Methadone Pharmacokinetics in Geriatric Critically Ill Patients Following Intramuscular and Intravenous Administration: A Pilot Study
-
Safoura Beik Rassouli
,
Mohammad Reza Rouini
,
Farhad Najmeddin
,
Azin Gheimati
,
Ali A Golabchifar
,
Kimia Tabib
,
Arezoo Ahmadi
,
Kourosh Sadeghi
,
Hooshyar Honarmand
,
Ali Mohammed Hadi
,
Mojtaba Mojtahedzadeh
Abstract
Background: Methadone is used for the pain management worldwide. Its special characteristics make it a potential alternative for pain management in critically ill and geriatric patients. Due to lack of studies in this population, we aimed to compare the pharmacokinetic behavior of Methadone following intramuscular and intravenous administration in geriatric ICU patients and with previously reports in healthy volunteers.
Methods: According to the limitations in ICU setting, we could include 11 patients over 65 years old, who required opioid for pain relief in this study. Patients were randomized to receive 5 mg of Methadone IM or IV injection every 8 hours for 6 days. The Methadone plasma level detected with LC-mass tandem mass spectrometry, and pharmacokinetics parameters were evaluated for each subject in both 1st and 6th days of treatment.
Results: Based on our results, bioavailability of intramuscular Methadone in geriatric ICU patients was low and less than 40% of the dose was absorbed within first 12 hours. The volume of distribution of Methadone in the first day was significantly lower than the previously reported values in healthy subjects and significantly increased during these 6 days. The Methadone half-life in this population also significantly increased through this period.
Conclusion: Pharmacokinetic behavior of Methadone in geriatric ICU patients is unpredictable. Reduced volume of distribution and half-life may be observed initially, following with an increase to the normal range. It seems that IM administration of Methadone in geriatric critically ill patients may not provide target analgesic Methadone serum levels.
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2. Erstad BL, Puntillo K, Gilbert HC, et al. Pain management principles in the critically ill. Chest 2009;135(4):1075-86.
3. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41(1):263-306.
4. Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 2005;19(4):13-24.
5. Rostami-Hodjegan A, Wolff K, Hay AW, Raistrick D, Calvert R, Tucker GT. Population pharmacokinetics of methadone in opiate users: characterization of time-dependent changes. Br J Clin Pharmacol 1999;48(1):43-52.
6. Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone. Clin Pharmacokinet 2002;41(14):1153-93.
7. Peng PW, Tumber PS, Gourlay D. Review article: perioperative pain management of patients on methadone therapy. Can J Anaesth 2005;52(5):513-23.
8. Kristensen K, Christensen CB, Christrup LL. The mu 1, mu 2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995;56(2):PL45-PL50.
9. Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley KM. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 1987;41(4):392-401.
10. Robinson AE, Williams FM. The distribution of methadone in man. J Pharm Pharmacol 11971;23(5):353-8.
11. Garrido MaJ, Trocóniz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods 1999;42(2):61-6.
12. Gabrielsson JL, Johansson P, Bondesson U, Paalzow LK. Analysis of methadone disposition in the pregnant rat by means of a physiological flow model. J Pharmacokinet Biopharm 1985;13(4):355-72.
13. Nilsson M-I, Widerlöv E, Meresaar U, Änggård E. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol 1982;22(4):337-42.
14. Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care 2012;16(2):R49.
15. Mercadante S, Sapio M, Serretta R, Caligara M. Patient-controlled analgesia with oral methadone in cancer pain: preliminary report. Ann Oncol 1996;7(6):613-7.
16. Srinivasan V, Pung D, O'Neill SP. Conversion from prolonged intravenous fentanyl infusion to enteral methadone in critically ill children. World J Clin Pediatr 2017;6(2):110-117.
17. Fredheim O, Moksnes K, Borchgrevink P, Kaasa S, Dale O. Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand 2008;52(7):879-89.
18. Coderre TJ, Melzack R. The role of NMDA receptor-operated calcium channels in persistent nociception after formalin-induced tissue injury. J Neurosci 1992;12(9):3671-5.
19. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000;27(7):524-528.
20. Mao J, Price DD, Lu J, Mayer DJ. Antinociceptive tolerance to the mu-opioid agonist DAMGO is dose-dependently reduced by MK-801 in rats. Neurosci Lett 1998;250(3):193-6.
21. Lynch ME. A review of the use of methadone for the treatment of chronic noncancer pain. Pain Res Manag 2005;10(3):133-144.
22. Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Palliat Med 2003;17(7):576-87.
23. Moryl N, Kogan M, Comfort C, Obbens E. Methadone in the treatment of pain and terminal delirium in advanced cancer patients. Palliat Support Care 2005;3(4):311-7.
24. Benítez-Rosario MA, Feria M, Salinas-Martín A, Martínez-Castillo LP, Martín-Ortega JJ. Opioid switching from transdermal fentanyl to oral methadone in patients with cancer pain. Cancer 2004;101(12):2866-73.
25. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage 2004;28(5):497-504.
26. Gourlay GK, Willis R, Wilson P. Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration--response relationships. Anesthesiology 1984;61(1):19-26.
27. Bodenham A, Shelly M, Park G. The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients. Clin Pharmacokinet 1988;14(6):347-73.
28. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient—concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 2014;77:3-11.
29. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 2003;38(8):843-53.
30. Liang HR, Foltz RL, Meng M, Bennett P. Method development and validation for quantitative determination of methadone enantiomers in human plasma by liquid chromatography/tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2004;806(2):191-198.
31. Shargel L, Yu ABC. Applied biopharmaceutics & pharmacokinetics. 7th ed. New York: McGraw-Hill Education; 2016.
32. Wolff K, Rostami-Hodjegan A, Shires S, et al. The pharmacokinetics of methadone in healthy subjects and opiate users. Br J Clin Pharmacol 1997;44(4):325-334.
33. Shaiova L, Berger A, Blinderman CD, et al. Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care 2008;6(2):165-176.
34. Beaver W, Wallenstein S, Houde R, Rogers A. A dinical eomparison of the analgesie effects of methadone and morphine administered intramuseularly, and oforally and parenterally administered methadone. Clin Pharmacol Ther 1967;8(3):415-426.
35. Smith BS, Yogaratnam D, Levasseur-Franklin KE, Forni A, Fong J. Introduction to drug pharmacokinetics in the critically ill patient. Chest 2012;141(5):1327-36.
36. Goldstein NE, Morrison RS. Treatment of pain in older patients. Crit Rev Oncol Hematol 2005;54(2):157-64.
37. Stemland CJ, Witte J, Colquhoun DA, et al. The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion. Paediatr Anaesth 2013;23(1):51-7.
38. Pugh KG, Wei JY. Clinical implications of physiological changes in the aging heart. Drugs Aging 2001;18(4):263-76.
39. Schaich M, Harbich-Brutscher E, Pascheberg U, et al. Association of specific cytogenetic aberrations with mdr1 gene expression in adult myeloid leukemia and its implication in treatment outcome. Haematologica 2002;87(5):455-64.
40. Lugo G, Castaneda-Hernandez G. Relationship between hemodynamic and vital support measures and pharmacokinetic variability of amikacin in critically ill patients with sepsis. Crit Care Med 1997;25(5):806-11.
41. Edwards DJ, Lalka D, Cerra F, Slaughter RL. Alpha1‐acid glycoprotein concentration and protein binding in trauma. Clin Pharmacol Ther 1982;31(1):62-7.
42. Turnheim K. Drug dosage in the elderly. Drugs Aging 1998;13(5):357-79.
2. Erstad BL, Puntillo K, Gilbert HC, et al. Pain management principles in the critically ill. Chest 2009;135(4):1075-86.
3. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41(1):263-306.
4. Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 2005;19(4):13-24.
5. Rostami-Hodjegan A, Wolff K, Hay AW, Raistrick D, Calvert R, Tucker GT. Population pharmacokinetics of methadone in opiate users: characterization of time-dependent changes. Br J Clin Pharmacol 1999;48(1):43-52.
6. Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone. Clin Pharmacokinet 2002;41(14):1153-93.
7. Peng PW, Tumber PS, Gourlay D. Review article: perioperative pain management of patients on methadone therapy. Can J Anaesth 2005;52(5):513-23.
8. Kristensen K, Christensen CB, Christrup LL. The mu 1, mu 2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995;56(2):PL45-PL50.
9. Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley KM. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 1987;41(4):392-401.
10. Robinson AE, Williams FM. The distribution of methadone in man. J Pharm Pharmacol 11971;23(5):353-8.
11. Garrido MaJ, Trocóniz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods 1999;42(2):61-6.
12. Gabrielsson JL, Johansson P, Bondesson U, Paalzow LK. Analysis of methadone disposition in the pregnant rat by means of a physiological flow model. J Pharmacokinet Biopharm 1985;13(4):355-72.
13. Nilsson M-I, Widerlöv E, Meresaar U, Änggård E. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol 1982;22(4):337-42.
14. Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care 2012;16(2):R49.
15. Mercadante S, Sapio M, Serretta R, Caligara M. Patient-controlled analgesia with oral methadone in cancer pain: preliminary report. Ann Oncol 1996;7(6):613-7.
16. Srinivasan V, Pung D, O'Neill SP. Conversion from prolonged intravenous fentanyl infusion to enteral methadone in critically ill children. World J Clin Pediatr 2017;6(2):110-117.
17. Fredheim O, Moksnes K, Borchgrevink P, Kaasa S, Dale O. Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand 2008;52(7):879-89.
18. Coderre TJ, Melzack R. The role of NMDA receptor-operated calcium channels in persistent nociception after formalin-induced tissue injury. J Neurosci 1992;12(9):3671-5.
19. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000;27(7):524-528.
20. Mao J, Price DD, Lu J, Mayer DJ. Antinociceptive tolerance to the mu-opioid agonist DAMGO is dose-dependently reduced by MK-801 in rats. Neurosci Lett 1998;250(3):193-6.
21. Lynch ME. A review of the use of methadone for the treatment of chronic noncancer pain. Pain Res Manag 2005;10(3):133-144.
22. Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Palliat Med 2003;17(7):576-87.
23. Moryl N, Kogan M, Comfort C, Obbens E. Methadone in the treatment of pain and terminal delirium in advanced cancer patients. Palliat Support Care 2005;3(4):311-7.
24. Benítez-Rosario MA, Feria M, Salinas-Martín A, Martínez-Castillo LP, Martín-Ortega JJ. Opioid switching from transdermal fentanyl to oral methadone in patients with cancer pain. Cancer 2004;101(12):2866-73.
25. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage 2004;28(5):497-504.
26. Gourlay GK, Willis R, Wilson P. Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration--response relationships. Anesthesiology 1984;61(1):19-26.
27. Bodenham A, Shelly M, Park G. The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients. Clin Pharmacokinet 1988;14(6):347-73.
28. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient—concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 2014;77:3-11.
29. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 2003;38(8):843-53.
30. Liang HR, Foltz RL, Meng M, Bennett P. Method development and validation for quantitative determination of methadone enantiomers in human plasma by liquid chromatography/tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2004;806(2):191-198.
31. Shargel L, Yu ABC. Applied biopharmaceutics & pharmacokinetics. 7th ed. New York: McGraw-Hill Education; 2016.
32. Wolff K, Rostami-Hodjegan A, Shires S, et al. The pharmacokinetics of methadone in healthy subjects and opiate users. Br J Clin Pharmacol 1997;44(4):325-334.
33. Shaiova L, Berger A, Blinderman CD, et al. Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care 2008;6(2):165-176.
34. Beaver W, Wallenstein S, Houde R, Rogers A. A dinical eomparison of the analgesie effects of methadone and morphine administered intramuseularly, and oforally and parenterally administered methadone. Clin Pharmacol Ther 1967;8(3):415-426.
35. Smith BS, Yogaratnam D, Levasseur-Franklin KE, Forni A, Fong J. Introduction to drug pharmacokinetics in the critically ill patient. Chest 2012;141(5):1327-36.
36. Goldstein NE, Morrison RS. Treatment of pain in older patients. Crit Rev Oncol Hematol 2005;54(2):157-64.
37. Stemland CJ, Witte J, Colquhoun DA, et al. The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion. Paediatr Anaesth 2013;23(1):51-7.
38. Pugh KG, Wei JY. Clinical implications of physiological changes in the aging heart. Drugs Aging 2001;18(4):263-76.
39. Schaich M, Harbich-Brutscher E, Pascheberg U, et al. Association of specific cytogenetic aberrations with mdr1 gene expression in adult myeloid leukemia and its implication in treatment outcome. Haematologica 2002;87(5):455-64.
40. Lugo G, Castaneda-Hernandez G. Relationship between hemodynamic and vital support measures and pharmacokinetic variability of amikacin in critically ill patients with sepsis. Crit Care Med 1997;25(5):806-11.
41. Edwards DJ, Lalka D, Cerra F, Slaughter RL. Alpha1‐acid glycoprotein concentration and protein binding in trauma. Clin Pharmacol Ther 1982;31(1):62-7.
42. Turnheim K. Drug dosage in the elderly. Drugs Aging 1998;13(5):357-79.
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| Issue | Vol 8, No 3 (Summer 2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/jpc.v8i3.4543 | |
| Keywords | ||
| Methadone Intensive Care Unit Pharmacokinetics | ||
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How to Cite
1.
Beik Rassouli S, Rouini MR, Najmeddin F, Gheimati A, Golabchifar AA, Tabib K, Ahmadi A, Sadeghi K, Honarmand H, Hadi AM, Mojtahedzadeh M. Methadone Pharmacokinetics in Geriatric Critically Ill Patients Following Intramuscular and Intravenous Administration: A Pilot Study. J Pharm Care. 2020;8(3):99-109.
