Clinical Pharmacokinetics

, Volume 31, Issue 6, pp 410–422 | Cite as

Pharmacokinetics of Opioids in Renal Dysfunction

  • Graham Davies
  • Christopher Kingswood
  • Martin Street
Review Article Special Populations


Patients with renal insufficiency commonly require the administration of an opioid analgesic to provide adequate pain relief. The handling of morphine, pethidine (meperidine) and dextropropoxyphene in patients with renal insufficiency is complicated by the potential accumulation of metabolites. While morphine itself remains largely unaffected by renal failure, accumulation, as denoted by an increase in both mean peak concentrations and the area under the concentration-time curve, of both the active metabolite (morphine-6-glucuronide) and the principal metabolite (morphine-3-glucuronide, thought to possess opiate antagonist properties) have been reported. The increased elimination half-lives of the toxic metabolites norpethidine and norpropoxyphene in patients with poor renal function administered pethidine and dextropropoxyphene, respectively, makes their routine use ill advised.

Case reports of prolonged narcosis associated with the use of both codeine and dihydrocodeine in patients with renal insufficiency call for care to be used when prescribing these agents under such conditions. Although the pharmacokinetics of buprenorphine, alfentanil, sufentanil and remifentanil change little in patients with renal failure, the continuous administration of fentanyl can lead to prolonged sedation.


Morphine Fentanyl Adis International Limited Remifentanil Buprenorphine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Corail I, Williams R. Management of liver failure. Br J Anaesth 1986; 58: 234–45CrossRefGoogle Scholar
  2. 2.
    Hughes TJ. A pharmacological basis to the rational use of potent analgesics. Hosp Update 1988 Nov; 14(11): 2159–69Google Scholar
  3. 3.
    Bower S, Hull CJ. Comparative pharmacokinetics of fentanyl and alfentanil. Br J Anaesth 1982; 54: 871–7PubMedCrossRefGoogle Scholar
  4. 4.
    McClain DA, Hugg CC. Intravenous fentanyl kinetics. Clin Pharmacol Ther 1980; 28: 106–14PubMedCrossRefGoogle Scholar
  5. 5.
    Guay DRP, Matzke GR, Findlay JWA, et al. Codeine pharmacokinetics and pharmacodynamics in hemodialysis patients [abstract]. Clin Pharmacol ther 1987; 41: 222Google Scholar
  6. 6.
    Jusko WJ, Gretch M. Plasma and tissue protein binding of drugs in pharmacokinetics. Drug Metab Rev 1976; 5: 43–140CrossRefGoogle Scholar
  7. 7.
    Bennett WM, Aronoff GR, Morrison G, et al. Drug prescribing in renal failure: dosing guidelines for adults. Am J Kidney Dis 1983; 3: 155–93PubMedGoogle Scholar
  8. 8.
    Hand CW, Sear JW, Uppington J, et al. Buprenorphine disposition in patients with renal impairment: single and continuous dosing with special reference to metabolites. Br J Anaesthesiol 1990; 64: 276–82CrossRefGoogle Scholar
  9. 9.
    Osborne R, Joel S, Trew D, et al. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 1990; 47: 12–9PubMedCrossRefGoogle Scholar
  10. 10.
    Hanna MH, Peat SJ, Knibb AA, et al. Disposition of morphine-6-glucuronide and morphine in healthy volunteers. Br J Anaesth 1991;66: 103–7PubMedCrossRefGoogle Scholar
  11. 11.
    Hanna MH, Peat SJ, Woodham M, et al. Analgesic efficacy and CSF pharmacokinetics of intrathecal morphine-6-glucuronide: comparison with morphine. Br J Anaesth 1990; 64: 547–50PubMedCrossRefGoogle Scholar
  12. 12.
    Bovill JG, Sebel PS, Blackburn CL, et al. The pharmokinetics of sufentanil in surgical patients. Anesthesiology 1984; 61: 502–6PubMedCrossRefGoogle Scholar
  13. 13.
    Meuldermans WEG, Hurkmans RMA, Heykants JJP. Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood. Arch Int Pharmacodyn Ther 1982; 257: 4–19PubMedGoogle Scholar
  14. 14.
    Westmoreland CL, Hoke JF, Sebel PS, et al. Pharmokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing inpatient surgery. Anesthesiology 1993; 79: 893–903PubMedCrossRefGoogle Scholar
  15. 15.
    Lemmens HJM. Pharmacokinetic-pharmacodynamic relationships for opioids in balanced anaesthesia. Clin Pharmacokinet 1995; 29(4): 231–42PubMedCrossRefGoogle Scholar
  16. 16.
    Moore A, Sear J, Baldwin D, et al. Morphine kinetics during and after renal transplantation. Clin Pharmacol Ther 1984; 35: 641–5PubMedCrossRefGoogle Scholar
  17. 17.
    Hoskin PJ, Hanks GW, Aherne GW, et al. The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers [abstract]. Br J Clin Pharmacol 1989; 27: 499PubMedCrossRefGoogle Scholar
  18. 18.
    Aitkinhead AR, Vater M, Achola K, et al. Pharmacokinetics of single-dose IV morphine in normal volunteers and patients with end-stage renal failure. Br J Anaesth 1984; 56: 813–9CrossRefGoogle Scholar
  19. 19.
    Sawe J. Morphine and its 3- and 6-glucuronides in plasma and urine during chronic oral administration in cancer patients. In: Foley KM, Inturrisi CE, editors. Opioid analgesics in the management of cancer pain. New York: Raven Press, 1986: 45–55Google Scholar
  20. 20.
    Osborne R, Joel S, Trew D, et al. Analgesic activity of morphine-6-glucuronide. Lancet 1988; II: 828CrossRefGoogle Scholar
  21. 21.
    Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci 1990; 47: 579–85PubMedCrossRefGoogle Scholar
  22. 22.
    Watt JA, Cramond T, Smith MT. Morphine-6-glucuronide: analgesic effects antagonised by morphine-3-glucuronide [abstract]. Clin Exp Pharmacol Physiol 1990; 17: 83CrossRefGoogle Scholar
  23. 23.
    Woolner DF, Winter D, Frendin TJ, et al. Renal failure does not impair the metabolism of morphine. Br J Clin Pharmacol 1986; 22: 55–9PubMedCrossRefGoogle Scholar
  24. 24.
    Chauvin M, Sandouk P, Scherrmann JM, et al. Morphine pharmacokinetics in renal failure. Anesthesiology 1987; 66: 327–31PubMedCrossRefGoogle Scholar
  25. 25.
    Sawe J, Odar-Cederlof I. Kinetics of morphine in patients with renal failure. Eur J Clin Pharmacol 1987; 32: 377–82PubMedCrossRefGoogle Scholar
  26. 26.
    Sear JW, Hand CW, Moore RA, et al. Studies on morphine disposition: influence of renal failure on the kinetics of morphine and its metabolites. Br J Anaesth 1989; 62: 28–32PubMedCrossRefGoogle Scholar
  27. 27.
    Osborne R, Joel S, Grebenik K, et al. The pharmokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 1993; 54: 158–67PubMedCrossRefGoogle Scholar
  28. 28.
    Bion JF, Logan BK, Newman PM, et al. Sedation in intensive care: morphine and renal function. Intensive Care Med 1986; 12: 359–65PubMedCrossRefGoogle Scholar
  29. 29.
    Hanna MH, D’Costa F, Peat SJ, et al. Morphine-6-glucuronide disposition in renal impairment. Br J Anaesth 1993; 70: 511–4PubMedCrossRefGoogle Scholar
  30. 30.
    Moore RA, Sear JW, Bullingham RES, et al. Morphine kinetics in renal failure. In: Foley KM, Inturrisi CE, editors. Opioid analgesics in the management of cancer pain. New York: Raven Press, 1986; 65–72Google Scholar
  31. 31.
    Ball M, McQuay HJ, Moore RA, et al. Renal failure and the use of morphine in intensive care. Lancet 1985 Apr 6; I: 784–6CrossRefGoogle Scholar
  32. 32.
    Shelly M, Park GR. Renal failure and use of morphine in intensive care [letter]. Lancet 1985 May 11; I: 1100CrossRefGoogle Scholar
  33. 33.
    Osborne RJ, Joel SP, Slevin ML. Morphine intoxication in renal failure: the role of morphine-6-glucuronide. BMJ 1986 Jun 14; 292: 1548–9PubMedCrossRefGoogle Scholar
  34. 34.
    Glare PA, Walsh TD. Clinical pharmacokinetics of morphine. Ther Drug Monit 1991; 13: 1–23PubMedCrossRefGoogle Scholar
  35. 35.
    Milne RW, Nation RL, Somogyi AA, et al. The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients. Br J Clin Pharmacol 1992; 34: 53–9PubMedCrossRefGoogle Scholar
  36. 36.
    Peterson GM, Randall CTC, Paterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol 1990; 38: 121–4PubMedCrossRefGoogle Scholar
  37. 37.
    D’Honneur G, Gilton A, Sandouk P, et al. Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. Anesthesiology 1994 Jul; 81: 87–93PubMedCrossRefGoogle Scholar
  38. 38.
    Davies JG, Coombes ID, Kingswood C, et al. The clearance of morphine and morphine-6-glucuronide in critically ill patients receiving continuous renal replacement therapies [abstract]. J Pharm Pharmacol 1994; 46 Suppl 2: 1045Google Scholar
  39. 39.
    Bentley JB, Borel JD, Nenad RE, et al. Age and fentanyl pharmacokinetics. Anesth Analg 1982; 61: 968–71PubMedCrossRefGoogle Scholar
  40. 40.
    Hug CC, Murphy MR. Fentanyl disposition in cerebrospinal fluid and plasma and its relationship to ventilatory depression in the dog. Anesthesiology 1979; 50: 342–9PubMedCrossRefGoogle Scholar
  41. 41.
    Stoeckel H, Hengstmann JH, Schuttler J. Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression. B J Anaesth 1979; 51: 741–5CrossRefGoogle Scholar
  42. 42.
    Coral IM, Moore AR, Strunin L. Plasma concentrations of fentanyl in normal surgical patients with severe renal failure. Br J Anaesth 1980; 52: 101PGoogle Scholar
  43. 43.
    Alazia M, Levron JC, Guidon C, et al. Pharmacokinetics of fentanyl during continuous infusion in critically ill patients [abstract]. Anesthesiology 1987; 67: 665CrossRefGoogle Scholar
  44. 44.
    Meuldermans W, Van Peer A, Hendricks J, et al. Alfentanil pharmacokinetics and metabolism in humans. Anesthesiology 1988; 69: 527–34PubMedCrossRefGoogle Scholar
  45. 45.
    Chauvin M, Lebrault C, Levron JC, et al. Pharmacokinetics of alfentanil in chronic renal failure. Anesth Analg 1987; 66: 53–6PubMedCrossRefGoogle Scholar
  46. 46.
    Bower S, Sear JW. Disposition of alfentanil in patients receiving a renal transplant. J Pharm Pharmacol 1989; 41: 654–7PubMedCrossRefGoogle Scholar
  47. 47.
    Davis PJ, Stiller RL, Cook DR, et al. Effects of cholestatic hepatic disease and chronic renal failure on alfentanil pharmacokinetics in children. Anesth Analg 1989; 68: 579–83PubMedGoogle Scholar
  48. 48.
    Roily G, Kay B, Cockx F. A double-blind comparison of high doses of fentanyl and sufentanil in man. Acta Anaesthesiol Belg 1979; 30: 247–56Google Scholar
  49. 49.
    Wiggum DC, Cork RC, Weldon ST, et al. Postoperative respiratory depression and elevated sufentanil levels in a patient with chronic renal failure. Anesthesiology 1985; 63: 708–10PubMedCrossRefGoogle Scholar
  50. 50.
    Lehmann KA, Sipakis K, Gasparini R, et al. Pharmacokinetics of sufentanil in general surgical patients under different conditions of anaesthesia. Acta Anaesthesiol Scand 1993; 37(2): 176–80PubMedCrossRefGoogle Scholar
  51. 51.
    Howie MB, Smith DF, Harrington K, et al. Serum concentrations of sufentanil and fentanyl in the post-operative course in cardiac surgery patients. Anesthesiology 1984; 61: A131CrossRefGoogle Scholar
  52. 52.
    Schwartz AE, Matteo RS, Ornsteine, et al. Pharmacokinetics of sufentanil in hyperventilated patients [abstract]. Anaesth Analg 1987;66 Suppl: 151CrossRefGoogle Scholar
  53. 53.
    Davis PJ, Stiller RL, Cook DR, et al. Pharmacokinetics of sufentanil in adolescent patients with chronic renal failure. Anesth Analg 1988; 67: 268–71PubMedGoogle Scholar
  54. 54.
    Fyman P, Avitable M, Moser F, et al. Sufentanil pharmacokinetics in patients undergoing renal transplantation [abstract]. Anesth Analg 1987; 66 Suppl.: 62CrossRefGoogle Scholar
  55. 55.
    Sear JW. Sufentanil disposition in patients undergoing renal transplantation: influence of choice of kinetic model. Br J Anaesth 1989; 63: 60–7PubMedCrossRefGoogle Scholar
  56. 56.
    Egan TD, Lemmens HJM, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993; 79: 881–92PubMedCrossRefGoogle Scholar
  57. 57.
    Glass PSA, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short acting opioid: remifentanil (GI87084B). Anesth Analg 1993; 77: 1031–40PubMedCrossRefGoogle Scholar
  58. 58.
    Hoke J, Muir K, Glass P, et al. Pharmacokinetics of remifentanil and its metabolite (GI90291) in subjects with renal disease [abstract]. Clin Pharmacol Ther 1995; 57: PI55Google Scholar
  59. 59.
    Shlugman D, Dufore S, Dershwitz M, et al. Respiratory effects of remifentanil in subjects with severe renal impairment compared to matched controls [abstract]. Anesthesiology 1994; 81: 1417CrossRefGoogle Scholar
  60. 60.
    Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology 1991; 74: 53–63PubMedCrossRefGoogle Scholar
  61. 61.
    Hull JH, Findlay JWA, Rogers JF, et al. An evaluation of the effects of smoking on codeine pharmacokinetics and bio-availability in normal human voluneteers. Drug Intell Clin Pharm 1982; 16: 849–54PubMedGoogle Scholar
  62. 62.
    Posey BL, Kimble SN. High-performance liquid chromatographic study of codeine, norcodeine and morphine as indicators of codeine ingestion. J Anal Toxicol 1984; 8: 68–74PubMedGoogle Scholar
  63. 63.
    Gilman AG, Goodman LS, Rail TW, et al., editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985Google Scholar
  64. 64.
    Way EL, Adler TK. The pharmacologic implications of the fate of morphine and its surrogates. Pharmacol Rev 1968; 12: 383–446Google Scholar
  65. 65.
    Parke TJ, Nandi PR, Bird KJ, et al. Profound hypotension following intravenous codeine phosphate. Anaesthesia 1992; 47: 852–4PubMedCrossRefGoogle Scholar
  66. 66.
    Pearson MA. A fatality due to the ingestion of codeine (methylmorphine). Clin Toxicol 1979; 15: 267–71PubMedCrossRefGoogle Scholar
  67. 67.
    Levine DF. Hypocalcaemia increases the narcotic effect of codeine. Postgrad Med J 1980; 56: 736–7PubMedCrossRefGoogle Scholar
  68. 68.
    Matzke GR, Chan GLC, Abrahim PA. Codeine dosage in renal failure. Clin Pharm 1986; 5: 15–6PubMedGoogle Scholar
  69. 69.
    Rowell FJ, Seymour RA, Rawlins MD. Pharmacokinetics of intravenous and oral dihydrocodeine and its acid metabolites. Eur J Clin Pharmacol 1983; 25: 419–24PubMedCrossRefGoogle Scholar
  70. 70.
    Barnes JN, Goodwin FJ. Dihydrocodeine narcosis in renal failure. BMJ 1983; 286: 438–9PubMedCrossRefGoogle Scholar
  71. 71.
    Redfern N. Dihydrocodeine overdose treated with naloxone infusion. BMJ 1983; 287: 751–2PubMedCrossRefGoogle Scholar
  72. 72.
    Barnes JN, Williams AJ, Tomson MJF, et al. Dihydrocodeine in renal failure: further evidence for an important role of the kidney in the handling of opioid drugs. BMJ 1985; 290: 740–2PubMedCrossRefGoogle Scholar
  73. 73.
    Mather LE, Tucker GT. Systemic availability of orally administered meperidine. Clin Pharmacol Ther 1976; 20: 535–40PubMedGoogle Scholar
  74. 74.
    Mather LE, Meffin PJ. Clinical pharmacokinetics of pethidine. Clin Pharmacokinet 1978; 3: 352–68PubMedCrossRefGoogle Scholar
  75. 75.
    Stambaugh JE, Wainer IW, Sanstead JK, et al. The clinical pharmacology of meperidine: comparison of routes of administration. J Clin Pharmacol 1976; 16: 245–56PubMedGoogle Scholar
  76. 76.
    Asatoor AM, London DR, Milne MD, et al. The excretion of pethidine and its derivatives. Br J Pharmacol 1963; 20: 285–98Google Scholar
  77. 77.
    Edwards DJ, Svensson CK, Visco JP, et al. Clinical pharmacokinetics of pethidine. Clin Pharmacokinet 1982; 7: 421–33PubMedCrossRefGoogle Scholar
  78. 78.
    Tang R, Shimomura SK, Rotblatt M. Meperidine-induced seizures in sickle cell patients. Hosp Formul 1980; 15: 764–72Google Scholar
  79. 79.
    Odar-Cederlof I, Boreus LO, Bondesson U, et al. Comparison of renal excretion of pethidine (meperidine) and its metabolites in old and young patients. Eur J Clin Pharmacol 1985; 28: 171–5PubMedCrossRefGoogle Scholar
  80. 80.
    Szeto HH, Inturrisi E, Houde E, et al. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure or cancer. Ann Intern Med 1977; 86: 738–41PubMedGoogle Scholar
  81. 81.
    Kaiko RF, Foley KM, Grabinski PY, et al. Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol 1982; 13: 180–5CrossRefGoogle Scholar
  82. 82.
    Jiraki K. Lethal effects of normeperidine. Am J Forensic Med Pathol 1992; 13(1): 42–3PubMedCrossRefGoogle Scholar
  83. 83.
    Inturrisi CE, Colburn WA, Verebely K, et al. Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene. Clin Pharmacol Ther 1982; 31: 157–67PubMedCrossRefGoogle Scholar
  84. 84.
    Wolen RL, Ziege EA, Gruber CM. Determination of propoxyphene and norproxyphene by chemical ionization mass fragmentography. Clin Pharmacol Ther 1974; 17: 15–20Google Scholar
  85. 85.
    Gram LF, Schou J, Way WL, et al. d-Propxyphene kinetics after single oral and intravenous doses in man. Clin Pharmacol Ther 1979; 26: 473–82PubMedGoogle Scholar
  86. 86.
    Gibson TP, Giacomini KM, Briggs WA, et al. Propoxyphene and norpropoxyphene plasma concentrations in the anephric patient. Clin Pharmacol Ther 1980; 27: 665–70PubMedCrossRefGoogle Scholar
  87. 87.
    Nickander R, Smits SE, Steinberg MI. Propoxyphene and norpropoxyphene: pharmacologic and toxic effects in animals. J Pharmacol Exp ther 1977; 200: 245–53PubMedGoogle Scholar
  88. 88.
    Giacomini KM, Gibson TP, Levy G. Effect of hemodialysis on propoxyphene and norpropoxyphene concentrations in blood of anephric patients. Clin Pharmacol Ther 1980; 27: 508–14PubMedCrossRefGoogle Scholar
  89. 89.
    Nilsson MI, Meresaar V, Anggard E. Clinical pharmacokinetics of methadone. Acta Anaesthesiol 1982; 74 Suppl: 66–9CrossRefGoogle Scholar
  90. 90.
    Berkowitz BA. The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone. Clin Pharmacokinet 1976; 1: 219–30PubMedCrossRefGoogle Scholar
  91. 91.
    Gourley GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology 1982; 57: 458–67CrossRefGoogle Scholar
  92. 92.
    Inturrisi CE, Verebely K. Disposition of methadone in man after a single oral dose. Clin Pharmacol Ther 1972; 13: 923–30PubMedGoogle Scholar
  93. 93.
    Kreek MJ, Schecter AJ, Gutjahar CL, et al. Methadone use in patients with chronic renal disease. Drug Alcohol Depend 1980; 5: 197–205PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Graham Davies
    • 1
  • Christopher Kingswood
    • 1
  • Martin Street
    • 1
  1. 1.Department of PharmacyUniversity of Brighton and Royal Sussex County HospitalMoulsecoomb, BrightonEngland

Personalised recommendations