Skip to main content

Advertisement

SpringerLink
Log in

Methadone: applications in pediatric anesthesiology and critical care medicine

  • Review Article
  • Published:
Journal of Anesthesia Aims and scope Submit manuscript

Abstract

Like morphine, methadone is a pure agonist at the µ opioid receptor. However, in distinction to morphine which has an elimination half-life of 2–3 h, methadone has an elimination half-life of 24–36 h. In addition to its effects at the µ opioid receptor, methadone is an antagonist at the n-methyl-d-aspartate (NMDA) receptor and also inhibits the reuptake of the neurotransmitters, serotonin and norepinephrine, in the central nervous system. Given its long half-life and high oral bioavailability, methadone has had a primary role in the outpatient treatment of patients with a history of opioid abuse or addiction. However, its unique pharmacology and cellular effects make it a valuable agent in the treatment of both acute and chronic pain of various etiologies. The following manuscript reviews the pharmacologic properties of methadone and discusses its clinical applications in the practice of pediatric anesthesiology and pediatric critical care medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CHD:

Congenital heart disease

ETCO2:

End-tidal carbon dioxide

NMDA:

N-methyl-d-aspartate

CNS:

Central nervous system

AMP:

Adenosine monophosphate

ICU:

Intensive care unit

ECMO:

Extracorporeal membrane oxygenation

FDA:

Food & Drug Administration

TdP:

Torsade de pointes

References

  1. Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982;57:458–67.

    Article  CAS  PubMed  Google Scholar 

  2. Gourlay GK, Willis RJ, Wilson PR. Postoperative pain control with methadone: Influence of supplementary methadone doses and blood concentration–response relationships. Anesthesiology. 1984;61:19–26.

    Article  CAS  PubMed  Google Scholar 

  3. Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-d-aspartate–induced hyperalgesia. J Pharmacol Exp Ther. 1999;289:1048–53.

    CAS  PubMed  Google Scholar 

  4. Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE. Cooperative N-methyl-d-aspartate (NMDA) receptor antagonism and μ-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009;60:284–90.

    Article  CAS  PubMed  Google Scholar 

  5. Codd EE, Shank RP, Schupsky JJ, Raffa RB. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: Structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995;274:1263–70.

    CAS  PubMed  Google Scholar 

  6. Rojas-Corrales MO, Berrocoso E, Gibert-Rahola J, Micó JA. Antidepressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake, in helpless rats. Life Sci. 2002;72:143–52.

    Article  CAS  PubMed  Google Scholar 

  7. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth. 2005;95:434–41.

    Article  CAS  PubMed  Google Scholar 

  8. Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. New Engl J Med. 2003;348:1223–32.

    Article  CAS  PubMed  Google Scholar 

  9. Anghelescu DL, Faughnan LG, Hankins GM, Ward DA, Oakes LL. Methadone use in children and young adults at a cancer center: a retrospective study. J Opioid Manag. 2011;7:353–61.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology. 1986;64:322–7.

    Article  CAS  PubMed  Google Scholar 

  11. Tobias JD, Schleien CL, Haun SE. Methadone as treatment for iatrogenic narcotic dependency in pediatric intensive care unit patients. Crit Care Med. 1990;18:1292–3.

    Article  CAS  PubMed  Google Scholar 

  12. Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Pall Care Pharm. 2005;19:13–24.

    Google Scholar 

  13. Price DD, Mayer DJ, Mao J, Caruso FS. NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage. 2000;19(1 Suppl):S7-11.

    Article  CAS  PubMed  Google Scholar 

  14. Davis AM, Inturrisi DE. d-Methadone blocks morphine tolerance and n-methyl-d-aspartate-induced hyperalgesia. J Pharm Exper Therap. 1999;289:1048–53.

    CAS  Google Scholar 

  15. Garrido MJ, Trocóniz IF. Methadone: a review of its pharmacokinetic and pharmacodynamic properties. J Pharmacol Toxicol Methods. 1999;42:61–6.

    Article  CAS  PubMed  Google Scholar 

  16. Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality. 2004;16:36–44.

    Article  CAS  PubMed  Google Scholar 

  17. Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition and miotic effects of methadone. Clin Pharmacol Ther. 2004;76:250–69.

    Article  CAS  PubMed  Google Scholar 

  18. Sharma A, Tallchief D, Blood J, Kim T, London A, Kharasch ED. Perioperative pharmacokinetics of methadone in adolescents. Anesthesiology. 2011;115:1153–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cobb MN, Desai J, Brown LS Jr, Zannikos PN, Rainey PM. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther. 1998;63:655–62.

    Article  CAS  PubMed  Google Scholar 

  20. Lozano R, Domeque N, Frutos AJ. Methadone dosing in patients on ritonavir-boosted-based highly active antiretroviral therapy. Med Clin (Barc). 2019;15(152):161–2.

    Article  Google Scholar 

  21. Shelton MJ, Cloen D, DiFrancesco R, Berenson CS, Esch A, de Caprariis PJ, Palic B, Schur JL, Buggé CJ, Ljungqvist A, Espinosa O, Hewitt RG. The effects of once-daily saquinavir/minidose ritonavir on the pharmacokinetics of methadone. J Clin Pharmacol. 2004;44:293–304.

    Article  CAS  PubMed  Google Scholar 

  22. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED. Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology. 2008;108:363–74.

    Article  CAS  PubMed  Google Scholar 

  23. Kreek MJ, Schecter AJ, Gutjahr CL, Hecht M. Methadone use in patients with chronic renal disease. Drug Alcohol Dep. 1980;5:197–205.

    Article  CAS  Google Scholar 

  24. Davison SN. Clinical pharmacology considerations in pain management in patients with advanced kidney failure. CJASN. 2019;14:917–31.

    Article  CAS  PubMed  Google Scholar 

  25. Furlan V, Hafi A, Dessalles MC, Bouchez J, Charpentier B, Taburet AM. Methadone is poorly removed by haemodialysis. Nephrol Dial Transplant. 1999;14:254–5.

    Article  CAS  PubMed  Google Scholar 

  26. Stemland CJ, Witte J, Colquhoun DA, Durieux ME, Langman LJ, Balireddy R, Thammishetti S, Abel MF, Anderson BJ. The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion. Paediatr Anaesth. 2013;23:51–7.

    Article  PubMed  Google Scholar 

  27. Ward RM, Drover DR, Hammer GB, Stemland CJ, Kern S, Tristani-Firouzi M, Lugo RA, Satterfield K, Anderson BJ. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Paediatr Anaesth. 2014;24:591–601.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Murphy GS, Szokol JW. Intraoperative methadone in surgical patients. Anesthesiology. 2019;131:678–92.

    Article  PubMed  Google Scholar 

  29. Shir Y, Shenkman Z, Shavelson V, Davidson EM, Rosen G. Oral methadone for the treatment of severe pain in hospitalized children: a report of five cases. Clin J Pain. 1998;14:350–3.

    Article  CAS  PubMed  Google Scholar 

  30. Berde CB, Beyer JE, Bournaki M-C, Levin CR, Sethna NF. Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children. J Pediatr. 1991;119:136–41.

    Article  CAS  PubMed  Google Scholar 

  31. Hamunen K. Ventilatory effects of morphine, pethidine and methadone in children. Br J Anaesth. 1993;70:414–8.

    Article  CAS  PubMed  Google Scholar 

  32. Singhal NR, Jones J, Semenova J, Williamson A, McCollum K, Tong D, Jerman J, Notrica DM, Nguyen H. Multimodal anesthesia with the addition of methadone is superior to epidural analgesia: a retrospective comparison of intraoperative anesthetic techniques and pain management for 124 pediatric patients undergoing the Nuss procedure. J Pediatr Surg. 2016;51:612–6.

    Article  PubMed  Google Scholar 

  33. Martin DP, Samora WP 3rd, Beebe AC, Klamar J, Gill L, Bhalla T, Veneziano G, Thung A, Tumin D, Barry N, Rice J, Tobias JD. Analgesic effects of methadone and magnesium following posterior spinal fusion for idiopathic scoliosis in adolescents: a randomized controlled trial. J Anesth. 2018;32:702–8.

    Article  PubMed  Google Scholar 

  34. Shir Y, Rosen G, Zeldin A, Davidson EM. Methadone is safe for treating hospitalized patients with severe pain. Can J Anaesth. 2001;48:1109–13.

    Article  CAS  PubMed  Google Scholar 

  35. Shir Y, Eimerl D, Magora F, Damm D, Schulte-Monting J, Chrubasik J. Plasma concentrations of methadone during postoperative patient-controlled extradural analgesia. Br J Anaesth. 1990;65:204–9.

    Article  CAS  PubMed  Google Scholar 

  36. Robinson JD, Caruso TJ, Wu M, Kleiman ZI, Kwiatkowski DM. Intraoperative methadone is associated with decreased perioperative opioid use without adverse events: a case-matched cohort study. J Cardiothorac Vasc Anesth. 2020;34:335–41.

    Article  CAS  PubMed  Google Scholar 

  37. Iguidbashian JP, Chang PH, Iguidbashian J, Lines J, Maxwell BG. Enhanced recovery and early extubation after pediatric cardiac surgery using single-dose intravenous methadone. Ann Card Anaesth. 2020;23:70–4.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Barnett AM, Machovec KA, Ames WA, Homi HM, Turi JL, Koo J, Fuller M, Jooste EH.. The effect of intraoperative methadone during pediatric cardiac surgery on postoperative opioid requirements. Paediatr Anaesth (in press)

  39. Ripamonti C, Groff L, Brunelli C, Polastri D, Stavrakis A, De Conno F. Switching from morphine to oral methadone in treating cancer pain: What is the equianalgesic dose ratio? J Clin Oncol. 1998;16:3216–21.

    Article  CAS  PubMed  Google Scholar 

  40. Morley JS, Watt JW, Wells JC, Miles JB, Finnegan MJ, Leng G. Methadone in pain uncontrolled by morphine. Lancet. 1993;342:1243–6.

    Article  CAS  PubMed  Google Scholar 

  41. Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain. 1997;70:99–101.

    Article  CAS  PubMed  Google Scholar 

  42. Bruera E, Pereira J, Watanabe S, Belzile M, Kuehn N, Hanson J. Opioid rotation in patients with cancer pain. A retrospective comparison of dose ratios between methadone, hydromorphone, and morphine. Cancer. 1996;78:852–7.

    Article  CAS  PubMed  Google Scholar 

  43. Martinson IM, Nixon S, Geis D, YaDeau R, Nesbit M, Kersey J. Nursing care in childhood cancer. Methadone. Am J Nurs. 1982;432–435

  44. Miser AW, Miser JS. The use of oral methadone to control moderate and severe pain in children and young adults with malignancy. Clin J Pain. 1986;1:243–8.

    Article  Google Scholar 

  45. Ettinger DS, Vitale PJ, Trump DL. Important clinical pharmacologic considerations in the use of methadone in cancer patients. Cancer Treat Rep. 1979;63:457–9.

    CAS  PubMed  Google Scholar 

  46. Kepes ER, Raj S, Thomas P, Vemulapalli K. Methadone and intravenous morphine requirements. Treatment of pain due to advanced cancer. N Y State J Med. 1983;83:925–7.

    CAS  PubMed  Google Scholar 

  47. Sabatowski R, Kasper SM, Radbruch L. Patient-controlled analgesia with intravenous L-methadone in a child with cancer pain refractory to high-dose morphine. J Pain Symptom Manage. 2002;23:3–5.

    Article  PubMed  Google Scholar 

  48. Davies D, DeVlaming D, Haines C. Methadone analgesia for children with advanced cancer. Pediatr Blood Cancer. 2008;51:393–7.

    Article  PubMed  Google Scholar 

  49. Arnold JH, Truog RD, Orav EJ, Scavone JM, Hershenson MB. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology. 1990;73:1136–40.

    Article  CAS  PubMed  Google Scholar 

  50. Arnold JH, Truog RD, Scavone JM, Fenton T. Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr. 1991;119:639–43.

    Article  CAS  PubMed  Google Scholar 

  51. Tobias JD, Deshpande JK, Gregory DF. Outpatient therapy of iatrogenic drug dependency following prolonged sedation in the pediatric intensive care unit. Intensive Care Med. 1994;20:504–7.

    Article  CAS  PubMed  Google Scholar 

  52. Tobias JD. Outpatient therapy of iatrogenic drug dependency following prolonged sedation in the pediatric intensive care unit. J Intensive Care Med. 1996;11:284–7.

    Article  Google Scholar 

  53. Robertson RC, Darsey E, Fortenberry JD, Pettignano R, Hartley G. Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatr Crit Care Med. 2000;1:119–23.

    Article  CAS  PubMed  Google Scholar 

  54. Lugo RA, MacLaren R, Cash J, Pribble CG, Vernon DD. Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU. Pharmacotherapy. 2001;21:1566–73.

    Article  CAS  PubMed  Google Scholar 

  55. Meyer MT, Berens RJ. Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients. Pediatr Crit Care Med. 2001;2:329–33.

    Article  CAS  PubMed  Google Scholar 

  56. Siddappa R, Fletcher JE, Heard AMB, Kielma D, Cimino M, Heard CM. Methadone dosage for prevention of opioid withdrawal in children. Pediatr Anesth. 2003;13:805–10.

    Article  Google Scholar 

  57. Berens RJ, Meyer MT, Mikhailov TA, Colpaert KD, Czarnecki ML, Ghanayem NS, Hoffman GM, Soetenga DJ, Nelson TJ, Weisman SJ. A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients. Anesth Analg. 2006;102:1045–50.

    Article  CAS  PubMed  Google Scholar 

  58. Ista E, van Dijk M, Gischler S, de Leeuw M, Poley MJ, Tibboel D. Weaning of opioids and benzodiazepines at home after critical illness in infants: a cost-effective approach. J Opioid Manag. 2010;6:55–62.

    Article  PubMed  Google Scholar 

  59. Vipond JM, Heiberger AL, Thompson PA, Huber JN. Shortened taper duration after implementation of a standardized protocol for iatrogenic benzodiazepine and opioid withdrawal in pediatric patients: results of a cohort study. Pediatr Qual Saf. 2018;18:e079.

    Article  Google Scholar 

  60. Steineck KJ, Skoglund AK, Carlson MK, Gupta S. Evaluation of a pharmacist-managed methadone taper. Pediatr Crit Care Med. 2014;15:206–10.

    Article  PubMed  Google Scholar 

  61. Tobias JD. Methadone: who tapers, when, where, and how? Pediatr Crit Care Med. 2014;15:268–70.

    Article  PubMed  Google Scholar 

  62. Dervan LA, Yaghmai B, Watson RS, Wolf FM. The use of methadone to facilitate opioid weaning in pediatric critical care patients: a systematic review of the literature and meta-analysis. Paediatr Anaesth. 2017;27:228–39.

    Article  PubMed  Google Scholar 

  63. Bichaff P, Setani KT, Motta EHG, Delgado AF, Carvalho WB, Luglio M. Opioid tapering and weaning protocols in pediatric critical care units: a systematic review. Rev Assoc Med Bras. 2018;64:909–15.

    Article  PubMed  Google Scholar 

  64. Fenn NE 3rd, Plake KS. Opioid and benzodiazepine weaning in pediatric patients: review of current literature. Pharmacotherapy. 2017;37:1458–68.

    Article  PubMed  Google Scholar 

  65. Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Shear TD, Deshur MA, Vender JS, Benson J, Newmark RL. Clinical effectiveness and safety of intraoperative methadone in patients undergoing posterior spinal fusion surgery: a randomized, double-blinded, controlled trial. Anesthesiology. 2017;126:822–33.

    Article  CAS  PubMed  Google Scholar 

  66. Chui PT, Gin T. A double-blind randomised trial comparing postoperative analgesia after perioperative loading doses of methadone or morphine. Anaesth Intensive Care. 1992;20:46–51.

    Article  CAS  PubMed  Google Scholar 

  67. Udelsmann A, Maciel FG, Servian DC, Reis E, de Azevedo TM, Melo S. Methadone and morphine during anesthesia induction for cardiac surgery: Repercussion in postoperative analgesia and prevalence of nausea and vomiting. Rev Bras Anestesiol. 2011;61:695–701.

    Article  CAS  PubMed  Google Scholar 

  68. Bowdle TA, Even A, Shen DD, Swardstrom M. Methadone for the induction of anesthesia: plasma histamine concentration, arterial blood pressure, and heart rate. Anesth Analg. 2004;98:1692–7.

    Article  CAS  PubMed  Google Scholar 

  69. Wheeler AD, Tobias JD. Bradycardia during methadone therapy in an infant. Pediatr Crit Care Med. 2006;7:83–5.

    Article  PubMed  Google Scholar 

  70. Metcalfe J, Dunham MJ, Olsen GD, Krall MA. Respiratory and hemodynamic effects of methadone in pregnant women. Respir Physiol. 1980;42:383–93.

    Article  CAS  PubMed  Google Scholar 

  71. Seyler DE, Borowitz JL, Maickel RP. Calcium channel blockade by certain opioids. Fundam Appl Toxicol. 1983;3:536–42.

    Article  CAS  PubMed  Google Scholar 

  72. Atkinson D, Dunne A, Parker M. Torsades de pointes and self-terminating ventricular fibrillation in a prescription methadone user. Anaesthesia. 2007;62:952–5.

    Article  CAS  PubMed  Google Scholar 

  73. Andrews CM, Krantz MJ, Wedam EF, Marcuson MJ, Capacchione JF, Haigney MC. Methadone-induced mortality in the treatment of chronic pain: role of QT prolongation. Cardiol J. 2009;16:210–7.

    PubMed  Google Scholar 

  74. Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT, Haigney MC, Inturrisi C, Knight JR, Otis-Green S, Marcus SM, Mehta D, Meyer MC, Portenoy R, Savage S, Strain E, Walsh S, Zeltzer L. American Pain Society; Heart Rhythm Society. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15:321–37.

    Article  CAS  PubMed  Google Scholar 

  75. Stringer J, Welsh C, Tommasello A. Methadone-associated QT interval prolongation and torsades de pointes. Am J Health Syst Pharm. 2009;66:825–33.

    Article  CAS  PubMed  Google Scholar 

  76. van den Beuken-van Everdingen MH, Geurts JW, Patijn J. Prolonged QT interval by methadone: relevance for daily practice? A prospective study in patients with cancer and noncancer pain. J Opioid Manag. 2013;9:263–7.

    Article  PubMed  Google Scholar 

  77. Anghelescu DL, Patel RM, Mahoney DP, Trujillo L, Faughnan LG, Steen BD, Baker JN, Dl Pei. Methadone prolongs cardiac conduction in young patients with cancer-related pain. J Opioid Manag. 2016;12:131–8.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Schwinghammer AJ, Wilson MD, Hall BA. Corrected QT interval prolongation in hospitalized pediatric patients receiving methadone. Pediatr Crit Care Med. 2018;19:e403–8.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387–95.

    Article  PubMed  Google Scholar 

  80. Baldo BA. Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. Arch Toxicol. 2018;92:2457–73.

    Article  CAS  PubMed  Google Scholar 

  81. Mastroianni A, Ravaglia G. Serotonin syndrome due to co-administration of linezolid and methadone. Infez Med. 2017;25:263–6.

    PubMed  Google Scholar 

  82. Kumai M, Maeda Y, Miura M, Tsuruga K, Yamada T, Takekuma Y, Sugawara M. Serotonin syndrome developing immediately after the initiation of low-dose methadone therapy: a case report. Case Rep Oncol. 2020;13:281–4.

  83. Kharasch ED. Intraoperative methadone: rediscovery, reappraisal, and reinvigoration. Anesth Analg. 2011;112:13–6.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Zanin A, Masiero S, Severino MS, Calderone M, Da Dalt L, Laverda AM. A delayed methadone encephalopathy: clinical and neuroradiological findings. J Child Neurol. 2010;25:748–51.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital and The Ohio State University, 700 Children’s Drive, Columbus, OH , 43205, USA

    Joseph D. Tobias

Authors
  1. Joseph D. Tobias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph D. Tobias.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tobias, J.D. Methadone: applications in pediatric anesthesiology and critical care medicine. J Anesth 35, 130–141 (2021). https://doi.org/10.1007/s00540-020-02887-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00540-020-02887-4

Keywords

Search

Navigation