Opioid-Free Anesthesia Benefit-Risk Balance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Arthur Salomé, Hakim Harkouk, Dominique Fletcher, Valeria Martinez, Arthur Salomé, Hakim Harkouk, Dominique Fletcher, Valeria Martinez

Abstract

Opioid-free anesthesia (OFA) is used in surgery to avoid opioid-related side effects. However, uncertainty exists in the balance between OFA benefits and risks. We searched for randomized controlled trials (RCTs) comparing OFA to opioid-based anesthesia (OBA) in five international databases. The co-primary outcomes were postoperative acute pain and morphine consumption at 2, 24, and 48 h. The secondary outcomes were the incidence of postoperative chronic pain, hemodynamic tolerance, severe adverse effects, opioid-related adverse effects, and specific adverse effects related to substitution drugs. Overall, 33 RCTs including 2209 participants were assessed. At 2 h, the OFA groups had lower pain scores at rest MD (0.75 (-1.18; -0.32)), which did not definitively reach MCID. Less morphine was required in the OFA groups at 2 and 24 h, but with very small reductions: 1.61 mg (-2.69; -0.53) and -1.73 mg (p < 0.05), respectively, both not reaching MCID. The reduction in PONV in the OFA group in the PACU presented an RR of 0.46 (0.38, 0.56) and an RR of 0.34 (0.21; 0.56), respectively. Less sedation and shivering were observed in the OFA groups with an SMD of -0.81 (-1.05; -0.58) and an RR of 0.48 (0.33; 0.70), respectively. Quantitative analysis did not reveal differences between the hemodynamic outcomes, although severe side effects have been identified in the literature. No clinically significant benefits were observed with OFA in terms of pain and opioid use after surgery. A clear benefit of OFA use was observed with respect to a reduction in PONV. However, more data on the safe use of OFAs should be collected and caution should be taken in the development of OFA.

Keywords: adverse effect; analgesia; anesthesia; opioid-free anesthesia; systematic review.

Conflict of interest statement

V.M. received payments and travel funds for lectures from Jansen and Grunenthal. D.F. received payments and travel funds for lectures from Grunenthal, Biocodex, andMundipharma. A.S. and H.H. have no competing interests to declare.

Figures

Figure 1
Figure 1
PRISMA flow chart detailing retrieved, excluded, assessed, and included trials.
Figure 2
Figure 2
Risk-of-bias summary: review of authors’ judgements about each risk-of-bias item for each included study.
Figure 3
Figure 3
Forest plot for nausea and vomiting in the PACU.

References

    1. Egan T.D. Are opioids indispensable for general anaesthesia? Br. J. Anaesth. 2019;122:e127–e135. doi: 10.1016/j.bja.2019.02.018.
    1. Koepke E.J., Manning E.L., Miller T.E., Ganesh A., Williams D.G.A., Manning M.W. The rising tide of opioid use and abuse: The role of the anesthesiologist. Perioper. Med. 2018;7:16. doi: 10.1186/s13741-018-0097-4.
    1. Beloeil H. Opioid-free anesthesia. Best Pract. Res. Clin. Anaesthesiol. 2019;33:353–360. doi: 10.1016/j.bpa.2019.09.002.
    1. Frauenknecht J., Kirkham K.R., Jacot-Guillarmod A., Albrecht E. Analgesic impact of intra-operative opioids vs. opioid-free anaesthesia: A systematic review and meta-analysis. Anaesthesia. 2019;74:651–662. doi: 10.1111/anae.14582.
    1. Grape S., Kirkham K.R., Frauenknecht J., Albrecht E. Intra-operative analgesia with remifentanil vs. dexmedetomidine: A systematic review and meta-analysis with trial sequential analysis. Anaesthesia. 2019;74:793–800. doi: 10.1111/anae.14657.
    1. Albrecht E., Grape S., Frauenknecht J., Kilchoer L., Kirkham K.R. Low- versus high-dose intraoperative opioids: A systematic review with meta-analyses and trial sequential analyses. Acta Anaesthesiol. Scand. 2020;64:6–22. doi: 10.1111/aas.13470.
    1. Beloeil H., Garot M., Martinez V. Comments on Albrecht et al. reviews. Anaesthesia. 2019;74:1195–1196. doi: 10.1111/anae.14752.
    1. Demiri M., Antunes T., Fletcher D., Martinez V. Perioperative adverse events attributed to alpha2-adrenoceptor agonists in patients not at risk of cardiovascular events: Systematic review and meta-analysis. Br. J. Anaesth. 2019;123:795–807. doi: 10.1016/j.bja.2019.07.029.
    1. Beloeil H., Laviolle B., Menard C., Paugam-Burtz C., Garot M., Asehnoune K., Minville V., Cuvillon P., Oger S., Nadaud J., et al. POFA trial study protocol: A multicentre, double-blind, randomised, controlled clinical trial comparing opioid-free versus opioid anaesthesia on postoperative opioid-related adverse events after major or intermediate non-cardiac surgery. BMJ Open. 2018;8:e020873. doi: 10.1136/bmjopen-2017-020873.
    1. Liberati A., Altman D.G., Tetzlaff J., Mulrow C., Gotzsche P.C., Ioannidis J.P., Clarke M., Devereaux P.J., Kleijnen J., Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ. 2009;339:b2700. doi: 10.1136/bmj.b2700.
    1. Visser K., Hassink E.A., Bonsel G.J., Moen J., Kalkman C.J. Randomized controlled trial of total intravenous anesthesia with propofol versus inhalation anesthesia with isoflurane-nitrous oxide: Postoperative nausea with vomiting and economic analysis. Anesthesiology. 2001;95:616–626. doi: 10.1097/00000542-200109000-00012.
    1. Apfel C.C., Turan A., Souza K., Pergolizzi J., Hornuss C. Intravenous acetaminophen reduces postoperative nausea and vomiting: A systematic review and meta-analysis. Pain. 2013;154:677–689. doi: 10.1016/j.pain.2012.12.025.
    1. Higgins J.P.T., Thomas J., Chandler J., Cumpston M., Li T., Page M.J., Welch V.A., editors. Cochrane Handbook for Systematic Reviews of Interventions. Cochrane; 2011. [(accessed on 12 May 2021)]. Version 5.1.0 (Updated February 2011) Available online: .
    1. Higgins J.P., White I.R., Wood A.M. Imputation methods for missing outcome data in meta-analysis of clinical trials. Clin. Trials. 2008;5:225–239. doi: 10.1177/1740774508091600.
    1. Hozo S.P., Djulbegovic B., Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med. Res. Methodol. 2005;5:13. doi: 10.1186/1471-2288-5-13.
    1. Verret M., Lauzier F., Zarychanski R., Perron C., Savard X., Pinard A.M., Leblanc G., Cossi M.J., Neveu X., Turgeon A.F., et al. Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis. Anesthesiology. 2020;133:265–279. doi: 10.1097/ALN.0000000000003428.
    1. Nielsen S., Degenhardt L., Hoban B., Gisev N. A synthesis of oral morphine equivalents (OME) for opioid utilisation studies. Pharm. Drug Saf. 2016;25:733–737. doi: 10.1002/pds.3945.
    1. Laigaard J., Pedersen C., Ronsbo T.N., Mathiesen O., Karlsen A.P.H. Minimal clinically important differences in randomised clinical trials on pain management after total hip and knee arthroplasty: A systematic review. Br. J. Anaesth. 2021 doi: 10.1016/j.bja.2021.01.021.
    1. Tsertsvadze A., Maglione M., Chou R., Garritty C., Coleman C., Lux L., Bass E., Balshem H., Moher D. Updating comparative effectiveness reviews: Current efforts in AHRQ’s Effective Health Care Program. J. Clin. Epidemiol. 2011;64:1208–1215. doi: 10.1016/j.jclinepi.2011.03.011.
    1. Bakan M., Umutoglu T., Topuz U., Uysal H., Bayram M., Kadioglu H., Salihoglu Z. Opioid-free total intravenous anesthesia with propofol, dexmedetomidine and lidocaine infusions for laparoscopic cholecystectomy: A prospective, randomized, double-blinded study. Braz. J. Anesthesiol. 2015;65:191–199. doi: 10.1016/j.bjan.2014.05.006.
    1. Choi J.W., Joo J.D., Kim D.W., In J.H., Kwon S.Y., Seo K., Han D., Cheon G.Y., Jung H.S. Comparison of an Intraoperative Infusion of Dexmedetomidine, Fentanyl, and Remifentanil on Perioperative Hemodynamics, Sedation Quality, and Postoperative Pain Control. J. Korean Med. Sci. 2016;31:1485–1490. doi: 10.3346/jkms.2016.31.9.1485.
    1. Choi E.K., Seo Y., Lim D.G., Park S. Postoperative nausea and vomiting after thyroidectomy: A comparison between dexmedetomidine and remifentanil as part of balanced anesthesia. Korean J. Anesthesiol. 2017;70:299–304. doi: 10.4097/kjae.2017.70.3.299.
    1. Curry C.S., Darby J.R., Janssen B.R. Evaluation of pain following electrocautery tubal ligation and effect of intraoperative fentanyl. J. Clin. Anesth. 1996;8:216–219. doi: 10.1016/0952-8180(95)00233-2.
    1. Feld J.M., Hoffman W.E., Stechert M.M., Hoffman I.W., Ananda R.C. Fentanyl or dexmedetomidine combined with desflurane for bariatric surgery. J. Clin. Anesth. 2006;18:24–28. doi: 10.1016/j.jclinane.2005.05.009.
    1. Goyal S., Gupta K.K., Mahajan V. A Comparative Evaluation of Intravenous Dexmedetomidine and Fentanyl in Breast Cancer Surgery: A Prospective, Randomized, and Controlled Trial. Anesth. Essays Res. 2017;11:611–616. doi: 10.4103/0259-1162.206860.
    1. Hwang W., Lee J., Park J., Joo J. Dexmedetomidine versus remifentanil in postoperative pain control after spinal surgery: A randomized controlled study. BMC Anesthesiol. 2015;15:21. doi: 10.1186/s12871-015-0004-1.
    1. Senol Karatas S., Eti Z., Saracoglu K.T., Gogus F.Y. Does perioperative opioid infusion increase postoperative opioid requirement? AGRI. 2015;27:47–53. doi: 10.5505/agri.2015.71676.
    1. Katz J., Clairoux M., Redahan C., Kavanagh B.P., Carroll S., Nierenberg H., Jackson M., Beattie J., Taddio A., Sandler A.N. High dose alfentanil pre-empts pain after abdominal hysterectomy. Pain. 1996;68:109–118. doi: 10.1016/S0304-3959(96)03172-7.
    1. Lee C., Kim Y.D., Kim J.N. Antihyperalgesic effects of dexmedetomidine on high-dose remifentanil-induced hyperalgesia. Korean J. Anesthesiol. 2013;64:301–307. doi: 10.4097/kjae.2013.64.4.301.
    1. Hontoir S., Saxena S., Gatto P., Khalife M., Ben Aziz A.M., Paesmans M., Sosnowski M. Opioid-free anesthesia: What about patient comfort? A prospective, randomized, controlled trial. Acta Anaesthesiol. Belg. 2016;67:183–190.
    1. Beloeil H., Garot M., Lebuffe G., Gerbaud A., Bila J., Cuvillon P., Dubout E., Oger S., Nadaud J., Becret A., et al. Balanced Opioid-free Anesthesia with Dexmedetomidine versus Balanced Anesthesia with Remifentanil for Major or Intermediate Noncardiac Surgery. Anesthesiology. 2021;134:541–551. doi: 10.1097/ALN.0000000000003725.
    1. Salman N., Uzun S., Coskun F., Salman M.A., Salman A.E., Aypar U. Dexmedetomidine as a substitute for remifentanil in ambulatory gynecologic laparoscopic surgery. Saudi Med. J. 2009;30:77–81.
    1. Toleska M., Dimitrovski A. Is Opioid-Free General Anesthesia More Superior for Postoperative Pain Versus Opioid General Anesthesia in Laparoscopic Cholecystectomy? Prilozi. 2019;40:81–87. doi: 10.2478/prilozi-2019-0018.
    1. Lee C., Song Y.K., Lee J.H., Ha S.M. The effects of intraoperative adenosine infusion on acute opioid tolerance and opioid induced hyperalgesia induced by remifentanil in adult patients undergoing tonsillectomy. Korean J. Pain. 2011;24:7–12. doi: 10.3344/kjp.2011.24.1.7.
    1. Bhardwaj S., Garg K., Devgan S. Comparison of opioid-based and opioid-free TIVA for laparoscopic urological procedures in obese patients. J. Anaesthesiol. Clin. Pharmacol. 2019;35:481–486. doi: 10.4103/joacp.JOACP_382_18.
    1. Gazi M., Abitagaoglu S., Turan G., Koksal C., Akgun F.N., Ari D.E. Evaluation of the effects of dexmedetomidine and remifentanil on pain with the analgesia nociception index in the perioperative period in hysteroscopies under general anesthesia. A randomized prospective study. Saudi Med. J. 2018;39:1017–1022. doi: 10.15537/smj.2018.10.23098.
    1. Hakim K.Y.K., Wahba W.Z.B. Opioid-Free Total Intravenous Anesthesia Improves Postoperative Quality of Recovery after Ambulatory Gynecologic Laparoscopy. Anesth. Essays Res. 2019;13:199–203. doi: 10.4103/aer.AER_74_19.
    1. Kataria A.P., Attri J.P., Kashyap R., Mahajan L. Efficacy of dexmedetomidine and fentanyl on pressor response and pneumoperitoneum in laparoscopic cholecystectomy. Anesth. Essays Res. 2016;10:446–450. doi: 10.4103/0259-1162.176407.
    1. Mansour M.A., Mahmoud A.A., Geddawy M. Nonopioid versus opioid based general anesthesia technique for bariatric surgery: A randomized double-blind study. Saudi J. Anaesth. 2013;7:387–391. doi: 10.4103/1658-354X.121045.
    1. Ryu J.H., Sohn I.S., Do S.H. Controlled hypotension for middle ear surgery: A comparison between remifentanil and magnesium sulphate. Br. J. Anaesth. 2009;103:490–495. doi: 10.1093/bja/aep229.
    1. Techanivate A., Dusitkasem S., Anuwattanavit C. Dexmedetomidine compare with fentanyl for postoperative analgesia in outpatient gynecologic laparoscopy: A randomized controlled trial. J. Med. Assoc. Thai. 2012;95:383–390.
    1. Tverskoy M., Oz Y., Isakson A., Finger J., Bradley E.L., Jr., Kissin I. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth. Analg. 1994;78:205–209. doi: 10.1213/00000539-199402000-00002.
    1. Bulow N.M., Barbosa N.V., Rocha J.B. Opioid consumption in total intravenous anesthesia is reduced with dexmedetomidine: A comparative study with remifentanil in gynecologic videolaparoscopic surgery. J. Clin. Anesth. 2007;19:280–285. doi: 10.1016/j.jclinane.2007.01.004.
    1. Inoue Y., Koga K., Sata T., Shigematsu A. Effects of fentanyl on emergence characteristics from anesthesia in adult cervical spine surgery: A comparison of fentanyl-based and sevoflurane-based anesthesia. J. Anesth. 2005;19:12–16. doi: 10.1007/s00540-004-0278-9.
    1. Javaherforooshzadeh F., Monajemzadeh S.A., Soltanzadeh M., Janatmakan F., Salari A., Saeed H. A Comparative Study of the Amount of Bleeding and Hemodynamic Changes between Dexmedetomidine Infusion and Remifentanil Infusion for Controlled Hypotensive Anesthesia in Lumbar Discopathy Surgery: A Double-Blind, Randomized, Clinical Trial. Anesth. Pain Med. 2018;8:e66959. doi: 10.5812/aapm.66959.
    1. Cortinez L.I., Brandes V., Munoz H.R., Guerrero M.E., Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br. J. Anaesth. 2001;87:866–869. doi: 10.1093/bja/87.6.866.
    1. Jung H.S., Joo J.D., Jeon Y.S., Lee J.A., Kim D.W., In J.H., Rhee H.Y., Choi J.W. Comparison of an intraoperative infusion of dexmedetomidine or remifentanil on perioperative haemodynamics, hypnosis and sedation, and postoperative pain control. J. Int. Med. Res. 2011;39:1890–1899. doi: 10.1177/147323001103900533.
    1. Mogahed M., Anwar A. The Effects of Dexmedetomidine or Remifentanil Continuous Infusion on End- Tidal Sevoflurane Concentration in Patients Undergoing Laparoscopic Cholecestectomies, Monitored by Bispectral Analysis. J. Anesth. Clin. Res. 2017;8 doi: 10.4172/2155-6148.1000729.
    1. Mulier J., Wouters R., Dillemans B., Dekock M. A Randomized Controlled, Double-Blind Trial Evaluating the Effect of Opioid-Free Versus Opioid General Anaesthesia on Postoperative Pain and Discomfort Measured by the QoR-40. J. Clin. Anesth. Pain Med. 2018;2:6.
    1. Subasi H., Kol I., Kaygusuz K.I., Isbir A.C., Gursoy S. Dexmedetomidine and remifentanil as adjuncts to total intravenous anesthesia with propofol. Pain Intensive Care. 2019;20:323–329.
    1. Sahoo J., Sujata P. Comparative study betweeen dexmedetomidine and remifentanyl for efficient pain and ponv management in propofol based total intravenous anesthesia after laparoscopic gynaecological surgeries. Int. J. Pharm. Sci. Rev. Res. 2016;36:212–216.
    1. Hossam M. Intravenous Dexmedetomidine Infusion Compared with that of Fentanyl in Patients UndergoingArthroscopic Shoulder Surgery under General Anesthesia. Anesth. Essays Res. 2017;11:1070–1074.
    1. Marret E., Kurdi O., Zufferey P., Bonnet F. Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: Meta-analysis of randomized controlled trials. Anesthesiology. 2005;102:1249–1260. doi: 10.1097/00000542-200506000-00027.
    1. Martinez V., Beloeil H., Marret E., Fletcher D., Ravaud P., Trinquart L. Non-opioid analgesics in adults after major surgery: Systematic review with network meta-analysis of randomized trials. Br. J. Anaesth. 2017;118:22–31. doi: 10.1093/bja/aew391.
    1. Fletcher D., Martinez V. Opioid-induced hyperalgesia in patients after surgery: A systematic review and a meta-analysis. Br. J. Anaesth. 2014;112:991–1004. doi: 10.1093/bja/aeu137.
    1. Apfel C.C., Korttila K., Abdalla M., Kerger H., Turan A., Vedder I., Zernak C., Danner K., Jokela R., Pocock S.J., et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N. Engl. J. Med. 2004;350:2441–2451. doi: 10.1056/NEJMoa032196.
    1. Tramer M.R. A rational approach to the control of postoperative nausea and vomiting: Evidence from systematic reviews. Part II. Recommendations for prevention and treatment, and research agenda. Acta Anaesthesiol. Scand. 2001;45:14–19. doi: 10.1034/j.1399-6576.2001.450103.x.
    1. Harkouk H., Fletcher D., Beloeil H. Opioid free anaesthesia: Myth or reality? Anaesth. Crit. Care Pain Med. 2019;38:111–112. doi: 10.1016/j.accpm.2019.01.005.
    1. Kharasch E.D., Clark J.D. Opioid-free Anesthesia: Time to Regain Our Balance. Anesthesiology. 2021;134:509–514. doi: 10.1097/ALN.0000000000003705.
    1. Martinez V., Fletcher D. Prevention of opioid-induced hyperalgesia in surgical patients: Does it really matter? Br. J. Anaesth. 2012;109:302–304. doi: 10.1093/bja/aes278.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi