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The Challenge of Opioid-Free Anesthesia

  • Maher Khalife
  • Graziela Biter
  • Marco Cascella
  • Raffaela Di Napoli
Protocol
Part of the Neuromethods book series (NM, volume 150)

Abstract

The introduction of opioids in the clinical practice of anesthesia was a revolution. By blocking the sympathetic response to surgical stimuli and obtaining a reduced requirement of hypnotic agents, a safer and a more stable hemodynamically perioperative period was made possible. However, administration of opioids can be associated with several side effects that can be responsible for delayed patient recovery and hospital discharge, as well as leading to increased health service costs. Furthermore, opioid use is related to a wide range of side effects including gastrointestinal (nausea, vomiting, ileus), respiratory (decreased central respiratory drive impacting respiratory rate, and tidal volume), central nervous system effects (sedation, delirium, dysphoria, catalepsy, hallucinations) effects, as well as urinary retention, pruritus, bradycardia, and dizziness. Another undesired effect of opioids as primary pain therapy in the perioperative period, is the development of “acute tolerance” to the analgesic effect of these drugs. This diminished analgesic effect may also be the result of the “opioid-induced hyperalgesia” (OIH) phenomenon. Again, some evidence has suggested that opioids may interfere with the immune system. Numerous studies have shown that opioids can influence the progression of cancer, metastasis, and cancer recurrence. In the 1990s, in the light of experience and studies conducted on opioids and their effects within the broader context of multimodal analgesia, their use came into question. New anesthesia techniques started to be developed that aimed to achieve the sparing use of opioids. These approaches culminated, in the 2000s, with the development of opioid-free anesthesia (OFA) pathways. The strategy of OFA is a realistic alternative that can lead to enhanced recovery and increased patient satisfaction by reducing important opioid related side effects; it can also facilitate the use of lower doses of opioids postoperatively in order to achieve a pain-free recovery and reduce pain scores while providing faster and safer mobilization and rehabilitation. The drugs used are hypnotics, N-methyl-d-aspartate (NMDA) antagonists (ketamine, magnesium sulfate), sodium channel blockers (local anesthetics), anti-inflammatory drugs [nonsteroidal anti-inflammatory drugs (NSAIDs), dexamethasone, local anesthetic], and alpha-2 agonists (dexmedetomidine, clonidine). The association of OFA and locoregional anesthetic techniques is very common. Several types of patients can benefit from this technique including narcotic history patients, obese patients with obstructive sleep apnea, patients with hyperalgesia and history of chronic pain, immune deficiency individuals, patients undergoing oncologic surgery as well as those affected by inflammatory conditions, chronic obstructive pulmonary disease, and asthma. While different OFA protocols have been reported in the literature, the publications rely mostly on case reports and small size investigations. More studies are necessary to assess what the interactions between these drugs are. Clinical researchers must design studies with rigorous methodology in order to correctly assess the risks and benefits of OFA for patients in different surgical settings.

Key words

Opioid-free anesthesia Opioids Opioid-related side effects Ketamine Dexmedetomidine Magnesium Lidocaine 

References

  1. 1.
    Cohen MM (1969) The history of opium and opiates. Tex Med 65:76–85PubMedGoogle Scholar
  2. 2.
    Yim M, Parsa FD (2018) From the origins of the opioid use (and misuse) to the challenge of opioid-free pain management in surgery. Pain Treat.  https://doi.org/10.5772/intechopen.82675Google Scholar
  3. 3.
    Janssen PA (1982) Potent new analgesics tailor-made for different purposes. Acta Anaesthesiol Scand 26:262–268PubMedCrossRefGoogle Scholar
  4. 4.
    Duarte DF (2005) Opium and opioids: a brief history. Rev Bras Anestesiol 55(1):135–146PubMedGoogle Scholar
  5. 5.
    Chia YY et al (1999) Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 46:872–877PubMedCrossRefGoogle Scholar
  6. 6.
    Guignard B et al (2000) Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 93:409–417PubMedCrossRefGoogle Scholar
  7. 7.
    Cuomo A, Bimonte S, Forte CA et al (2019) Multimodal approaches and tailored therapies for pain management: the trolley analgesic model. J Pain Res 12:711–714.  https://doi.org/10.2147/JPR.S178910PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Elkassabany NM, Mariano ER (2019) Opioid-free anaesthesia – what would Inigo Montoya say? Anesth Edit 74(5):560–563.  https://doi.org/10.1111/anae.14611CrossRefGoogle Scholar
  9. 9.
    Kehlet H, Dahl JB (1993) The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 77(5):1048–1056PubMedCrossRefGoogle Scholar
  10. 10.
    Mulier J (2017) Opioid free general anesthesia: a paradigm shift? Rev Españ Anestesiol Reanim 64(8):427–430CrossRefGoogle Scholar
  11. 11.
    Weinbroum A (2015) Role of anaesthetics and opioids in perioperative hyperalgesia. Eur J Anaesthesiol 32:230–231PubMedCrossRefGoogle Scholar
  12. 12.
    Van Zee A (2009) The promotion and marketing of oxycontin: commercial triumph, public health tragedy. Am J Public Health 99(2):221–227PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Joly V, Richebe P, Guignard B et al (2005) Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 103(1):147–155PubMedCrossRefGoogle Scholar
  14. 14.
    Brummett CM, Waljee JF, Goesling J et al (2017) New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg 152(6):e170504.  https://doi.org/10.1001/jamasurg.2017.0504PubMedCrossRefGoogle Scholar
  15. 15.
    Shah A, Hayes CJ, Martin BC (2017) Factors influencing long-term opioid use among opioid naive patients: an examination of initial prescription characteristics and pain etiologies. J Pain 18(11):1374–1383.  https://doi.org/10.1016/j.jpain.2017.06.010PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Levy N, Mills P (2018) Controlled-release opioids cause harm and should be avoided in management of postoperative pain in opioid naı¨ve patients. Br J Anaesth 122(6):e86–e90.  https://doi.org/10.1016/j.bja.2018.09.005PubMedCrossRefGoogle Scholar
  17. 17.
    Dumas EO (2018) Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J 4:537Google Scholar
  18. 18.
    Allouche S, Noble F, Marie N (2014) Opioid receptor desensitization: mechanisms and its link to tolerance. Front Pharmacol 5:280PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Hayhurst CJ, Durieux ME (2016) Differential opioid tolerance and opioid-induced hyperalgesia: a clinical reality. Anesthesiology 2(124):483–488CrossRefGoogle Scholar
  20. 20.
    Fletcher D, Martinez V (2014) Opioid-induced hyperalgesia in patient after surgery: a systematic review and a meta-analysis. Br J Anesth 112(6):991–1004CrossRefGoogle Scholar
  21. 21.
    Afsharimani B, Baran J, Watanabe S (2014) Morphine and tumor growth and metastasis. Clin Exp Metastasis 31(2):149–158.  https://doi.org/10.1007/s10585-013-9616-3PubMedCrossRefGoogle Scholar
  22. 22.
    Gach K, Wyrębska A, Fichna J et al (2011) The role of morphine in regulation of cancer cell growth. Naunyn Schmiedeberg’s Arch Pharmacol 384(3):221–230.  https://doi.org/10.1007/s00210-011-0672-4CrossRefGoogle Scholar
  23. 23.
    Gupta K, Kshirsagar S, Chang L (2002) Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 62(3):4491–4498PubMedGoogle Scholar
  24. 24.
    Lennon FE, Mirzapoiazova T, Mambetsariev B (2012) Overexpression of the mu-opioid receptor in human non-small cell lung cancer promotes Akt and mTor activation, tumor growth, and metastasis. Anesthesiology 116(4):857–867PubMedCrossRefGoogle Scholar
  25. 25.
    Mathew B, Lennon FE, Siegler J (2011) The novel role of the mu-opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg 112(3):558–567PubMedCrossRefGoogle Scholar
  26. 26.
    Singleton PA, Mirzapoiazova T, Hasina R (2014) Increased mu-opioid receptor expression in metastatic lung cancer. Br J Anaesth 113(Suppl 1):i103–i108PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Bimonte S, Barbieri A, Cascella M et al (2019) Naloxone counteracts the promoting tumor growth effects induced by morphine in an animal model of triple-negative breast cancer. In Vivo 33(3):821–825PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Frauenknecht J, Kirkham KR, Jacot-Guillarmod A (2019) Analgesic impact of intra-operative opioid vs. opioid-free anaesthesia: a systematic review and meta-analysis. Anesthesia 74(5):651–662.  https://doi.org/10.1111/anae.14582CrossRefGoogle Scholar
  29. 29.
    Kawasaki Y, Kohno T, Zhuang ZY et al (2004) Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci 24(38):8310–8321PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Thompson T, Whiter F, Gallop K et al (2019) NMDA receptor antagonists and pain relief A meta-analysis of experimental trials. Neurology 92(14):e1652–e1662.  https://doi.org/10.1212/WNL.0000000000007238PubMedCrossRefGoogle Scholar
  31. 31.
    Guillou N, Tanguy M, Seguin P et al (2003) The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg 97(3):843–847PubMedCrossRefGoogle Scholar
  32. 32.
    Yang Y, Cui Y, Sang K et al (2018) Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554(7692):317–322PubMedCrossRefGoogle Scholar
  33. 33.
    Kirby T (2015) Ketamine for depression: the highs and lows. Lancet Psychiatry 9:783–784.  https://doi.org/10.1016/S2215-0366(15)00392-2CrossRefGoogle Scholar
  34. 34.
    Gorlin AW, Rosenfeld DM, Ramakrishna H (2016) Intravenous sub-anesthetic ketamine for perioperative analgesia. J Anaesthesiol Clin Pharmacol 2:160–167.  https://doi.org/10.4103/0970-9185.182085CrossRefGoogle Scholar
  35. 35.
    Feria M, Abad F, Sanchez A et al (1993) Magnesium sulphate injected subcutaneously suppresses autotomy in peripherally deafferented rats. Pain 53:287–293PubMedCrossRefGoogle Scholar
  36. 36.
    McCarthy RJ, Kroin JS, Tuman KJ et al (1998) Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats. Anesth Analg 86:830–836PubMedCrossRefGoogle Scholar
  37. 37.
    Albrecht E, Kirkham KR, Liu SS (2013) Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia 68(1):79–90.  https://doi.org/10.1111/j.1365-2044.2012.07335.xPubMedCrossRefGoogle Scholar
  38. 38.
    Kawamata M, Sugino S, Narimatsu E et al (2006) Effects of systemic administration of lidocaine and QX-314 on hyperexcitability of spinal dorsal horn neurons after incision in the rat. Pain 122:68–80PubMedCrossRefGoogle Scholar
  39. 39.
    Abelson KS, Hoglund AU (2002) Intravenously administered lidocaine in therapeutic doses increases the intraspinal release of acetylcholine in rats. Neurosci Lett 317:93–96PubMedCrossRefGoogle Scholar
  40. 40.
    Wright J, Durieux M, Groves D (2008) A brief review of innovative uses for local anesthetics. Curr Opin Anaesthesiol 21(5):651–656PubMedCrossRefGoogle Scholar
  41. 41.
    Dunn LK, Durieux ME (2017) Perioperative use of intravenous lidocaine. Anesthesiology 126(4):729–737.  https://doi.org/10.1097/ALN.0000000000001527PubMedCrossRefGoogle Scholar
  42. 42.
    Koppert W, Weigand M, Neumann F et al (2004) Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery. Anesth Analg 98:1050–1055PubMedCrossRefGoogle Scholar
  43. 43.
    Herroeder S, Pecher S, Schönherr ME et al (2007) Systemic lidocaine shortens length of hospital stay after colorectal surgery: a double-blinded, randomized, saline-controlled trial. Ann Surg 246:192–200PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Tikuišis R, Miliauskas P, Samalavičius NE et al (2014) Intravenous lidocaine for post-operative pain relief after hand-assisted laparoscopic colon surgery: a randomized, saline-controlled clinical trial. Tech Coloproctol 18(4):373–380.  https://doi.org/10.1007/s10151-013-1065-0PubMedCrossRefGoogle Scholar
  45. 45.
    Weibel S, Jelting Y, Pace NL et al (2018) Intravenous infusion of lidocaine starting at the time of surgery for reduction of pain and improvement of recovery after surgery. Cochrane Database Syst Rev 6:Art. No.:CD009642Google Scholar
  46. 46.
    Eipe N, Gupta S, Penning J (2016) Intravenous lidocaine for acute pain: an evidence-based clinical update. BJA Education 16(9):292–298CrossRefGoogle Scholar
  47. 47.
    Dexamethasone (DB01234) – dexamethasone- DrugBank. https://www.drugbank.ca/drugs/DB01234. Accessed 27 May 2019
  48. 48.
    De Oliveira GS Jr, Castro-Alves LJ, Ahmad S et al (2013) Dexamethasone to prevent postoperative nausea and vomiting: an updated meta-analysis of randomized controlled trials. Anesth Analg 116:58–74PubMedCrossRefGoogle Scholar
  49. 49.
    Pehora C, Pearson AM, Kaushal A et al (2017) Dexamethasone as an adjuvant to peripheral nerve block. Cochrane Database Syst Rev 11:CD011770PubMedGoogle Scholar
  50. 50.
    De Oliveira GS Jr, Almeida MD, Benzon HT et al (2012) Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology 115:575–588.  https://doi.org/10.1097/ALN.0b013e31822a24c2CrossRefGoogle Scholar
  51. 51.
    Fauci AS, Dale DC, Balow JE (1976) Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med 84:304–315PubMedCrossRefGoogle Scholar
  52. 52.
    Polderman JAW, Farhang-Razi V, van Dieren S et al (2019) Adverse side-effects of dexamethasone in surgical patients – an abridged. Cochrane systematic review. Anaesthesia.  https://doi.org/10.1111/anae.14610PubMedCrossRefGoogle Scholar
  53. 53.
    Davies DS, Wing LHM, Reid JL et al (1997) Pharmacokinetics and concentration-effect relationships of intravenous and oral clonidine. Clin Pharmacol Ther 21:593–601CrossRefGoogle Scholar
  54. 54.
    Lowenthal DT, Matzek KM, MacGregor TR (1988) Clinical pharmacokinetics of clonidine. Clin Pharmacokinet 14:287–310PubMedCrossRefGoogle Scholar
  55. 55.
    Sanchez Munoz MC, De Kock M, Forget P (2017) What is the place of clonidine in anesthesia? Systematic review and meta-analyses of randomized controlled trials. J Clin Anesth 38:140–153.  https://doi.org/10.1016/j.jclinane.2017.02.003PubMedCrossRefGoogle Scholar
  56. 56.
    Carabine UA, Wright PM, Moore J (1991) Preanaesthetic medication with clonidine: a dose-response study. Br J Anaesth 67(1):79–83PubMedCrossRefGoogle Scholar
  57. 57.
    Wagner DS, Brummett CM (2006) Dexmedetomidine: as safe as safe can be. Semin Anesth Perioper Med Pain 25:77–83CrossRefGoogle Scholar
  58. 58.
    Fairbanks CA, Stone LS, Wilcox GL (2009) Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis. Pharmacol Ther 123(2):224–238PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Afsani N (2010) Clinical application of dexmedetomidine. S Afr J Anaesthesiol Analg 16:50–56Google Scholar
  60. 60.
    Scheinin B, Lindgren L, Randell T et al (1992) Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone and peroperative fentanyl. Br J Anaesth 68(2):126–131PubMedCrossRefGoogle Scholar
  61. 61.
    Guler G, Akin A, Tosun Z et al (2005) Single-dose dexmedetomidine attenuates airway and circulatory reflexes during extubation. Acta Anaesthesiol Scand 49(8):1088–1091PubMedCrossRefGoogle Scholar
  62. 62.
    Bekker A, Sturaitis MK (2005) Dexmedetomidine for neurological surgery. Neurosurgery 57(1 Suppl):1–10. discussion 1–10PubMedGoogle Scholar
  63. 63.
    Scott-Warren VL, Sebastian J (2016) Dexmedetomidine: its use in intensive care medicine and anaesthesia. BJA Edu 16(7):242–246CrossRefGoogle Scholar
  64. 64.
    Sultana A, Torres D, Schumann R (2017) Special indications for opioid free anaesthesia and analgesia, patient and procedure related: including obesity, sleep apnoea, chronic obstructive pulmonary disease, complex regional pain syndromes, opioid addiction and cancer surgery. Best Pract Res Clin Anaesthesiol 31(4):547–560.  https://doi.org/10.1016/j.bpa.2017.11.002PubMedCrossRefGoogle Scholar
  65. 65.
    Bakan M, Umutoglu T, Topuz U et al (2015) Opioid-free total intravenous anesthesia with propofol, dexmedetomidine and lidocaine infusions for laparoscopic cholecystectomy: a prospective, randomized, double-blinded study. Braz J Anesthesiol 65(3):191–199.  https://doi.org/10.1016/j.bjane.2014.05.001PubMedCrossRefGoogle Scholar
  66. 66.
    Aronsohn J, Orner G, Palleschi G et al (2019) Opioid-free total intravenous anesthesia with ketamine as part of an enhanced recovery protocol for bariatric surgery patients with sleep disordered breathing. J Clin Anesth 52:65–66PubMedCrossRefGoogle Scholar
  67. 67.
    Landry E, Burns S, Pelletier MP et al (2018) A successful opioid- free anesthetic in a patient undergoing cardiac surgery. J Cardiothorac Vasc Anesth pii:S1053-0770(18)31092-9.  https://doi.org/10.1053/j.jvca.2018.11.040CrossRefGoogle Scholar
  68. 68.
    Hontoir S, Saxena S, Gatto P et al (2016) Opioid-free anesthesia: what about patient comfort? A prospective, randomized, controlled trial. Acta Anaesthesiol Belg 67(4):183–190PubMedGoogle Scholar
  69. 69.
    Bello M, Oger S, Bedon-Carte S (2019) Effect of opioid-free anaesthesia on postoperative epidural ropivacaine requirement after thoracic surgery: a retrospective unmatched case-control study. Anaesth Crit Care Pain Med pii:S2352-5568(18)30281-9.  https://doi.org/10.1016/j.accpm.2019.01.013CrossRefGoogle Scholar
  70. 70.
    Boloeil H, Lavoille B, Menard C et al (2018) POFA trial study protocol: a multicentre, double-bind,randomized, controlled clinical trial comparing opioid-free versus opioid anaesthesia on postoperative opioid-related adverse events after major or intermediate non-cardiac surgery. BMJ Open 8(6):e020873.  https://doi.org/10.1136/bmjopen-2017-020873CrossRefGoogle Scholar
  71. 71.
    Cascella M, Muzio MR, Bimonte S, Cuomo A, Jakobsson JG (2018) Postoperative delirium and postoperative cognitive dysfunction: updates in pathophysiology, potential translational approaches to clinical practice and further research perspectives. Minerva Anestesiol 84(2):246–260Google Scholar
  72. 72.
    Kim N, Matzon JL, Abboudi J et al (2016) A prospective evaluation of opioid utilization after upper-extremity surgical procedures. J Bone Joint Surg Am 98(20):e89PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Maher Khalife
    • 1
  • Graziela Biter
    • 2
  • Marco Cascella
    • 3
  • Raffaela Di Napoli
    • 1
  1. 1.Department of Anesthesiology, Institut Jules BordetUniversité Libre de BruxellesBruxellesBelgium
  2. 2.Department of Anesthesiology, CHU Saint-PierreUniversité Libre de BruxellesBruxellesBelgium
  3. 3.Istituto Nazionale Tumori - IRCCS - Fondazione PascaleNapoliItaly

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