Skip to main content
SpringerLink
Log in

Opioid Analgesics

  • Chapter
  • First Online:
Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents

  • 2807 Accesses

Abstract

Opioid analgesics represent a major therapeutic approach to pain management but challenge clinicians and healthcare systems for appropriate usage and long-term patient benefits. Opioids can be full agonists and partial agonists–antagonists for therapeutic effects that involve the mu, kappa, and delta opioid receptors. Opioids can be administered by different routes that include intravenous, intramuscular, oral, sublingual, transdermal, nasal spray, and rectal suppositories. Opioids can be short-acting and medium-acting agents based upon their elimination half-life that requires multiple daily dosing regimens. Sustained-release formulations have been developed for several opioids. The transdermal formulation allows for once-daily application. Some opioids are metabolized by the CYP enzyme system, while other opioids are primarily metabolized via glucuronidation. Depending upon the opioid, these agents are metabolized to active metabolites that possess analgesic effects that can be greater than, equal to, or less than the parent drug. Morphine has been the prototypical opioid analgesic agent and its pharmacokinetic and pharmacodynamic profile extensively studied in various patient populations. Besides their therapeutic analgesic effects, opioids can produce a variety of adverse effects related to their pharmacokinetic and pharmacodynamic actions that includes physical dependence, tolerance, respiratory depression, cardiovascular effects, sedation, cognitive impairment, gastrointestinal effects, histamine effects, and miosis. An integrated pharmacokinetic–pharmacodynamic approach to opioid treatment can lead to its optimal pharmacotherapy.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Portenoy RK, Ahmed E (2014) Principles of opioid use in cancer pain. J Clin Oncol 32(16):1662–1670

    Article  CAS  PubMed  Google Scholar 

  2. Trescot AM, Datta S, Lee M, Hansen H (2008) Opioid pharmacology. Pain Physician 11(2 Suppl):S133–S153

    PubMed  Google Scholar 

  3. Lin JH, Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42(1):59–98

    Article  CAS  PubMed  Google Scholar 

  4. Mercer SL, Coop A (2011) Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance. Curr Top Med Chem 11(9):1157–1164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Eap CB, Buclin T, Baumann P (2002) Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 41(14):1153–1193

    Article  CAS  PubMed  Google Scholar 

  6. Gourevitch MN, Hartel D, Tenore P et al (1999) Three oral formulations of methadone. A clinical and pharmacodynamic comparison. J Subst Abuse Treat 17(3):237–241

    Article  CAS  PubMed  Google Scholar 

  7. Lee CR, McTavish D, Sorkin EM (1993) Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 46(2):313–340

    Article  CAS  PubMed  Google Scholar 

  8. Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43(13):879–923

    Article  CAS  PubMed  Google Scholar 

  9. Benziger DP, Kaiko RF, Miotto JB, Fitzmartin RD, Reder RF, Chasin M (1996) Differential effects of food on the bioavailability of controlled-release oxycodone tablets and immediate-release oxycodone solution. J Pharm Sci 85(4):407–410

    Article  CAS  PubMed  Google Scholar 

  10. Streisand JB, Varvel JR, Stanski DR et al (1991) Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology 75(2):223–229

    Article  CAS  PubMed  Google Scholar 

  11. Findlay JW, Butz RF, Welch RM (1977) Codeine kinetics as determined by radioimmunoassay. Clin Pharmacol Ther 22(4):439–446

    Article  CAS  PubMed  Google Scholar 

  12. Kim I, Barnes AJ, Oyler JM et al (2002) Plasma and oral fluid pharmacokinetics and pharmacodynamics after oral codeine administration. Clin Chem 48(9):1486–1496

    CAS  PubMed  Google Scholar 

  13. Rowell FJ, Seymour RA, Rawlins MD (1983) Pharmacokinetics of intravenous and oral dihydrocodeine and its acid metabolites. Eur J Clin Pharmacol 25(3):419–424

    Article  CAS  PubMed  Google Scholar 

  14. Inturrisi CE, Max MB, Foley KM, Schultz M, Sin S-U, Houde RW (1984) The pharmacokinetics of heroin in patients with chronic pain. N Engl J Med 310(19):1213–1217

    Article  CAS  PubMed  Google Scholar 

  15. Valtier S, Bebarta VS (2012) Excretion profile of hydrocodone, hydromorphone and norhydrocodone in urine following single dose administration of hydrocodone to healthy volunteers. J Anal Toxicol 36:507–514, Jul 10:bks058

    Article  CAS  PubMed  Google Scholar 

  16. Vallner JJ, Stewart JT, Kotzan JA, Kirsten EB, Honigberg IL (1981) Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects. J Clin Pharmacol 21(4):152–156

    Article  CAS  PubMed  Google Scholar 

  17. Dixon R, Crews T, Inturrisi C, Foley K (1983) Levorphanol: pharmacokinetics and steady-state plasma concentrations in patients with pain. Res Commun Chem Pathol Pharmacol 41(1):3–17

    CAS  PubMed  Google Scholar 

  18. Edwards D, Svensson CK, Visco JP, Lalka D (1982) Clinical pharmacokinetics of pethidine: 1982. Clin Pharmacokinet 7(5):421–433

    Article  CAS  PubMed  Google Scholar 

  19. Mather LE, Meffin PJ (1978) Clinical pharmacokinetics pethidine. Clin Pharmacokinet 3(5):352–368

    Article  CAS  PubMed  Google Scholar 

  20. Osborne R, Joel S, Trew D, Sleven M (1990) Morphine and metabolite behavior after different routes of administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 47(1):12–19

    Article  CAS  PubMed  Google Scholar 

  21. Sawe J, Dahlstrom B, Paalzow L, Rane A (1981) Morphine kinetics in cancer patients. Clin Pharmacol Ther 30:629–635

    Article  CAS  PubMed  Google Scholar 

  22. Sawe J, Svensson JO, Rane A (1983) Morphine metabolism in cancer patients on increasing oral doses – no evidence for autoinduction or dose-dependence. Br J Clin Pharmacol 16(1):85–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sawe J (1986) High dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations on oral treatment. Clin Pharmacokinet 11(2):87–106

    Article  CAS  PubMed  Google Scholar 

  24. Hoskin PJ, Hanks GW, Aherne GW, Chapman D, Littleton P, Filshie J (1989) The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers. Br J Clin Pharmacol 27(4):499–505

    Google Scholar 

  25. Gourlay GK, Cherry DA, Cousins MJ (1986) A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain 25(3):297–312

    Article  CAS  PubMed  Google Scholar 

  26. Pöyhiä R, Seppälä T, Olkkola KT, Kalso E (1992) The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol 33(6):617–621

    Article  PubMed  PubMed Central  Google Scholar 

  27. Smith HS (2009) Clinical pharmacology of oxymorphone. Pain Med 10(1 Suppl):S3–S10, Oxymorphone

    Article  Google Scholar 

  28. Lintz W, Barth H, Osterloh G, Schmidt-Böthelt E (1986) Bioavailability of enteral tramadol formulations. 1st communication: capsules. Arzneimittel Forschung 36(8):1278–1283

    CAS  PubMed  Google Scholar 

  29. Bullingham RES, McQuay HJ, Porter EJB, Allen MC, Moore RA (1982) Sublingual buprenorphine used postoperatively: ten hour plasma drug concentration analysis. Br J Clin Pharmacol 13(5):665–673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pachter IJ, Evens RP (1985) Butrophanol. Drug Alcohol Depend 14(3):325–338

    Article  CAS  PubMed  Google Scholar 

  31. Inturrisi CE (2002) Clinical pharmacology of opioids for pain. Clin J Pain 18(4 Suppl):S3–S13

    Article  PubMed  Google Scholar 

  32. Wood M (1986) Plasma drug binding: implications for anesthesiologists. Anesth Analg 65(7):786–804

    Article  CAS  PubMed  Google Scholar 

  33. Lemmens HJ (1995) Pharmacokinetic-pharmacodynamic relationships for opioids in balanced anaesthesia. Clin Pharmacokinet 29(4):231–242

    Article  CAS  PubMed  Google Scholar 

  34. Gulaboski R, Cordeiro MN, Milhazes N et al (2007) Evaluation of the lipophilic properties of opioids, amphetamine-like drugs, and metabolites through electrochemical studies at the interface between two immiscible solutions. Anal Biochem 361(2):236–243

    Article  CAS  PubMed  Google Scholar 

  35. Lombardo F, Shalaeva MY, Tupper KA, Gao F (2001) ElogD(oct): a tool for lipophilicity determination in drug discovery. 2. Basic and neutral compounds. J Med Chem 44(15):2490–2497

    Article  CAS  PubMed  Google Scholar 

  36. Garrett ER, Chandran VR (1985) Pharmacokinetics of morphine and its surrogates VI: bioanalysis, solvolysis kinetics, solubility, pK’a values, and protein binding of buprenorphine. J Pharm Sci 74(5):515–524

    Article  CAS  PubMed  Google Scholar 

  37. Vree TB, Wissen CPWGMV-V (1992) Pharmacokinetics and metabolism of codeine in humans. Biopharm Drug Dispos 13(6):445–460

    Article  CAS  PubMed  Google Scholar 

  38. Quiding H, Anderson P, Bondesson U, Boréus LO, Hynning P-Å (1986) Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration. Eur J Clin Pharmacol 30(6):673–677

    Article  CAS  PubMed  Google Scholar 

  39. Gasche Y, Daali Y, Fathi M et al (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351(27):2827–2831

    Article  CAS  PubMed  Google Scholar 

  40. Moolenaar F, Grasmeuer G, Visser J, Meijer DKF (1983) Rectal versus oral absorption of codeine phosphate in man. Biopharm Drug Dispos 4(2):195–199

    Article  CAS  PubMed  Google Scholar 

  41. Kirkwood LC, Nation RL, Somogyi AA (1997) Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. Br J Clin Pharmacol 44(6):549–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ammon S, Hofmann U, Griese E-U, Gugeler N, Mikus G (1999) Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing. Br J Clin Pharmacol 48(3):317–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fromm MF, Hofmann U, Griese E-U, Mikus G (1995) Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans. Clin Pharmacol Ther 58(4):374–382

    Article  CAS  PubMed  Google Scholar 

  44. Davies KN, Castleden CM, McBurney A, Jagger C (1989) The effect of ageing on the pharmacokinetics of dihydrocodeine. Eur J Clin Pharmacol 37(4):375–379

    Article  CAS  PubMed  Google Scholar 

  45. Cohn GL, Cramer JA, McBride W, Brown RC, Kleber HD (1974) Heroin and morphine binding with human serum proteins and red blood cells. Exp Biol Med 147(3):664–666

    Article  CAS  Google Scholar 

  46. Giardin F, Rentsch KM, Schwab M-A et al (2003) Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts. Clin Pharmacol Ther 74(4):341–352

    Article  CAS  Google Scholar 

  47. Rook EJ, Huitema ADR, van den Brink W, van Ree JM, Beijnen JH (2006) Population pharmacokinetics of heroin and its major metabolites. Clin Pharmacokinet 45(4):401–417

    Article  CAS  PubMed  Google Scholar 

  48. Yeh SY, Gorodetzky CR, McQuinn RL (1976) Urinary excretion of heroin and its metabolites in man. J Pharmacol Exp Ther 196(2):249–256

    CAS  PubMed  Google Scholar 

  49. Cone EJ, Darwin WD, Gorodetzky CW, Tan T (1978) Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog. Drug Metab Dispos 6(4):488–493

    CAS  PubMed  Google Scholar 

  50. Otton S, Schadel M, Cheung SW, Kaplan HL, Busto UE, Sellers EM (1993) CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther 54(5):463–472

    Article  CAS  PubMed  Google Scholar 

  51. Ritschel W, Parab PV, Denson DD, Coyle DE, Gregg RV (1987) Absolute bioavailability of hydromorphone after peroral and rectal administration in humans: saliva/plasma ratio and clinical effects. J Clin Pharmacol 27(9):647–653

    Article  CAS  PubMed  Google Scholar 

  52. Murray A, Hagen NA (2005) Hydromorphone. J Pain Symptom Manage 29(5):57–66

    Article  CAS  Google Scholar 

  53. Parab PV, Ritschel WA, Coyle DE, Gregg RV, Denson DD (1988) Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects. Biopharm Drug Dispos 9(2):187–199

    Article  CAS  PubMed  Google Scholar 

  54. Dilaudid and Dilaudid-HP Injection (hydromorphone hydrochloride). Prescribing information. Manufactured by Hospira, Inc., Lake Forest, IL 60045, USA for Purdue Pharma L.P. Stamford, CT 06901–3431. Revised June 2008

    Google Scholar 

  55. Umans JG, Inturrisi CE (1982) Antinociceptive activity and toxicity of meperidine and normeperidine in mice. J Pharmacol Exp Ther 223(1):203–206

    CAS  PubMed  Google Scholar 

  56. Kirkwood CF, Edwards DJ, Lalka D, Lasezkay G, Hassett JM, Slaughter RL (1986) The pharmacokinetics of meperidine in acute trauma patients. J Trauma 26(12):1090–1093

    Article  CAS  PubMed  Google Scholar 

  57. Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley KM (1987) Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 41(4):392–401

    Article  CAS  PubMed  Google Scholar 

  58. Oda Y, Kharasch ED (2001) Metabolism of methadone and levo-α-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presytemic clearance and bioactivation. J Pharmacol Exp Ther 298(3):1021–1032

    CAS  PubMed  Google Scholar 

  59. Wolff K, Rostami-Hodjegan A, Shires S, Hay AWM, Feely M, Calvert R, Raistrick D, Tucher GT (1997) The pharmacokinetics of methadone in healthy subjects and opiate users. Br J Clin Pharmacol 44:325–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nilsson M-I, Widerlöv E, Meresaar U, Änggåard E (1982) Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol 22(4):337–342

    Article  CAS  PubMed  Google Scholar 

  61. Olsen GD, Bennett WM, Porter GA (1975) Morphine and phenytoin binding to plasma proteins in renal and hepatic failure. Clin Pharmacol Ther 17(6):677–684

    Article  CAS  PubMed  Google Scholar 

  62. Yeh SY, Gorodetzky CW, Krebs HA (1977) Isolation and identification of morphine 3- and 6-glucuronides, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, and normorphine 6-glucuronide as morphine metabolites in humans. J Pharm Sci 66(9):1288–1293

    Article  CAS  PubMed  Google Scholar 

  63. Cone EJ, Huestis MA (2007) Interpretation of oral fluid tests for drugs of abuse. Ann N Y Acad Sci 1098(1):51–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pöyhiä R, Vainio A, Kalso E (1993) A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage 8(2):63–67

    Article  PubMed  Google Scholar 

  65. Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen L-Y, Shen DD (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 79(5):461–479

    Article  CAS  PubMed  Google Scholar 

  66. Adams MP, Ahdieh H (2005) Single- and multiple-dose pharmacokinetic and dose-proportionality study of oxymorphone immediate-release tablets. Drugs R D 6:91–99

    Article  CAS  PubMed  Google Scholar 

  67. Adams MP, Ahdieh H (2004) Pharmacokinetics and dose‐proportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study. Pharmacother J Human Pharmacol Drug Ther 24(4):468–476

    Article  CAS  Google Scholar 

  68. Cone EJ, Darwin WD, Buchwald WF, Gorodetzky CW (1983) Oxymorphone metabolism and urinary excretion in human, rat, guinea pig, rabbit and dog. Drug Metab Dispos 11(5):446–450

    CAS  PubMed  Google Scholar 

  69. Lee CR, McTavish D, Sorkin EM (1993) Tramadol: a preliminary review of its pharmacodynamics and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 46(2):313–340

    Article  CAS  PubMed  Google Scholar 

  70. Lintz W, Erlacin S, Frankus E et al (1981) Biotransformation of tramadol in man and animal (in German). Arzneimittel Forschung 31(11):1932–1943

    CAS  PubMed  Google Scholar 

  71. Paar WD, Poche S, Gerloff J, Dengler HJ (1997) Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 53(3–4):235–239

    Article  CAS  PubMed  Google Scholar 

  72. Meuldermens W, Woestenborghs R, Noorduin H, Cmu F, van Steenberge A, Heykants J (1986) Protein binding of the analgesics alfentanil and sufentanil in maternal and neonatal plasma. Eur J Clin Pharmacol 30(2):217–219

    Article  Google Scholar 

  73. Meuldermans W, Van Peer A, Hendrickx J et al (1988) Alfentanil pharmacokinetics and metabolism in humans. Anesthesiology 69(4):527–534

    Article  CAS  PubMed  Google Scholar 

  74. Labroo RB, Thummel KE, Lunze KL, Podoll T, Trager WF, Kharasch ED (1995) Catalytic role of cytochrome P4503A4 in multiple pathways of alfentanil metabolism. Drug Metab Dispos 23(4):490–496

    CAS  PubMed  Google Scholar 

  75. Scholz J, Steinfath M, Schulz M (1996) Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil, an update. Clin Pharmacokinet 31(4):275–292

    Article  CAS  PubMed  Google Scholar 

  76. Meuldermans WEB, Hurkmans RMA, Heykants JJP (1982) Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood. Arch Int Pharmacodyn Ther 257(1):4–19

    CAS  PubMed  Google Scholar 

  77. McClain DA, Hug CC (1980) Intravenous fentanyl kinetics. Clin Pharmacol Ther 28(1):106–114

    Article  CAS  PubMed  Google Scholar 

  78. Labroo RB, Paine MF, Thummel KE, Kharasch ED (1997) Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos 25(9):1072–1080

    CAS  PubMed  Google Scholar 

  79. Bovill JG, Sebel PS (1980) Pharmacokinetics of high-dose fentanyl. Br J Anaesth 52(8):795–801

    Article  CAS  PubMed  Google Scholar 

  80. Glass PSA, Gan TJ, Scott H (1999) A review of the pharmacokinetics and pharmacodynamics of remifentanil. Anesth Analg 89(4 Suppl):7

    Article  Google Scholar 

  81. Egan TD, Lemmens HJM, Fiset P et al (1993) The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 79(5):881–892

    Article  CAS  PubMed  Google Scholar 

  82. Glass PSA, Hardman D, Kamiyama Y et al (1993) Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B). Anesth Analg 77(5):1031–1040

    Article  CAS  PubMed  Google Scholar 

  83. Westmoreland CL, Hoke JF, Sebe PS, Hug CC, Muir KT (1993) Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 79(5):893–903

    Article  CAS  PubMed  Google Scholar 

  84. Bovill JG, Seel PS, Blackburn CL, Oei-Lim V, Heykants JJ (1984) The pharmacokinetics of sufentanil in surgical patients. Anesthesiology 61(5):502–506

    Article  CAS  PubMed  Google Scholar 

  85. Tateishi T, Krivoruk Y, Ueng Y-F, Wood AJJ, Guengerich FP, Wood M (1996) Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg 82(1):167–172

    CAS  PubMed  Google Scholar 

  86. Scholz J, Bause H, Schulz M et al (1994) Pharmacokinetics and effects on intracranial pressure of sufentanil in head trauma patients. Br J Clin Pharmacol 38(4):369–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Garrett ER, Chandran VR (1985) Pharmacokinetics of morphine and its surrogates VI: bioanalysis, solvolysis kinetics, solubility, pKa values, and protein binding of buprenorphine. J Pharm Sci 74(5):515–524

    Article  CAS  PubMed  Google Scholar 

  88. Kuhlman JJ, Lalani S, Magluilo J et al (1996) Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol 20(6):369–378

    Article  CAS  PubMed  Google Scholar 

  89. Cone EJ, Gorodetzky CW, Yousefnejad D, Buchwald W, Johnson RE (1984) The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos 12(5):577–581

    CAS  PubMed  Google Scholar 

  90. Gaver RC, Vasijev M, Wong H et al (1980) Disposition of parenteral butorphanol in man. Drug Metab Dispos 8(4):230–235

    CAS  PubMed  Google Scholar 

  91. Shyu WC, Pittman KA, Robinson DS, Barbhaiya RH (1993a) The absolute bioavailability of transnasal butorphanol in patients experiencing rhinitis. Eur J Pharmacol 45(6):559–562

    Article  CAS  Google Scholar 

  92. van Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A (2006) Morphine-6-glucuronide: morphine’s successor for postoperative pain relief? Anesth Analg 102(6):1789–1797

    Article  PubMed  CAS  Google Scholar 

  93. Wasan AD, Michna E, Janfaza D, Greenfield S, Teter CJ, Jamison RN (2008) Interpreting urine drug tests: prevalence of morphine metabolism to hydromorphone in chronic pain patients treated with morphine. Pain Med 9(7):918–923

    Article  PubMed  Google Scholar 

  94. Somogyi AA, Barratt DT, Coller JK (2007) Pharmacogenetics of opioids. Clin Pharmacol Ther 81(3):429–444

    Article  CAS  PubMed  Google Scholar 

  95. Sadhasivam S, Chidambaran V (2012) Pharmacogenomics of opioids and perioperative pain management. Pharmacogenomics 13(15):1719–1740

    Article  CAS  PubMed  Google Scholar 

  96. Gasche Y, Daali Y, Fathi M et al (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351(27):2827–2831

    Article  CAS  PubMed  Google Scholar 

  97. Kaplan HL, Busto UE, Baylon GJ et al (1997) Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharmacol Exp Ther 281(1):103–108

    CAS  PubMed  Google Scholar 

  98. Murtagh FE, Chai MO, Donohoe P, Edmonds PM, Higginson IJ (2007) The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother 21(2):5–16

    PubMed  Google Scholar 

  99. Mercadante S, Arcuri E (2004) Opioids and renal function. J Pain 5(1):2–19

    Article  CAS  PubMed  Google Scholar 

  100. Filitz J, Griessinger N, Sittl R, Likar R, Schüttler J, Koppert W (2006) Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine. Eur J Pain 10(8):743–748

    Article  CAS  PubMed  Google Scholar 

  101. Hand CW, Sear JW, Uppington J, Ball MJ, McQuay HJ, Moore RA (1990) Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites. Br J Anaesth 64(3):276–282

    Article  CAS  PubMed  Google Scholar 

  102. Kestenbaum MG, Vilches AO, Messersmith S et al (2014) Alternative routes to oral opioid administration in palliative care: a review and clinical summary. Pain Med 15(7):1129–1153

    Article  PubMed  Google Scholar 

  103. Nestorov I (2003) Whole body pharmacokinetic models. Clin Pharmacokinet 42(10):883–908

    Article  CAS  PubMed  Google Scholar 

  104. Mathias NR, Hussain MA (2010) Non-invasive systemic drug delivery: developability considerations for alternate routes of administration. J Pharm Sci 99(1):1–20

    Article  CAS  PubMed  Google Scholar 

  105. Plosker GL (2011) Buprenorphine 5, 10 and 20 μg/h transdermal patch. A review of its use in the management of chronic nonmalignant pain. Drugs 71(18):2491–2509

    Article  CAS  PubMed  Google Scholar 

  106. Shyu WC, Mayol RF, Pfeffer M, Pittman KA, Gammans RE, Barbhaiya RH (1993b) Biopharmaceutical evaluation of transnasal, sublingual, and buccal disk dosage forms of butorphanol. Biopharm Drug Dispos 14(5):371–379

    Article  CAS  PubMed  Google Scholar 

  107. Lötsch J, Walter C, Parnham MJ, Oertel BG, Geisslinger G (2013) Pharmacokinetics of non-intravenous formulations of fentanyl. Clin Pharmacokinet 52(1):23–36

    Article  PubMed  CAS  Google Scholar 

  108. Exalgo (hydromorphone HCl) Extended-Release Tablets. Prescribing Information. Mallinckrodt Brand Pharmaceutical, Inc. Hazelwood, MO 63042. Revised: April 2014

    Google Scholar 

  109. Babul N, Darke AC (1993) Disposition of morphine and its glucuronide metabolites after oral and rectal administration: evidence of route specificity. Clin Pharmacol Ther 54(3):286–292

    Article  CAS  PubMed  Google Scholar 

  110. Lintz W, Barth H, Osterloh G, Smith-Böthelt E (1998) Bioavailability of enteral tramadol formulations. 3rd communication: suppositories. Arzneimittel Forschung 48(9):889–899

    CAS  PubMed  Google Scholar 

  111. Panagiotou I, Mystakidou K (2010) Intranasal fentanyl: from pharmacokinetics and bioavailability to current treatment applications. Expert Rev Anticancer Ther 10(7):1009–1021

    Article  CAS  PubMed  Google Scholar 

  112. Lane ME (2013) The transdermal delivery of fentanyl. Eur J Pharm Biopharm 84(3):449–455

    Article  CAS  PubMed  Google Scholar 

  113. Grond S, Radbruch L, Lehmann KA (2000) Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl. Clin Pharmacokinet 38(1):59–89

    Article  CAS  PubMed  Google Scholar 

  114. Beaver WT, Feise GA (1977) A comparison of the analgesic effect of oxymorphone by rectal suppository and intramuscular injection in patients with postoperative pain. J Clin Pharmacol 17(5–6):276–291

    Article  CAS  PubMed  Google Scholar 

  115. IUPHAR/BPS Guide to Pharmacology. Available at: www.guidetopharmacology.org. Last accessed on 23 Mar 2015

  116. Volpe DA, McMahon Tobin GA, Mellon RD et al (2011) Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol 59(3):385–390

    Article  CAS  PubMed  Google Scholar 

  117. Yaksh T, Wallace M (2014) Chapter 18: Opioids, analgesia, and pain management. In: Goodman & Gilman’s the pharmacological basis of therapeutics, 12th ed. The Mc Graw Hill Company, Inc. (e-version). McGraw-Hill publishing, Boston, MA.

    Google Scholar 

  118. Olkkola KT, Kontinen VK, Saari TI, Kalso EA (2013) Does the pharmacology of oxycodone justify its increasing use as an analgesic? Trends Pharmacol Sci 34(4):206–214

    Article  CAS  PubMed  Google Scholar 

  119. Washington State Agency Medical Directors’ Group. Opioid dose calculator. Available at: http://agencymeddirectors.wa.gov/mobile.html. Last accessed 23 Mar 2015

  120. VA/DoD Clinical Practice Guidelines (2010) Management of opioid therapy (OT) for chronic pain. Available at: www.healthquality.va.gov/guidelines/Pain/cot/. Last accessed 23 Mar 2015

  121. Vieweg WV, Lipps WF, Fernandez A (2005) Opioids and methadone equivalents for clinicians. Prim Care Companion J Clin Psychiatry 7(3):86–88

    Article  PubMed  PubMed Central  Google Scholar 

  122. Center to Advance Palliative Care. Methadone for the treatment of pain. Fast Fact #75. Available at: https://www.capc.org/fast-facts/75-methadone-treatment-pain/. Last accessed 23 Mar 2015

  123. Waxman SA (2013) Clinical neuroanatomy, 27th edn. McGraw-Hill Education, New York

    Google Scholar 

  124. Lexi-Comp Online [Internet] (2015) Hudson, OH: Lexi-Comp. Last accessed and cited 23 Mar 2015 from institutional university access database

    Google Scholar 

  125. Hewitt DJ (2000) The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain 16(2 Suppl):S73–S79

    Article  CAS  PubMed  Google Scholar 

  126. Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF (2001) Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 25(4):729–741

    Article  CAS  PubMed  Google Scholar 

  127. Xi ZX, Stein EA (2002) GABAergic mechanisms of opiate reinforcement. Alcohol Alcohol 37(5):485–494

    Article  CAS  PubMed  Google Scholar 

  128. Bailey CP, Connor M (2005) Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin Pharmacol 5(1):60–68

    Article  CAS  PubMed  Google Scholar 

  129. Christie MJ (2008) Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol 154(2):384–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Dang VC, Christie MJ (2012) Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons. Br J Pharmacol 165(6):1704–1716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Morgan MM, Christie MJ (2011) Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br J Pharmacol 164(4):1322–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Pattinson KT (2008) Opioids and the control of respiration. Br J Anaesth 100(6):747–758

    Article  CAS  PubMed  Google Scholar 

  133. O’Connor RE, Brady W, Brooks SC et al (2010) Part 10: acute coronary syndromes: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 122(18 Suppl 3):S787–S817

    Article  PubMed  Google Scholar 

  134. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC (2009) QTc interval screening in methadone treatment. Ann Intern Med 150(6):387–395

    Article  PubMed  Google Scholar 

  135. Hemstapat K, Monteith GR, Smith D, Smith MT (2003) Morphine-3-glucuronide’s neuro-excitatory effects are mediated via indirect activation of N-methyl-D-aspartic acid receptors: mechanistic studies in embryonic cultured hippocampal neurones. Anesth Analg 97(2):494–505, table of contents

    Article  CAS  PubMed  Google Scholar 

  136. Seifert CF, Kennedy S (2004) Meperidine is alive and well in the new millennium: evaluation of meperidine usage patterns and frequency of adverse drug reactions. Pharmacotherapy 24(6):776–783

    Article  CAS  PubMed  Google Scholar 

  137. Wood JD, Galligan JJ (2004) Function of opioids in the enteric nervous system. Neurogastroenterol Motil 16(Suppl 2):17–28

    Article  PubMed  Google Scholar 

  138. Rosow CE, Gomery P, Chen TY, Stefanovich P, Stambler N, Israel R (2007) Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone. Clin Pharmacol Ther 82(1):48–53

    Article  CAS  PubMed  Google Scholar 

  139. Suri A, Estes KS, Geisslinger G, Derendorf H (1997) Pharmacokinetic-pharmacodynamic relationships for analgesics. Int J Clin Pharmacol Ther 35(8):307–323

    CAS  PubMed  Google Scholar 

  140. Lötsch J (2005) Pharmacokinetic-pharmacodynamic modeling of opioids. J Pain Symptom Manage 29(5 Suppl):S90–S103

    Article  PubMed  CAS  Google Scholar 

  141. Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley KM (1987) Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 41(4):392–401

    Article  CAS  PubMed  Google Scholar 

  142. Inturrisi CE, Portenoy RK, Max MB, Colburn WA, Foley KM (1990) Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain. Clin Pharmacol Ther 47(5):565–577

    Article  CAS  PubMed  Google Scholar 

  143. Lötsch J, Skarke C, Schmidt H, Grösch S, Geisslinger G (2001) The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiology 95(6):1329–1338

    Article  PubMed  Google Scholar 

  144. Martini C, Olofsen E, Yassen A, Aarts L, Dahan A (2011) Pharmacokinetic–pharmacodynamic modeling in acute and chronic pain: an overview of the recent literature. Expert Rev Clin Pharmacol 4(6):719–728

    Article  CAS  PubMed  Google Scholar 

  145. Mazoit JX, Butscher K, Samii K (2007) Morphine in postoperative patients: pharmacokinetics and pharmacodynamics of metabolites. Anesth Analg 105(1):70–78

    Article  CAS  PubMed  Google Scholar 

  146. Olofsen E, van Dorp E, Teppema L et al (2010) Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study. Anesthesiology 112(6):1417–1427

    Article  CAS  PubMed  Google Scholar 

  147. Scott JC, Cooke JE, Stanski DR (1991) Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiology 74(1):34–42

    Article  CAS  PubMed  Google Scholar 

  148. Scott JC, Stanski DR (1987) Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther 240(1):159–166

    CAS  PubMed  Google Scholar 

  149. Scott JC, Ponganis KV, Stanski DR (1985) EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 62(3):234–241

    Article  CAS  PubMed  Google Scholar 

  150. Skarke C, Darimont J, Schmidt H, Geisslinger G, Lötsch J (2003) Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 73(1):107–121

    Article  CAS  PubMed  Google Scholar 

  151. Staahl C, Upton R, Foster DJ et al (2008) Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. J Clin Pharmacol 48(5):619–631

    Article  CAS  PubMed  Google Scholar 

  152. Yassen A, Kan J, Olofsen E, Suidgeest E, Dahan A, Danhof M (2006) Mechanism-based pharmacokinetic-pharmacodynamic modeling of the respiratory-depressant effect of buprenorphine and fentanyl in rats. J Pharmacol Exp Ther 319(2):682–692

    Article  CAS  PubMed  Google Scholar 

  153. Yassen A, Olofsen E, Romberg R et al (2007) Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther 81(1):50–58

    Article  CAS  PubMed  Google Scholar 

  154. Shiran MR, Lennard MS, Iqbal MZ et al (2012) Pharmacokinetic-pharmacodynamic modeling of mood and withdrawal symptoms in relation to plasma concentrations of methadone in patients undergoing methadone maintenance treatment. J Clin Psychopharmacol 32(5):666–671

    Article  CAS  PubMed  Google Scholar 

  155. Boulton DW, Arnaud P, DeVane CL (2001) Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate. Clin Pharmacol Ther 70(1):48–57

    Article  CAS  PubMed  Google Scholar 

  156. Murthy BR, Pollack GM, Brouwer KL (2002) Contribution of morphine-6-glucuronide to antinociception following intravenous administration of morphine to healthy volunteers. J Clin Pharmacol 42(5):569–576

    Article  CAS  PubMed  Google Scholar 

  157. Romberg R, Olofsen E, Sarton E, den Hartigh J, Taschner PE, Dahan A (2004) Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology 100(1):120–133

    Article  CAS  PubMed  Google Scholar 

  158. Nakamura A, Hasegawa M, Ito H et al (2011) Distinct relations among plasma concentrations required for different pharmacological effects in oxycodone, morphine, and fentanyl. J Pain Palliat Care Pharmacother 25(4):318–334

    Article  PubMed  Google Scholar 

  159. Dyer KR, White JM, Foster DJ, Bochner F, Menelaou A, Somogyi AA (2001) The relationship between mood state and plasma methadone concentration in maintenance patients. J Clin Psychopharmacol 21(1):78–84

    Article  CAS  PubMed  Google Scholar 

  160. Florian J, Garnett CE, Nallani SC, Rappaport BA, Throckmorton DC (2012) A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients. Clin Pharmacol Ther 91(4):666–672

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA

    Sally K. Guthrie PharmD

  2. Department of Pharmacy Practice, University of New England, Portland, ME, USA

    Christian Teter PharmD

Authors
  1. Sally K. Guthrie PharmD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Teter PharmD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sally K. Guthrie PharmD .

Editor information

Editors and Affiliations

  1. Univ. North Texas Sys, Col Pharmacy, Department of Pharmacotherapy, FORT WORTH, Texas, USA

    Michael W. Jann

  2. Department of Pharmacotherapy, Univ. North Texas Sys, Col Pharm, FORT WORTH, Texas, USA

    Scott R. Penzak

  3. Department of Pharmacotherapy, Univ. North Texas Sys, Col Pharm., FORT WORTH, Texas, USA

    Lawrence J. Cohen

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Guthrie, S.K., Teter, C. (2016). Opioid Analgesics. In: Jann, M., Penzak, S., Cohen, L. (eds) Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents. Adis, Cham. https://doi.org/10.1007/978-3-319-27883-4_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-27883-4_11

  • Published:

  • Publisher Name: Adis, Cham

  • Print ISBN: 978-3-319-27881-0

  • Online ISBN: 978-3-319-27883-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation