Skip to main content
SpringerLink
Log in

Opioid Pharmacology and Pharmacokinetics

  • Chapter
  • First Online:
Controlled Substance Management in Chronic Pain

Abstract

The appropriate prescribing of opioids requires an in-depth understanding of the pharmacology and pharmacokinetics of these broad-spectrum analgesics. This chapter discusses opioid receptors, opioid mechanism of action, routes of administration, pharmacogenetics, side effects, and future directions of opioid analgesics.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 89.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 99.99
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. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(opioid special issue):S133–53.

    Google Scholar 

  2. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179(4077):1011–4.

    Article  CAS  PubMed  Google Scholar 

  3. 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(5536):577–80.

    Article  CAS  PubMed  Google Scholar 

  4. Trescot AM, Boswell MV, Atluri SL, Hansen HC, Deer TR, Abdi S, et al. Opioid guidelines in the management of chronic non-cancer pain. Pain Physician. 2006;9(1):1–39.

    PubMed  Google Scholar 

  5. Makman MH. Morphine receptors in immunocytes and neurons. Adv Neuroimmunol. 1994;4(2):69–82.

    Article  CAS  PubMed  Google Scholar 

  6. Chahl LA. Opioids—mechanism of action. Aust Prescr. 1996;19:63–5.

    Article  Google Scholar 

  7. Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci. 2001;2(2):119–28.

    Article  CAS  PubMed  Google Scholar 

  8. McCarberg B, Barkin R. Long-acting opioids for chronic pain; pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001;8:181–6.

    Article  CAS  PubMed  Google Scholar 

  9. Kaplan R, Parris WC, Citron ML, Zhukovsky D, Reder RF, Buckley BJ, et al. Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain. J Clin Oncol. 1998;16(10):3230–7.

    CAS  PubMed  Google Scholar 

  10. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. Glenview, IL: American Pain Society; 2003.

    Google Scholar 

  11. Rauck RL. What is the case for prescribing long-acting opioids over short-acting opioids for patients with chronic pain? A critical review. Pain Pract. 2009;9(6):468–79.

    Article  PubMed  Google Scholar 

  12. Coluzzi PH, Schwartzberg L, Conroy JD, Charapata S, Gay M, Busch MA, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001;91(1–2):123–30.

    Article  CAS  PubMed  Google Scholar 

  13. Karlsen AP, Pedersen DM, Trautner S, Dahl JB, Hansen MS. Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study. Ann Emerg Med. 2014;63(6):699–703.

    Article  PubMed  Google Scholar 

  14. Mercadante S, Radbruch L, Popper L, Korsholm L, Davies A. Efficacy of intranasal fentanyl spray (INFS) versus oral transmucosal fentanyl citrate (OTFC) for breakthrough cancer pain: open-label crossover trial. Eur J Pain. 2009;13:S198.

    Article  Google Scholar 

  15. Bausewein C, Simon ST. Inhaled nebulized and intranasal opioids for the relief of breathlessness. Curr Opin Support Palliat Care. 2014;8(3):208–12.

    Article  PubMed  Google Scholar 

  16. Ripamonti C, Fagnoni E, Campa T, Brunelli C, De Conno F. Is the use of transdermal fentanyl inappropriate according to the WHO guidelines and the EAPC recommendations? A study of cancer patients in Italy. Support Care Cancer. 2006;14(5):400–7.

    Article  PubMed  Google Scholar 

  17. McCaffery M, Martin L, Ferrell BR. Analgesic administration via rectum or stoma. J ET Nurs (official publication, International Association for Enterostomal Therapy). 1992;19(4):114–21.

    CAS  Google Scholar 

  18. De Conno F, Ripamonti C, Saita L, MacEachern T, Hanson J, Bruera E. Role of rectal route in treating cancer pain: a randomized crossover clinical trial of oral versus rectal morphine administration in opioid-naive cancer patients with pain. J Clin Oncol. 1995;13(4):1004–8.

    PubMed  Google Scholar 

  19. Jeal W, Benfield P. Transdermal fentanyl. A review of its pharmacological properties and therapeutic efficacy in pain control. Drugs. 1997;53(1):109–38.

    Article  CAS  PubMed  Google Scholar 

  20. Muijsers RB, Wagstaff AJ. Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs. 2001;61(15):2289–307.

    Article  CAS  PubMed  Google Scholar 

  21. Rathmell JP, Lair TR, Nauman B. The role of intrathecal drugs in the treatment of acute pain. Anesth Analg. 2005;101(5 Suppl):S30–43.

    Article  PubMed  Google Scholar 

  22. Gustafsson LL, Schildt B, Jacobsen K. Adverse effects of extradural and intrathecal opiates: report of a nationwide survey in Sweden. 1982. Br J Anaesth. 1998;81(1):86–93; discussion 85.

    Google Scholar 

  23. Food and Drug Administration. Public Health Advisory: use of codeine by some breastfeeding mothers may lead to life-threatening side effects in nursing babies 2007 [1/1/15]. Available from: http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm054717.htm.

  24. Rodriguez RF, Castillo JM, Del Pilar Castillo M, Nunez PD, Rodriguez MF, Restrepo JM, et al. Codeine/acetaminophen and hydrocodone/acetaminophen combination tablets for the management of chronic cancer pain in adults: a 23-day, prospective, double-blind, randomized, parallel-group study. Clin Ther. 2007;29(4):581–7.

    Article  CAS  PubMed  Google Scholar 

  25. Otton SV, Schadel M, Cheung SW, Kaplan HL, Busto UE, Sellers EM. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther. 1993;54(5):463–72.

    Article  CAS  PubMed  Google Scholar 

  26. Murray A, Hagen NA. Hydrocodone. J Pain Symptom Manage. 2005;29:S57–66.

    Article  CAS  PubMed  Google Scholar 

  27. Vallner JJ, Stewart JT, Kotzan JA, Kirsten EB, Honigberg IL. Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects. J Clin Pharmacol. 1981;21(4):152–6.

    Article  CAS  PubMed  Google Scholar 

  28. Davis MP, McPherson ML. Tabling hydromorphone: do we have it right? J Palliat Med. 2010.

    Google Scholar 

  29. Wright AW, Mather LE, Smith MT. Hydromorphone-3-glucuronide: a more potent neuro-excitant than its structural analogue, morphine-3-glucuronide. Life Sci. 2001;69(4):409–20.

    Article  CAS  PubMed  Google Scholar 

  30. Coluzzi F, Mattia C. OROS(R) hydromorphone in chronic pain management: when drug delivery technology matches clinical needs. Minerva Anestesiol. 2010;76(12):1072–84.

    CAS  PubMed  Google Scholar 

  31. Poyhia R, Seppala T, Olkkola KT, Kalso E. The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol. 1992;33(6):617–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gabrail NY, Dvergsten C, Ahdieh H. Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study. Curr Med Res Opin. 2004;20(6):911–8.

    Article  CAS  PubMed  Google Scholar 

  33. Lotsch J, Geisslinger G. Morphine-6-glucuronide: an analgesic of the future? Clin Pharmacokinet. 2001;40(7):485–99.

    Article  CAS  PubMed  Google Scholar 

  34. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol. 2000;27(7):524–8.

    Article  CAS  PubMed  Google Scholar 

  35. Wasan AD, Michna E, Janfaza D, Greenfield S, Teter CJ, Jamison RN. Interpreting urine drug tests: prevalence of morphine metabolism to hydromorphone in chronic pain patients treated with morphine. Pain Med. 2008;9(7):918–23.

    Article  PubMed  Google Scholar 

  36. Mercadante S. Switching methadone: a 10-year experience of 345 patients in an acute palliative care unit. Pain Med. 2012;13(3):399–404.

    Article  PubMed  Google Scholar 

  37. Li Y, Kantelip JP, Gerritsen-van Schieveen P, Davani S. Interindividual variability of methadone response: impact of genetic polymorphism. Mol Diagn Ther. 2008;12(2):109–24.

    Article  CAS  PubMed  Google Scholar 

  38. Reddy S, Hui D, El Osta B, de la Cruz M, Walker P, Palmer JL, et al. The effect of oral methadone on the QTc interval in advanced cancer patients: a prospective pilot study. J Palliat Med. 2009;13(1):33–8.

    Article  Google Scholar 

  39. Leavitt SB, Bruce RD, Eap CB, Kharasch E, Kral L, McCance-Katz E, et al. Addiction treatment forum: methadone-drug interactions 2009. Available from: http://www.atforum.com/SiteRoot/pages/rxmethadone/methadone.shtml.

  40. De Bels D, Staroukine M, Devriendt J. Torsades de pointes due to methadone. Ann Intern Med. 2003;139:58.

    Google Scholar 

  41. Gil M, Sala M, Anguera I, Chapinal O, Cervantes M, Guma JR, et al. QT prolongation and Torsades de Pointes in patients infected with human immunodeficiency virus and treated with methadone. Am J Cardiol. 2003;92(8):995–7.

    Article  CAS  PubMed  Google Scholar 

  42. Hanon S, Seewald RM, Yang F, Schweitzer P, Rosman J. Ventricular arrhythmias in patients treated with methadone for opioid dependence. J Interv Card Electrophysiol. 2010;28(1):19–22.

    Article  PubMed  Google Scholar 

  43. Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very high dose methadone. Ann Int Med. 2002;137:501–4.

    Article  CAS  PubMed  Google Scholar 

  44. Latowsky M. Methadone death, dosage and torsade de pointes: risk-benefit policy implications. J Psychoactive Drugs. 2006;38(4):513–9.

    Article  PubMed  Google Scholar 

  45. Kornick CA, Kilborn MJ, Santiago-Palma J, Schulman G, Thaler HT, Keefe DL, et al. QTc interval prolongation associated with intravenous methadone. Pain. 2003;105(3):499–506.

    Article  CAS  PubMed  Google Scholar 

  46. Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A community-based evaluation of sudden death associated with therapeutic levels of methadone. Am J Med. 2008;121(1):66–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Herrlin K, Segerdahl M, Gustafsson LL, Kalso E. Methadone, ciprofloxacin, and adverse drug reactions. Lancet. 2000;356(9247):2069–70.

    Article  CAS  PubMed  Google Scholar 

  48. Cruciani RA. Methadone: to ECG or not to ECG…That is still the question. J Pain Symptom Manage. 2008;36(5):545–52.

    Article  CAS  PubMed  Google Scholar 

  49. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387–95.

    Article  PubMed  Google Scholar 

  50. Gazelle G, Fine PG. Methadone for the treatment of pain. Palliat Med. 2003;6:621–2.

    Google Scholar 

  51. Aghabiklooei A, Hassanian-Moghaddam H, Zamani N, Shadnia S, Mashayekhian M, Rahimi M, et al. Effectiveness of naltrexone in the prevention of delayed respiratory arrest in opioid-naive methadone-intoxicated patients. BioMed Res Int. 2013;2013:903172.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos. 1996;24(9):932–9.

    CAS  PubMed  Google Scholar 

  53. Hanks GW, Fallon MT. Transdermal fentanyl in cancer pain: conversion from oral morphine. J Pain Symptom Manage. 1995;10(2):87.

    Article  CAS  PubMed  Google Scholar 

  54. Helm S, Trescot AM, Colson J, Sehgal N, Silverman S. Opioid antagonists, partial agonists, and agonists/antagonists: the role of office-based detoxification. Pain Physician. 2008;11(2):225–35.

    PubMed  Google Scholar 

  55. Gruber VA, McCance-Katz EF. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV/AIDS Rep. 2010;7(3):152–60.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Silverman SM. Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician. 2009;12(3):679–84.

    PubMed  Google Scholar 

  57. Webster LR, Fine PG. Review and critique of opioid rotation practices and associated risks of toxicity. Pain Med. 2012;13(4):562–70.

    Article  PubMed  Google Scholar 

  58. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105–20.

    PubMed  Google Scholar 

  59. McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli-Goudas M, Chew PW, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain. 2003;4(5):231–56.

    Article  PubMed  Google Scholar 

  60. Swegle JM, Logemann C. Opioid-induced adverse effects. Am Fam Physician. 2006;74(8):1347–52.

    PubMed  Google Scholar 

  61. Meuser T, Pietruck C, Radbruch L, Stute P, Lehmann KA, Grond S. Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain. 2001;93(3):247–57.

    Article  CAS  PubMed  Google Scholar 

  62. Flake ZA, Scalley RD, Bailey AG. Practical selection of antiemetics. Am Fam Physician. 2004;69(5):1169–74.

    PubMed  Google Scholar 

  63. McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli-Goudas M, Chew PW, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain. 2003;231–256.

    Google Scholar 

  64. Cherny NI, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol. 2001;19:2542–54.

    CAS  PubMed  Google Scholar 

  65. Cherny NI. The management of cancer pain. CA: Cancer J Clin. 2000;50(2):70–116; quiz 7–20.

    Google Scholar 

  66. Teichtahl H, Prodromidis A, Miller B, Cherry G, Kronborg I. Sleep-disordered breathing in stable methadone programme patients: a pilot study. Addiction. 2001;96(3):395–403.

    Article  CAS  PubMed  Google Scholar 

  67. Downey R, Gold PM. Obstructive sleep apnea 2014 [12/15/14]. Available from: http://emedicine.medscape.com/article/295807-print.

  68. Wang D, Teichtahl H, Drummer O, Goodman C, Cherry G, Cunnington D, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest. 2005;128(3):1348–56.

    Article  PubMed  Google Scholar 

  69. Howlett TA, Rees LH. Endogenous opioid peptides and hypothalamo-pituitary function. Annu Rev Physiol. 1986;48:527–36.

    Article  CAS  PubMed  Google Scholar 

  70. Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained action opioids for control of nonmalignant pain. J Pain. 2008;9:28–36.

    Article  CAS  PubMed  Google Scholar 

  71. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377–84.

    Article  PubMed  Google Scholar 

  72. Merza Z. Chronic use of opioids and the endocrine system. Horm Metab Res. 2010 (epublish):1–6.

    Google Scholar 

  73. Roy S, Loh HH. Effects of opioids on the immune system. Neurochem Res. 1996;21(11):1375–86.

    Article  CAS  PubMed  Google Scholar 

  74. Zacny JP. Morphine responses in humans: a retrospective analysis of sex differences. Drug Alcohol Depend. 2001;63:23–8.

    Article  CAS  PubMed  Google Scholar 

  75. Zun LS, Downey LV, Gossman W, Rosenbaumdagger J, Sussman G. Gender differences in narcotic-induced emesis in the ED. Am J Emerg Med. 2002;20(3):151–4.

    Article  PubMed  Google Scholar 

  76. Cepeda MS, Farrar JT, Roa JH, Boston R, Meng QC, Ruiz F, et al. Ethnicity influences morphine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2001;70(4):351–61.

    Article  CAS  PubMed  Google Scholar 

  77. Ripamonti C, Conno FD, Groff L, et al. Equianalgesic dose/ratio between methadone and other opioid agonists in cancer pain: comparison of two clinical experiences. Ann Oncol. 1998;9(1):79–83.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pain and Headache Center, 5431 Mayflower Lane, Suite 4, Wasilla, AK, 99654, USA

    Andrea M. Trescot

Authors
  1. Andrea M. Trescot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea M. Trescot .

Editor information

Editors and Affiliations

  1. Shrewsbury, New Jersey, USA

    Peter S. Staats

  2. Comprehensive Pain Medicine, Pompano Beach, Florida, USA

    Sanford M. Silverman

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Trescot, A.M. (2016). Opioid Pharmacology and Pharmacokinetics. In: Staats, P., Silverman, S. (eds) Controlled Substance Management in Chronic Pain. Springer, Cham. https://doi.org/10.1007/978-3-319-30964-4_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-30964-4_4

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-30962-0

  • Online ISBN: 978-3-319-30964-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation