The Pharmacology of Intravenous Opioids

  • Stephanie Whitener
  • Matthew D. McEvoy
  • Steven L. Shafer
  • Pamela Flood
Chapter

Abstract

This chapter reviews the pharmacology of the intravenously administered opioids in the practice of geriatric anesthesiology. These drugs include morphine, meperidine, hydromorphone, fentanyl, sufentanil, and methadone. It is important that anesthesiologists understand the differences in pharmacology of opioids in elderly patients, in order to choose the appropriate drug and titrate precisely to achieve the desired analgesic effects while minimizing the risks of opioid toxicity. The key points for this chapter are as follows: (1) Elderly patients need about half the dose as younger patients, (2) The primary reason is pharmacodynamics (the elderly brain is more sensitive to opioids), (3) The pharmacokinetic changes with age are modest, (4) Studies in elderly animals show reduced numbers of μ receptors with increased age. That does not explain the reduction in dose, as decreased receptor density should decrease sensitivity to opioids. The enhancement in drug effect seen in the clinic is more likely attributable to changes in cyclonucleotide coupling and other downstream changes that occur in aging, and (5) Mepiridine should be used with caution in elderly patients due to its effects on myocardium, pharmacokinetics related to its metabolites, and its delirogenic properties.

Keywords

Aging Continuous infusion Effect site Fentayl Geriatric anesthesia and analgesia Hydromorphone Intravenous anesthesia Intravenous analgesia Meperidine Methadone Morphine Patient controlled analgesia (PCA) Postoperative analgesia Sufentanil 

References

  1. 1.
    Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the WHO method for cancer pain relief. Cancer. 1987;59:850–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Jacox A, Carr DB, Payne R. New clinical-practice guidelines for the management of pain in patients with cancer. N Engl J Med. 1994;330:651–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Bafitis H, Sargent F. Human physiological adaptability through the life sequence. J Gerontol. 1977;32:402–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Klein U, Klein M, Sturm H, et al. The frequency of adverse drug reactions as dependent upon age, sex and duration of hospitalization. Int J Clin Pharmacol Biopharm. 1976;13:187–95.PubMedGoogle Scholar
  5. 5.
    Crooks J. Aging and drug disposition—pharmacodynamics. J Chronic Dis. 1983;36:85–90.PubMedCrossRefGoogle Scholar
  6. 6.
    Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179:1011–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic (3H) Etorphine to ratbrain homogenate. Proc Natl Acad Sci U S A. 1973;70:1947–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Terenius L. Characteristics of the “receptor” for narcotic analgesics in synaptic plasma membrane fraction from rat brain. Acta Pharmacol Toxicol (Copenh). 1973;33:377–84.CrossRefGoogle Scholar
  9. 9.
    Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975;258:577–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Li CH, Chung D. Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands. Proc Natl Acad Sci U S A. 1976;73:1145–8.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L. Dynorphin-(1–13), an extraordinarily potent opioid peptide. Proc Natl Acad Sci U S A. 1979;76:6666–70.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976;197:517–32.PubMedGoogle Scholar
  13. 13.
    Chang KJ, Cooper BR, Hazum E, Cuatrecasas P. Multiple opiate receptors: different regional distribution in the brain and differential binding of opiates and opioid peptides. Mol Pharmacol. 1979;16:91–104.PubMedGoogle Scholar
  14. 14.
    Robson LE, Kosterlitz HW. Specific protection of the binding sites of D-Ala2-D-Leu5-enkephalin (delta-receptors) and dihydromorphine (mu-receptors). Proc R Soc Lond B Biol Sci. 1979;205:425–32.PubMedCrossRefGoogle Scholar
  15. 15.
    Schulz R, Wuster M, Krenss H, Herz A. Selective development of tolerance without dependence in multiple opiate receptors of mouse vas deferens. Nature. 1980;285:242–3.PubMedCrossRefGoogle Scholar
  16. 16.
    Pasternak GW, Childers SR, Snyder SH. Opiate analgesia: evidence for mediation by a subpopulation of opiate receptors. Science. 1980;208:514–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Ling GS, Spiegel K, Nishimura SL, Pasternak GW. Dissociation of morphine’s analgesic and respiratory depressant actions. Eur J Pharmacol. 1983;86:487–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Ling GS, Spiegel K, Lockhart SH, Pasternak GW. Separation of opioid analgesia from respiratory depression: evidence for different receptor mechanisms. J Pharmacol Exp Ther. 1985;232:149–55.PubMedGoogle Scholar
  19. 19.
    Brown GP, Yang K, King MA, et al. 3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist. FEBS Lett. 1997;412:35–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Crews JC, Sweeney NJ, Denson DD. Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics. Cancer. 1993;72:2266–72.PubMedCrossRefGoogle Scholar
  21. 21.
    Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects. Cancer. 1999;86:1856–66.PubMedCrossRefGoogle Scholar
  22. 22.
    Chang A, Emmel DW, Rossi GC, Pasternak GW. Methadone analgesia in morphine-insensitive CXBK mice. Eur J Pharmacol. 1998;351:189–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Abbadie C, Rossi GC, Orciuolo A, Zadina JE, Pasternak GW. Anatomical and functional correlation of the endomorphins with mu opioid receptor splice variants. Eur J Neurosci. 2002;16:1075–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Cadet P. Mu opiate receptor subtypes. Med Sci Monit. 2004;10:MS28–32.PubMedGoogle Scholar
  25. 25.
    Stefano GB, Hartman A, Bilfinger TV, et al. Presence of the mu3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. J Biol Chem. 1995;270:30290–3.PubMedCrossRefGoogle Scholar
  26. 26.
    Kozak CA, Filie J, Adamson MC, Chen Y, Yu L. Murine chromosomal location of the mu and kappa opioid receptor genes. Genomics. 1994;21:659–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Belknap JK, Mogil JS, Helms ML, et al. Localization to chromosome 10 of a locus influencing morphine analgesia in crosses derived from C57BL/6 and DBA/2 strains. Life Sci. 1995;57:PL117–24.PubMedCrossRefGoogle Scholar
  28. 28.
    Lötsch J, Geisslinger G. Are mu-opioid receptor polymorphisms important for clinical opioid therapy? Trends Mol Med. 2005;11:82–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Romberg RR, Olofsen E, Bijl H, et al. Polymorphism of mu-opioid receptor gene (OPRM1:c.118A > G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology. 2005;102:522–30.PubMedCrossRefGoogle Scholar
  30. 30.
    Pasternak GW. Multiple opiate receptors: deja vu all over again. Neuropharmacology. 2004;47(Suppl 1):312–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Chen Y, Mestek A, Liu J, Hurley JA, Yu L. Molecular cloning and functional expression of a mu-opioid receptor from rat brain. Mol Pharmacol. 1993;44:8–12.PubMedGoogle Scholar
  32. 32.
    Wang JB, Imai Y, Eppler CM, Gregor P, Spivak CE, Uhl GR. Mu opiate receptor: cDNA cloning and expression. Proc Natl Acad Sci U S A. 1993;90:10230–4.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Pan YX, Xu J, Mahurter L, Xu M, Gilbert AK, Pasternak GW. Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun. 2003;301:1057–61.PubMedCrossRefGoogle Scholar
  34. 34.
    Connor M, Christie MD. Opioid receptor signalling mechanisms. Clin Exp Pharmacol Physiol. 1999;26:493–9.PubMedCrossRefGoogle Scholar
  35. 35.
    North RA. Opioid actions on membrane ion channels. In: Herz A, editor. Opioids. Handbook of experimental pharmacology, vol. 104. Berlin: Springer-Verlag; 1993. p. 773–97.Google Scholar
  36. 36.
    Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science. 1999;286:2495–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Raehal KM, Walker JK, Bohn LM. Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther. 2005;314:1195–201.PubMedCrossRefGoogle Scholar
  38. 38.
    DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD. A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013;344:708–17.PubMedCrossRefGoogle Scholar
  39. 39.
    Soergel DG, Subach RA, Burnham N, Lark MW, James IE, Sadler BM, Skobieranda F, Violin JD, Webster LR. Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain. 2014;155:1829–35.PubMedCrossRefGoogle Scholar
  40. 40.
    Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hübner H, Huang XP, Sassano MF, Giguère PM, Löber S, Da Duan, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK. Structure-based discovery of opioid analgesics with reduced side effects. Nature. 2016;537:185–90.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, Soergel DG, Subach RA, Cook E, Skobieranda F. A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain. Pain. 2016;157:264–72.PubMedCrossRefGoogle Scholar
  42. 42.
    Ueno E, Liu DD, Ho IK, Hoskins B. Opiate receptor characteristics in brains from young, mature and aged mice. Neurobiol Aging. 1988;9:279–83.PubMedCrossRefGoogle Scholar
  43. 43.
    Hess GD, Joseph JA, Roth GS. Effect of age on sensitivity to pain and brain opiate receptors. Neurobiol Aging. 1981;2:49–55.PubMedCrossRefGoogle Scholar
  44. 44.
    Petkov VV, Petkov VD, Grahovska T, Konstantinova E. Enkephalin receptor changes in rat brain during aging. Gen Pharmacol. 1984;15:491–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Fulop T Jr, Kekessy D, Foris G. Impaired coupling of naloxone sensitive opiate receptors to adenylate cyclase in PMNLs of aged male subjects. Int J Immunopharmacol. 1987;9(6):651–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Hoskins B, Ho IK. Age-induced differentiation of morphine’s effect on cyclic nucleotide metabolism. Neurobiol Aging. 1987;8:473–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Smith MA, Gray JD. Age-related differences in sensitivity to the antinociceptive effects of opioids in male rats. Influence of nociceptive intensity and intrinsic efficacy at the mu receptor. Psychopharmacology. 2001;156:445–53.PubMedCrossRefGoogle Scholar
  48. 48.
    Van Crugten JT, Somogyi AA, Nation RL, Reynolds G. The effect of old age on the disposition and antinociceptive response of morphine and morphine-6 betaglucuronide in the rat. Pain. 1997;71:199–205.PubMedCrossRefGoogle Scholar
  49. 49.
    Hoskins B, Burton CK, Ho IK. Differences in morphine-induced antinociception and locomotor activity in mature adult and aged mice. Pharmacol Biochem Behav. 1986;25:599–605.PubMedCrossRefGoogle Scholar
  50. 50.
    Ayers E, Warmington M, Reid MC. Chronic pain perspectives: managing chronic pain in older adults: 6 steps to overcoming medication barriers. J Fam Pract. 2012;61:S16–21.Google Scholar
  51. 51.
    Helme RD, Gibson SJ. The epidemiology of pain in elderly people. Clin Geriatr Med. 2001;17:417–31.PubMedCrossRefGoogle Scholar
  52. 52.
    Verhaak PF, Kerssens JJ, Dekker J, Sorbi MJ, Bensing JM. Prevalence of chronic benign pain disorder among adults: a review of the literature. Pain. 1998;77:231–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Sorkin BA, Rudy TE, Hanlon RB, Turk DC, Stieg RL. Chronic pain in old and young patients: differences appear less important than similarities. J Gerontol. 1990;45:P64–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Edwards RR, Fillingim RB. Age-associated differences in responses to noxious stimuli. J Gerontol A Biol Sci Med Sci. 2001;56:M180–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Edwards RR, Fillingim RB, Ness TJ. Age-related differences in endogenous pain modulation: a comparison of diffuse noxious inhibitory controls in healthy older and younger adults. Pain. 2003;101:155–65.PubMedCrossRefGoogle Scholar
  56. 56.
    Washington LL, Gibson SJ, Helme RD. Age-related differences in the endogenous analgesic response to repeated cold water immersion in human volunteers. Pain. 2000;89:89–96.PubMedCrossRefGoogle Scholar
  57. 57.
    Casale G, Pecorini M, Cuzzoni G, de Nicola P. Betaendorphin and cold pressor test in the aged. Gerontology. 1985;31:101–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Zheng Z, Gibson SJ, Khalil Z, Helme RD, McMeeken JM. Age-related differences in the time course of capsaicininduced hyperalgesia. Pain. 2000;85:51–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Chakour MC, Gibson SJ, Bradbeer M, Helme RD. The effect of age on A delta- and C-fibre thermal pain perception. Pain. 1996;64:143–52.PubMedCrossRefGoogle Scholar
  60. 60.
    Cepeda MS, Farrar JT, Baumgarten M, Boston R, Carr DB, Strom BL. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther. 2003;74:102–12.PubMedCrossRefGoogle Scholar
  61. 61.
    Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted? Anesthesiology. 1999;91:109–18.PubMedCrossRefGoogle Scholar
  62. 62.
    Junger A, Hartmann B, Benson M, et al. The use of an anesthesia information management system for prediction of antiemetic rescue treatment at the postanesthesia care unit. Anesth Analg. 2001;92(5):1203–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Scott JC, Stanski DR. Decreased fentanyl/alfentanil dose requirement with increasing age: a pharmacodynamic basis. J Pharmacol Exp Ther. 1987;240:159–66.PubMedGoogle Scholar
  64. 64.
    Hudson RJ, Bergstrom RG, Thomson IR, Sabourin MA, Rosenbloom M, Strunin L. Pharmacokinetics of sufentanil in patients undergoing abdominal aortic surgery. Anesthesiology. 1989;70:426–31.PubMedCrossRefGoogle Scholar
  65. 65.
    Minto CF, Schnider TW, Egan T, et al. The influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology. 1997;86:10–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Lotsch J, Skarke C, Schmidt H, Liefhold J, Geisslinger G. Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers. Clin Pharmacol Ther. 2002;72:151–62.PubMedCrossRefGoogle Scholar
  67. 67.
    Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley KM. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther. 1987;41:392–401.PubMedCrossRefGoogle Scholar
  68. 68.
    Bjorkman S. Reduction and lumping of physiologically based pharmacokinetic models: prediction of the disposition of fentanyl and pethidine in humans by successively simplified models. J Pharmacokinet Pharmacodyn. 2003;30:285–307.PubMedCrossRefGoogle Scholar
  69. 69.
    Drover DR, Angst MS, Valle M, et al. Input characteristics and bioavailability after administration of immediate and a new extended-release formulation of hydromorphone in healthy volunteers. Anesthesiology. 2002;97:827–36.PubMedCrossRefGoogle Scholar
  70. 70.
    Qiao GL, Fung KF. Pharmacokinetic-pharmacodynamic modelling of meperidine in goats (II): modelling. J Vet Pharmacol Ther. 1994;17:127–34.PubMedCrossRefGoogle Scholar
  71. 71.
    Inturrisi CE, Portenoy RK, Max MB, Colburn WA, Foley KM. Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain. Clin Pharmacol Ther. 1990;47:565–77.PubMedCrossRefGoogle Scholar
  72. 72.
    Hill JL, Zacny JP. Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers. Psychopharmacology. 2000;152:31–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology. 1991;74:53–63.PubMedCrossRefGoogle Scholar
  74. 74.
    Shafer SL, Gregg KM. Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer-controlled infusion pump. J Pharmacokinet Biopharm. 1992;20:147–69.PubMedCrossRefGoogle Scholar
  75. 75.
    Henthorn TK, Krejcie TC, Shanks CA, Avram MJ. Time-dependent distribution volume and kinetics of the pharmacodynamic effector site. J Pharm Sci. 1992;81:1136–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Wada DR, Drover DR, Lemmens HJ. Determination of the distribution volume that can be used to calculate the intravenous loading dose. Clin Pharmacokinet. 1998;35:1–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Gourlay GK, Kowalski SR, Plummer JL, Cousins MJ, Armstrong PJ. Fentanyl blood concentration-analgesic response relationship in the treatment of postoperative pain. Anesth Analg. 1988;67:329–37.PubMedCrossRefGoogle Scholar
  78. 78.
    Lehmann KA, Ribbert N, Horrichs-Haermeyer G. Postoperative patient-controlled analgesia with alfentanil: analgesic efficacy and minimum effective concentrations. J Pain Symptom Manag. 1990;5:249–58.CrossRefGoogle Scholar
  79. 79.
    Scott JC, Cooke JE, Stanski DR. Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiology. 1991;74:34–42.PubMedCrossRefGoogle Scholar
  80. 80.
    Dahlstrom B, Tamsen A, Paalzow L, Hartvig P. Patient-controlled analgesic therapy. Part IV. Pharmacokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinet. 1982;7:266–79.PubMedCrossRefGoogle Scholar
  81. 81.
    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.PubMedCrossRefGoogle Scholar
  82. 82.
    Mather LE, Glynn CJ. The minimum effective analgetic blood concentration of pethidine in patients with intractable pain. Br J Clin Pharmacol. 1982;14:385–90.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Coda B, Tanaka A, Jacobson RC, Donaldson G, Chapman CR. Hydromorphone analgesia after intravenous bolus administration. Pain. 1997;71:41–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology. 1992;76:334–41.PubMedCrossRefGoogle Scholar
  85. 85.
    Youngs EJ, Shafer SL. Pharmacokinetic parameters relevant to recovery from opioids. Anesthesiology. 1994;81:833–42.PubMedCrossRefGoogle Scholar
  86. 86.
    Gintzler AR, Gershon MD, Spector S. A nonpeptide morphine-like compound: immunocytochemical localization in the mouse brain. Science. 1978;199:447–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Goldstein A, Barrett RW, James IF, et al. Morphine and other opiates from beef brain and adrenal. Proc Natl Acad Sci U S A. 1985;82:5203–7.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Donnerer J, Oka K, Brossi A, Rice KC, Spector S. Presence and formation of codeine and morphine in the rat. Proc Natl Acad Sci U S A. 1986;83:4566–7.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Cardinale GJ, Donnerer J, Finck AD, Kantrowitz JD, Oka K, Spector S. Morphine and codeine are endogenous components of human cerebrospinal fluid. Life Sci. 1987;40:301–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Lotsch J, Geisslinger G. Morphine-6-glucuronide: an analgesic of the future? Clin Pharmacokinet. 2001;40:485–99.PubMedCrossRefGoogle Scholar
  91. 91.
    Paul D, Standifer KM, Inturrisi CE, Pasternak GW. Pharmacological characterization of morphine-6 beta-glucuro-nide, a very potent morphine metabolite. J Pharmacol Exp Ther. 1989;251:477–83.PubMedGoogle Scholar
  92. 92.
    Lotsch J, Kobal G, Stockmann A, Brune K, Geisslinger G. Lack of analgesic activity of morphine-6-glucuronide after short-term intravenous administration in healthy volunteers. Anesthesiology. 1997;87(6):1348–58.PubMedCrossRefGoogle Scholar
  93. 93.
    Lotsch J, Kobal G, Geisslinger G. No contribution of morphine-6-glucuronide to clinical morphine effects after short-term administration. Clin Neuropharmacol. 1998;21:351–4.PubMedGoogle Scholar
  94. 94.
    Wolff T, Samuelsson H, Hedner T. Morphine and morphine metabolite concentrations in cerebrospinal fluid and plasma in cancer pain patients after slow-release oral morphine administration. Pain. 1995;62:147–54.PubMedCrossRefGoogle Scholar
  95. 95.
    Portenoy RK, Foley KM, Stulman J, et al. Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: plasma profiles, steady-state concentrations and the consequences of renal failure. Pain. 1991;47:13–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.PubMedCrossRefGoogle Scholar
  97. 97.
    Lotsch J, Skarke C, Schmidt H, Grosch S, Geisslinger G. The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiology. 2001;95:1329–38.PubMedCrossRefGoogle Scholar
  98. 98.
    Skarke C, Jarrar M, Erb K, Schmidt H, Geisslinger G, Lotsch J. Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine. Clin Pharmacol Ther. 2003;74:303–11.PubMedCrossRefGoogle Scholar
  99. 99.
    Skarke C, Darimont J, Schmidt H, Geisslinger G, Lotsch J. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther. 2003;73:107–21.PubMedCrossRefGoogle Scholar
  100. 100.
    Letrent SP, Polli JW, Humphreys JE, Pollack GM, Brouwer KR, Brouwer KL. P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells. Biochem Pharmacol. 1999;58:951–7.PubMedCrossRefGoogle Scholar
  101. 101.
    Dahan A, Romberg R, Teppema L, Sarton E, Bijl H, Olofsen E. Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion. Anesthesiology. 2004;101:1201–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Aubrun F, Monsel S, Langeron O, Coriat P, Riou B. Postoperative titration of intravenous morphine in the elderly patient. Anesthesiology. 2002;96:17–23.PubMedCrossRefGoogle Scholar
  103. 103.
    Aubrun F, Bunge D, Langeron O, Saillant G, Coriat P, Riou B. Postoperative morphine consumption in the elderly patient. Anesthesiology. 2003;99:160–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Wagner LE 2nd, Eaton M, Sabnis SS, Gingrich KJ. Meperidine and lidocaine block of recombinant voltage-dependent Na+ channels: evidence that meperidine is a local anesthetic. Anesthesiology. 1999;91:1481–90.PubMedCrossRefGoogle Scholar
  105. 105.
    Wolff M, Olschewski A, Vogel W, Hempelmann G. Meperidine suppresses the excitability of spinal dorsal horn neurons. Anesthesiology. 2004;100:947–55.PubMedCrossRefGoogle Scholar
  106. 106.
    Holmberg L, Odar-Cederlof I, Boreus LO, Heyner L, Ehrnebo M. Comparative disposition of pethidine and norpethidine in old and young patients. Eur J Clin Pharmacol. 1982;22:175–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Seifert CF, Kennedy S. Meperidine is alive and well in the new millennium: evaluation of meperidine usage patterns and frequency of adverse drug reactions. Pharmacotherapy. 2004;24:776–83.PubMedCrossRefGoogle Scholar
  108. 108.
    Odar-Cederlof I, Boreus LO, Bondesson U, Holmberg L, Heyner L. Comparison of renal excretion of pethidine (meperidine) and its metabolites in old and young patients. Eur J Clin Pharmacol. 1985;28:171–5.PubMedCrossRefGoogle Scholar
  109. 109.
    Huang YF, Upton RN, Rutten AJ, Mather LE. The hemodynamic effects of intravenous bolus doses of meperidine in conscious sheep. Anesth Analg. 1994;78:442–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and congnitive decline in elderly patients: a systematic review. Anesth Analg. 2006;102:1255–66.PubMedCrossRefGoogle Scholar
  111. 111.
    Zornberg GL, Bodkin JA, Cohen BM. Severe adverse interaction between pethidine and selegiline. Lancet. 1991;337:246.PubMedCrossRefGoogle Scholar
  112. 112.
    Keeri-Szanto M. Anaesthesia time/dose curves IX the use of hydromorphone in surgical anaesthesia and postoperative pain relief in comparison to morphine. Can Anaesth Soc J. 1976;23:587–95.PubMedCrossRefGoogle Scholar
  113. 113.
    Kopp A, Wachauer D, Hoerauf KH, Zulus E, Reiter WJ, Steltzer H. Effect of preemptive hydromorphone administration on postoperative pain relief—a randomized controlled trial. Wien Klin Wochenschr. 2000;112:1002–6.PubMedGoogle Scholar
  114. 114.
    Rapp SE, Egan KJ, Ross BK, Wild LM, Terman GW, Ching JM. A multidimensional comparison of morphine and hydromorphone patient-controlled analgesia. Anesth Analg. 1996;82:1043–8.PubMedGoogle Scholar
  115. 115.
    Liu S, Carpenter RL, Mulroy MF, et al. Intravenous versus epidural administration of hydromorphone. Effects on analgesia and recovery after radical retropubic prostatectomy. Anesthesiology. 1995;82:682–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Brose WG, Tanelian DL, Brodsky JB, Mark JB, Cousins MJ. CSF and blood pharmacokinetics of hydromorphone and morphine following lumbar epidural administration. Pain. 1991;45:11–5.PubMedCrossRefGoogle Scholar
  117. 117.
    Halpern SH, Arellano R, Preston R, et al. Epidural morphine vs hydromorphone in post-caesarean section patients. Can J Anaesth. 1996;43:595–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Bentley JB, Borel JD, Nenad RE Jr, Gillespie TJ. Age and fentanyl pharmacokinetics. Anesth Analg. 1982;61:968–71.PubMedCrossRefGoogle Scholar
  119. 119.
    Singleton MA, Rosen JI, Fisher DM. Pharmacokinetics of fentanyl in the elderly. Br J Anaesth. 1988;60:619–22.PubMedCrossRefGoogle Scholar
  120. 120.
    Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology. 1985;62:234–41.PubMedCrossRefGoogle Scholar
  121. 121.
    Martin G, Glass PS, Breslin DS, et al. A study of anesthetic drug utilization in different age groups. J Clin Anesth. 2003;15:194–200.PubMedCrossRefGoogle Scholar
  122. 122.
    Holdsworth MT, Forman WB, Killilea TA, et al. Transdermal fentanyl disposition in elderly subjects. Gerontology. 1994;40:32–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Davis MP, Srivastava M. Demographics, assessment and management of pain in the elderly. Drugs Aging. 2003;20:23–57.PubMedCrossRefGoogle Scholar
  124. 124.
    Kharasch ED, Hoffer C, Whittington D. Influence of age on the pharmacokinetics and pharmacodynamics of oral transmucosal fentanyl citrate. Anesthesiology. 2004;101:738–43.PubMedCrossRefGoogle Scholar
  125. 125.
    Shafer A, Sung ML, White PF. Pharmacokinetics and pharmacodynamics of alfentanil infusions during general anesthesia. Anesth Analg. 1986;65:1021–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Sitar DS, Duke PC, Benthuysen JL, Sanford TJ, Smith NT. Aging and alfentanil disposition in healthy volunteers and surgical patients. Can J Anaesth. 1989;36:149–54.PubMedCrossRefGoogle Scholar
  127. 127.
    Kent AP, Dodson ME, Bower S. The pharmacokinetics and clinical effects of a low dose of alfentanil in elderly patients. Acta Anaesthesiol Belg. 1988;39:25–33.PubMedGoogle Scholar
  128. 128.
    Lemmens HJ, Burm AG, Hennis PJ, Gladines MP, Bovill JG. Influence of age on the pharmacokinetics of alfentanil. Gender dependence. Clin Pharmacokinet. 1990;19:416–22.PubMedCrossRefGoogle Scholar
  129. 129.
    Maitre PO, Vozeh S, Heykants J, Thomson DA, Stanski DR. Population pharmacokinetics of alfentanil: the average dose-plasma concentration relationship and interindividual variability in patients. Anesthesiology. 1987;68:59–67.CrossRefGoogle Scholar
  130. 130.
    Raemer DB, Buschman A, Varvel JR, et al. The prospective use of population pharmacokinetics in a computer driven system for alfentanil. Anesthesiology. 1990;73:66–72.PubMedCrossRefGoogle Scholar
  131. 131.
    Lemmens HJ, Burm AG, Bovill JG, Hennis PJ. Pharmacodynamics of alfentanil as a supplement to nitrous oxide anaesthesia in the elderly patient. Br J Anaesth. 1988;61:173–9.PubMedCrossRefGoogle Scholar
  132. 132.
    Lemmens HJ, Bovill JG, Hennis PJ, Burm AG. Age has no effect on the pharmacodynamics of alfentanil. Anesth Analg. 1988;67:956–60.PubMedCrossRefGoogle Scholar
  133. 133.
    Lemmens HJ, Burm AG, Bovill JG, Hennis PJ, Gladines MP. Pharmacodynamics of alfentanil. The role of plasma protein binding. Anesthesiology. 1992;76:65–70.PubMedCrossRefGoogle Scholar
  134. 134.
    Lemmens HJ, Bovill JG, Burm AG, Hennis PJ. Alfentanil infusion in the elderly. Prolonged computer-assisted infusion of alfentanil in the elderly surgical patient. Anaesthesia. 1988;43:850–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Helmers JH, van Leeuwen L, Zuurmond WW. Sufentanil pharmacokinetics in young adult and elderly surgical patients. Eur J Anaesthesiol. 1994;11:181–5.PubMedGoogle Scholar
  136. 136.
    Gepts E, Shafer SL, Camu F, et al. Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology. 1995;83:1194–204.PubMedCrossRefGoogle Scholar
  137. 137.
    Matteo RS, Schwartz AE, Ornstein E, Young WL, Chang WJ. Pharmacokinetics of sufentanil in the elderly surgical patient. Can J Anaesth. 1990;37:852–6.PubMedCrossRefGoogle Scholar
  138. 138.
    Hofbauer R, Tesinsky P, Hammerschmidt V, et al. No reduction in the sufentanil requirement of elderly patients undergoing ventilatory support in the medical intensive care unit. Eur J Anaesthesiol. 1999;16:702–7.PubMedCrossRefGoogle Scholar
  139. 139.
    Minto CF, Schnider TW, Shafer SL. The influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology. 1997;86:24–33.PubMedCrossRefGoogle Scholar
  140. 140.
    Shimoyama N, Shimoyama M, Elliott KJ, Inturrisi CE. d-Methadone is antinociceptive in the rat formalin test. J Pharmacol Exp Ther. 1997;283:648–52.PubMedGoogle Scholar
  141. 141.
    Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther. 1999;289:1048–53.PubMedGoogle Scholar
  142. 142.
    Callahan RJ, Au JD, Paul M, Liu C, Yost CS. Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in Xenopus oocytes: stereospecific and subunit effects. Anesth Analg. 2004;98:653–9.PubMedCrossRefGoogle Scholar
  143. 143.
    Alinejad S, Kazemi T, Zamani N, Hoffman RS, Mehrpour O. A systematic review of the cardiotoxicity of methadone. EXCLI J. 2015;14:577–600.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Lavand’Homme P, De Kock M. Practical guidelines on the postoperative use of patient-controlled analgesia in the elderly. Drugs Aging. 1998;13:9–16.PubMedCrossRefGoogle Scholar
  145. 145.
    Macintyre PE, Jarvis DA. Age is the best predictor of postoperative morphine requirements. Pain. 1996;64:357–64.PubMedCrossRefGoogle Scholar
  146. 146.
    Gagliese L, Jackson M, Ritvo P, Wowk A, Katz J. Age is not an impediment to effective use of patient-controlled analgesia by surgical patients. Anesthesiology. 2000;93:601–10.PubMedCrossRefGoogle Scholar
  147. 147.
    Woodhouse A, Mather LE. The influence of age upon opioid analgesic use in the patient-controlled analgesia environment. Anaesthesia. 1997;52:949–55.PubMedCrossRefGoogle Scholar
  148. 148.
    Ready LB. PCA is effective for older patients, but are there limits? Anesthesiology. 2000;93:597–8.PubMedCrossRefGoogle Scholar
  149. 149.
    Beattie WS, Warriner CB, Etches R, et al. The addition of continuous intravenous infusion of ketorolac to a patient-controlled analgetic morphine regime reduced postoperative myocardial ischemia in patients undergoing elective total hip or knee arthroplasty. Anesth Analg. 1997;84:715–22.PubMedCrossRefGoogle Scholar
  150. 150.
    Malmberg AB, Yaksh TL. Pharmacology of the spinal action of ketorolac, morphine, ST-91, U50488H, and L-PIA on the formalin test and an isobolographic analysis of the NSAID interaction. Anesthesiology. 1993;79:270–81.PubMedCrossRefGoogle Scholar
  151. 151.
    Lashbrook JM, Ossipov MH, Hunter JC, Raffa RB, Tallarida RJ, Porreca F. Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX and COX2-inhibitors in nerve-injured rats. Pain. 1999;82:65–72.PubMedCrossRefGoogle Scholar
  152. 152.
    Gloth FM. Pain management in older adults: prevention and treatment. J Am Geriatr Soc. 2001;49:188–99.PubMedCrossRefGoogle Scholar
  153. 153.
    Wilder-Smith OH. Opioid use in the elderly. Eur J Pain. 2005;9:137–40.PubMedCrossRefGoogle Scholar
  154. 154.
    Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med. 2001;345:935–40.PubMedCrossRefGoogle Scholar
  155. 155.
    Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63:649–71.PubMedCrossRefGoogle Scholar
  156. 156.
    Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology. 2003;98:312–22.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Stephanie Whitener
    • 1
  • Matthew D. McEvoy
    • 2
  • Steven L. Shafer
    • 3
  • Pamela Flood
    • 3
  1. 1.Department of AnesthesiologyMedical University of South CarolinaCharlestonUSA
  2. 2.Department of AnesthesiologyVanderbilt University Medical CenterNashvilleUSA
  3. 3.Department of Anesthesiology, Perioperative and Pain MedicineStanford UniversityPalo AltoUSA

Personalised recommendations