydn F, Akan B, Susleyen C, et al. Comparison of bupivacaine alone and in combination with sufentanil in patients undergoing arthroscopic knee surgery. Knee Surg Sports Traumatol Arthrosc. 2011;19:1915−9.

72. Bang YS, Chung KH, Lee JH, et al. Comparison of clinical effects according to the dosage of sufentanil added to 0.5% hyperbaric bupivacaine for spinal anesthesia in patients undergoing cesarean section. Korean J Anesthesiol. 2012;63:321−6.
73. Braga A de F de A, Braga FS da S, Poterio GMB, et al. Sufentanil added to hyperbaric bupivacaine for subarachnoid block in caesarean section. Eur J Anaesthesiol. 2003;20:631−5.
74. Braga AA, Frias JAF, Braga FS, et al. Spinal anesthesia for cesarean section. Use of hyperbaric bupivacaine (10mg) combined with different adjuvants. Rev Bras Anestesiol. 2012;62:775−87.
75. Demiraran Y, Ozdemir I, Kocaman B, et al. Intrathecal sufentanil (1.5mg) added to hyperbaric bupivacaine (0.5%) for elective cesarean section provides adequate analgesia without need for pruritus therapy. J Anesth. 2006;20:274−8.
76. Derakhshan P, Imani F, Koleini ZS, et al. Comparison of adding sufentanil and low-dose epinephrine to bupivacaine in spinal anesthesia: a randomized, double-blind, clinical trial. Anesthesiol Pain Med. 2018;8:e69600.
77. Doger C, Y€uksel BE, Canoler O, et al. Effects of intrathecal bupivacaine and bupivacaine plus sufentanil in elderly patients undergoing transurethral resection. Niger J Clin Pract. 2014;17:149−53.
78. Donadoni R, Vermeulen H, Noorduin H, et al. Intrathecal sufentanil as a supplement to subarachnoid anaesthesia with lignocaine. Br J Anaesth. 1987;59:1523−7.
79. Kaur M, Katyal S, Kathuria S, et al. A comparative evaluation of intrathecal bupivacaine alone, sufentanil or butorphanol in combination with bupivacaine for endoscopic urological surgery. Saudi J Anaesth. 2011;5:202−7.
80. Olofsson C, Nyga rds EB, Bjersten AB, et al. Low-dose bupivacaine with sufentanil prevents hypotension after spinal anesthesia for hip repair in elderly patients. Acta Anaesthesiol Scand. 2004;48:1240−4. 
81. Vyas N, Sahu DK, Parampill R. Comparative study of intrathecal sufentanil bupivacaine versus intrathecal bupivacaine in patients undergoing elective cesarean section. J Anaesthesiol Clin Pharmacol. 2010;26:488−92.
82. Waxler B, Mondragon SA, Patel SN, et al. Intrathecal lidocaine and sufentanil shorten postoperative recovery after outpatient rectal surgery. Can J Anaesth J Can Anesth. 2004;51:680−4.
83. Hakkim A, Kirubahar R, Kanna V, et al. Comparative study of 0.5% hyperbaric bupivacaine with sufentanil and 0.5% hyperbaric bupivacaine for spinal anesthesia. Int J Res Med Sci. 2015;3:3367−71.
84. Ngiam SK, Chong JL. The addition of intrathecal sufentanil and fentanyl to bupivacaine for caesarean section. Singapore Med J. 1998;39:290−4.
85. Acharya B, Acharya K, Sigdel S, et al. Effect of low dose bupivacaine and fentanyl during elective cesarean section. J Anesth Clin Res. 2019;10:1−6.
86. Walsh KH, Murphy C, Iohom G, et al. Comparison of the effects of two intrathecal anaesthetic techniques for transurethral prostatectomy on haemodynamic and pulmonary function. Eur J Anaesthesiol. 2003;20:560−4.
87. Hamber EA, Viscomi CM. Intrathecal lipophilic opioids as adjuncts to surgical spinal anesthesia. Reg Anesth Pain Med. 1999;24:255−63.
88. Hu J, Zhang C, Yan J, et al. Sufentanil and bupivacaine combination versus bupivacaine alone for spinal anesthesia during cesarean delivery: a meta-analysis of randomized trials. PloS One. 2016;11:e0152605.
89. Bainbridge D, Martin J, Arango M, et al. Perioperative and anaesthetic-related mortality in developed and developing countries: a systematic review and meta-analysis. Lancet Lond Engl. 2012;380:1075−81.
90. Ko S, Goldstein DH, VanDenKerkhof EG. Definitions of “respiratory depression” with intrathecal morphine postoperative analgesia: a review of the literature. Can J Anaesth J Can Anesth. 2003;50:679−88.
91. Rathmell JP, Lair TR, Nauman B. The role of intrathecal drugs in the treatment of acute pain. Anesth Analg. 2005;101:S30−43.
92. Bauchat JR, Weiniger CF, Sultan P, et al. Society for Obstetric Anesthesia and Perinatology Consensus Statement: monitoring recommendations for prevention and detection of respiratory depression associated with administration of neuraxial morphine for cesarean delivery analgesia. Anesth Analg. 2019;129:458−74.
93. Roberts GW, Bekker TB, Carlsen HH, et al. Postoperative nausea and vomiting are strongly influenced by postoperative opioid use in a dose-related manner. Anesth Analg. 2005;101:1343−8.
94. Kuipers PW, Kamphuis ET, Venrooij GE van, et al. Intrathecal opioids and lower urinary tract function. Anesthesiology. 2004;100:1497−503.
95. Schmelz M. Opioid-induced pruritus. Mechanisms and treatment regimens. Anaesthesist. 2009;58:61−5.
96. Figueiredo Locks G de. Incidence of shivering after cesarean section under spinal anesthesia with or without intrathecal sufentanil: a randomized study. Rev Bras Anestesiol.
2012;62:676−84.
97. Negishi C, Lenhardt R, Ozaki M, et al. Opioids inhibit febrile responses in humans, whereas epidural analgesia does not: an explanation for hyperthermia during epidural analgesia. Anesthesiology. 2001;94:218−22.
98. Smith SW, Hauben M, Aronson JK. Paradoxical and bidirectional drug effects. Drug Saf. 2012;35:173−89.


Submitted date:
06/24/2021

Accepted date:
10/02/2021

621688afa9539512e324fc03 rba Articles
Links & Downloads

Braz J Anesthesiol

Share this page
Page Sections