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Patient-Controlled Analgesia

Pharmacokinetic and Therapeutic Considerations

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  • Drug Disposition
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Summary

The opioid analgesic agents exhibit relatively large pharmacokinetic differences between drugs, and there is substantial pharmacokinetic and pharmacodynamic variability across subjects or patients with each agent. The advent of patient-controlled analgesic administration techniques and their widespread use in contemporary pain management, especially in postsurgical and cancer patients, has decreased the unfortunate impact of interpatient variability on achieving the optimal balance between pain relief and opioid adverse effect intensity. The improvements in pain management provided by patient-controlled analgesia do not, however, decrease the importance of knowledge of opioid pharmacokinetics towards enlightened use of these drugs and attainment of maximal benefits from them in any patient. Future improvements in patient-controlled analgesia technology will probably be based on the pharmacokinetic behaviour of different opioid analgesic agents in specific receptor-containing regions. Finally, physicochemical and pharmacokinetic characteristics of these agents are important determinants of the speed of onset of effects, duration of action and spinal selectivity of epidurally and intrathecally administered analgesics. Thus, effective patient-controlled analgesia depends on an understanding of the differential pharmacokinetics of opioids self-administered by a variety of possible modes.

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References

  • Ainslie SG, Eisele JH, Corkill G. Fentanyl concentrations in brain and serum during respiratory acid base changes in the dog. Anesthesiology 51: 293–297, 1979

    Article  PubMed  CAS  Google Scholar 

  • Aitkenhead AR, Lin ES, Achola KJ. The pharmacokinetics of oral and intravenous nalbuphine in healthy volunteers. British Journal of Clinical Pharmacology 25: 264–268, 1988

    Article  PubMed  CAS  Google Scholar 

  • Aitkenhead AR, Vater M, Achola K, Cooper CMS, Smith G. Pharmacokinetics of single-dose i.v. morphine in normal volunteers and patients with end-stage renal failure. British Journal of Anaesthesia 56: 813–818, 1984

    Article  PubMed  CAS  Google Scholar 

  • Austin KL, Stapleton JV, Mather LE. Multiple intramuscular injections: a major source of variability in analgesic response to meperidine. Pain 8: 47–62, 1980a

    Article  PubMed  CAS  Google Scholar 

  • Austin KL, Stapleton JV, Mather LE. Relationship between blood meperidine concentrations and analgesic response. Anesthesiology 53: 460–466, 1980b

    Article  PubMed  CAS  Google Scholar 

  • Bovin JG, Sebel PS, Blackburn CL, Heykants J. The pharmacokinetics of alfentanil (R39209): a new opioid analgesic. Anesthesiology 57: 439–443, 1982

    Article  Google Scholar 

  • Bovin JG, Sebel PS, Waquier A, Rog P. Electroencephalographic effects of sufentanil anaesthesia in man. British Journal of Anaesthesia 54: 45–52, 1982

    Article  Google Scholar 

  • Bower S, Hull CJ. Comparative pharmacokinetics of fentanyl and alfentanil. British Journal of Anaesthesia 54: 871–877, 1982

    Article  PubMed  CAS  Google Scholar 

  • Bullingham RES, McQuay HJ, Moore RA. Clinical pharmacokinetics of narcotic agonist-antagonist drugs. Clinical Pharmacokinetics 8: 332–343, 1983

    Article  PubMed  CAS  Google Scholar 

  • Bums JW, Hodsman NBA, McLintock TTC, Gillies GWA, Kenny GNC, et al. The influence of patient characteristics on the requirements for postoperative analgesia. Anaesthesia 44: 2–6, 1989

    Article  Google Scholar 

  • Campbell CF, Mason JB, Weiler MD. Continuous subcutaneous infusion of morphine for the pain of terminal malignancy. Annals of Internal Medicine 98: 51–52, 1983

    PubMed  CAS  Google Scholar 

  • Chapman CR, Hill HF. Prolonged morphine self-administration and addiction liability: evaluation of two theories in a bone marrow transplant unit. Cancer 63: 1636–1655, 1989

    Article  PubMed  CAS  Google Scholar 

  • Cherry DA. Use of opioids by implanted systems and self administration. Baillière’s Clinical Anaesthesiology 1: 955–972, 1987

    Article  Google Scholar 

  • Chrubasik J, Wust H, Schulte-Monting J, Thon K, Zindler M. Relative analgesic potency of epidural fentanyl, alfentanil and morphine in the treatment of postoperative pain. Anesthesiology 68: 929–933, 1988

    Article  PubMed  CAS  Google Scholar 

  • Citron M, Johnston-Early A, Boyer M, Krasnow SH, Hood M, et al. Patient-controlled analgesia for severe cancer pain. Archives of Internal Medicine 146: 734–736, 1986a

    Article  PubMed  CAS  Google Scholar 

  • Citron M, Johnston-Early A, Fossieck BE, Hellman M, Ackert G, et al. Safety and efficacy of continuous intravenous morphine for severe cancer pain. American Journal of Medicine 77: 199–204, 1984

    Article  PubMed  CAS  Google Scholar 

  • Citron M, Walczak M, Seltzer V, Hellman M, Ackert G, et al. The safety and efficacy of patient-controlled analgesia (PCA) for severe cancer pain: a long-term study of inpatient and outpatient use. Proceedings of the American Society of Clinical Oncology 5: 260A, 1986b

    Google Scholar 

  • Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 61: 276–310, 1984

    Article  PubMed  CAS  Google Scholar 

  • Cousins MJ, Plummer JL. Spinal opioids in acute and chronic pain. In Max et al. (Eds) Advances in pain research and therapy, Vol. 18, pp. 457–479, Raven Press, New York, 1991

    Google Scholar 

  • Coyle N, Mauskop A, Maggard J, Foley KM. Continuous subcutaneous infusions of opiates in cancer patients with pain. Oncological Nursing Forum 13: 53–57, 1986

    CAS  Google Scholar 

  • Dixon R. Pharmacokinetics of levorphanol. In Foley & Inturrisi (Eds) Advances in pain research and therapy, Vol. 8, pp. 217–224, Raven Press, New York, 1986

    Google Scholar 

  • Eimerl D, Magora F, Shir Y, Chrubasik J. Patient-controlled analgesia with epidural methadone by means of an external infusion pump. Schmerz-Pain-Douleur 4: 156–160, 1986

    Google Scholar 

  • Foley KM. The treatment of cancer pain. New England Journal of Medicine 313: 84–95, 1985

    Article  PubMed  CAS  Google Scholar 

  • Gabrielsson JL, Johansson P, Bondesson U, Karlsson M, Paalzow LK. Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model. Journal of Pharmacokinetics and Biopharmaceutics 14: 381–393, 1986

    PubMed  CAS  Google Scholar 

  • Glynn CJ. Intrathecal and epidural administration of opiates. Baillière’s Clinical Anaesthesiology 1: 915–933, 1987

    Article  Google Scholar 

  • Glynn CJ, Mather LE, Cousins MJ, Graham JR, Wilson PR. Peridural meperidine in man: analgetic response, pharmacokinetics and transmission into CSF. Anesthesiology 55: 520–526, 1981

    Article  PubMed  CAS  Google Scholar 

  • Gourlay GK, Kowalski SR, Plummer JL, Cousins MJ, Armstrong PJ. Fentanyl blood concentration analgesic response relationship in the treatment of postoperative pain. Anesthesia and Analgesia 67: 329–337, 1988

    Article  PubMed  CAS  Google Scholar 

  • Harmer M, Slattery PJ, Rosen M, Vickers MD. Intramuscular on demand analgesia: double blind controlled trial of pethidine, buprenorphine, morphine and meptazinol. British Medical Journal 286: 680–683, 1983

    Article  PubMed  CAS  Google Scholar 

  • Herz A, Teschemacher HJ. Activities and sites of antinociceptive action of morphine-like analgesics and kinetics of distributions following intravenous, intracerebral and intraventricular application. In Harper & Simmonds (Eds) Advances in drug research, pp. 79–117, Academic Press, London, 1971

    Google Scholar 

  • Hill HF, Chapman CR, Kornell JA, Sullivan KM, Saeger LC, et al. Self-administration of morphine in bone marrow transplant patients reduces drug requirement. Pain 40: 121–129, 1990a

    Article  PubMed  CAS  Google Scholar 

  • Hill HF, Chapman CR, Saeger LS, Bjurstrom R, Walter MH, et al. Steady-state infusions of opioids in humans II: concentration-effect relationships and therapeutic margins. Pain 43: 69–79, 1990b

    Article  PubMed  CAS  Google Scholar 

  • Hill HF, Coda BA, Mackie AM, Iverson K, Barensten R. Patient-controlled analgesic infusions: alfentanil versus morphine. Pain 49: 301–310, 1992

    Article  PubMed  CAS  Google Scholar 

  • Hill HF, Coda BA, Tanaka A, Schaffer R. Multi dose evaluation of intravenous hydromorphone pharmacokinetics in normal human subjects. Anaesthesia and Analgesia, in press, 1992

    Google Scholar 

  • Hill HF, Jacobson RC, Coda BA, Mackie A. A computer-based system for controlling plasma opioid concentration according to patient need. Clinical Pharmacokinetics 20: 319–330, 1991a

    Article  PubMed  CAS  Google Scholar 

  • Hill HF, Mackie AM, Coda BA, Iverson K, Chapman CR. Patient-controlled analgesic administration: comparison of steady-state morphine infusions to bolus doses. Cancer 67: 873–882, 1991b

    Article  PubMed  CAS  Google Scholar 

  • Hill HF, Saeger LC, Chapman CR. Patient-controlled analgesia after bone marrow transplantation for cancer. Postgraduate Medicine 28: 33–40, 1986

    Google Scholar 

  • Hull CJ, Sibbald A. Control of postoperative pain by interactive demand analgesia. British Journal of Anaesthesia 53: 385–391, 1981

    Article  PubMed  CAS  Google Scholar 

  • Inturrisi C, Colburn WA. Pharmacokinetics of methadone. In Foley & Inturrisi (Eds) Advances in pain research and therapy, Vol. 8, pp. 191–200, Raven Press, New York, 1986

    Google Scholar 

  • Keeri-Szanto M. Demand analgesia for the relief of pain problems in ‘terminal’ illness. Anesthesia Reviews: 19–21, 1976

    Google Scholar 

  • Keeri-Szanto M. Drugs or drums: what relieves postoperative pain? Pain 6: 217–230, 1979

    Article  PubMed  CAS  Google Scholar 

  • Kerr I, Sone M, DeAngelis C. Continuous narcotic infusion with patient-controlled analgesia for chronic cancer pain in outpatients. Annals of Internal Medicine 108: 554–557, 1988

    PubMed  CAS  Google Scholar 

  • Lehmann KA. Patient-controlled intravenous analgesia for postoperative pain relief In Max et al. (Eds) Advances in pain research and therapy. Vol. 18, pp. 481–506, Raven Press, New York, 1991

    Google Scholar 

  • Loper KA, Ready LB, Downey M, Sandler AN, Nessly M, et al. Epidural and intravenous fentanyl infusions are clinically equivalent after knee surgery. Anesthesia and Analgesia 70: 72–75, 1990

    Article  PubMed  CAS  Google Scholar 

  • Mackie AM, Coda BC, Hill HF. Adolescents use patient-controlled analgesia effectively for relief from prolonged oropharyngeal mucositis pain. Pain 46: 265–269, 1991

    Article  PubMed  CAS  Google Scholar 

  • Mather LE. Pharmacokinetic studies of meperidine. In Foley & Inturrisi (Eds) Advances in pain research and therapy, Vol. 8, pp. 155–165, Raven Press, New York, 1986

    Google Scholar 

  • Mather LE. Opioid pharmacokinetics in relation to their effects. Anaesthesia and Intensive Care 15: 15–22, 1987

    PubMed  CAS  Google Scholar 

  • Mather LE. Pharmacokinetics and pharmacodynamic profiles of opioid analgesics: a sameness amongst equals. Pain 43: 3–6, 1990

    Article  PubMed  CAS  Google Scholar 

  • Mather LE, Owen H. The scientific basis of patient-controlled analgesia. Anaesthesia and Intensive Care 16: 427–436, 1988

    PubMed  CAS  Google Scholar 

  • Mather LE, Selby DG, Runciman WB. Effects of propofol and of thiopentone anaesthesia on the regional kinetics of pethidine in the sheep. British Journal of Anaesthesia 65: 365–372, 1990

    Article  PubMed  CAS  Google Scholar 

  • Mazoit JX, Sandouk P, Zetlaoui P, Scherrmann JM. Pharmacokinetics of unchanged morphine in normal and cirrhotic subjects. Anesthesia and Analgesia 66: 293–298, 1987

    Article  PubMed  CAS  Google Scholar 

  • McArdle CS. Continuous and patient controlled analgesic infusions. In Doyle (Ed.) 1986 International Symposium on Pain Control. Royal Society of Medicine International Congress and Symposium Series No. 123, pp. 17–22, 1987

    Google Scholar 

  • McClain DA, Hug Jr CC. Intravenous fentanyl kinetics. Clinical Pharmacology and Therapeutics 28: 106–114, 1980

    Article  PubMed  CAS  Google Scholar 

  • McQuay HJ, Sullivan AF, Smallman K, Dickenson AH. Intrathecal opioids, potency and lipophilicity. Pain 36: 111–115, 1989

    Article  PubMed  CAS  Google Scholar 

  • Mitchell RWD, Smith G. The control of acute pain. British Journal of Anaesthesia 63: 147–158, 1989

    Article  PubMed  CAS  Google Scholar 

  • Moore RA, Sear JW, Baldwin D, Allen M, Hunniset A, et al. Morphine kinetics during and after renal transplantation. Clinical Pharmacology and Therapeutics 35: 641–645, 1984

    Article  PubMed  CAS  Google Scholar 

  • Morgan M. The rational use of intrathecal and epidural opioids. British Journal of Anaesthesia 63: 165–188, 1989

    Article  PubMed  CAS  Google Scholar 

  • Murphy MR, Hug Jr CC. Pharmacokinetics of morphine in patients anesthetized with enflurane-nitrous oxide. Anesthesiology 54: 187–192, 1981

    Article  PubMed  CAS  Google Scholar 

  • Nishitateno K, Ngai SH, Finck AD, Berkowitz BA. Pharmacokinetics of morphine: concentrations in the serum and the brain of the dog during hyperventilation. Anesthesiology 50: 520–523, 1979

    Article  PubMed  CAS  Google Scholar 

  • Owen H, Armstrong I, Plummer JL, Mather LE, Cousins MJ. Varying the variables of patient-Controlled analgesia I: bolus size. Anaesthesia 44: 7–10, 1989a

    Article  PubMed  CAS  Google Scholar 

  • Owen H, Currie JC, Plummer JL. Variation in the blood concentration-analgesic response relationship during patient-controlled analgesia with alfentanil. Anaesthesia and Intensive Care 19: 555–560, 1991

    PubMed  CAS  Google Scholar 

  • Owen H, Mather, LE, Rowley K. The development and clinical use of patient-controlled analgesia. Anaesthesia and Intensive Care 16: 437–447, 1988

    PubMed  CAS  Google Scholar 

  • Owen H, Mather LE, Runciman WB, Carapetis RJ, Upton RN. The lockout interval in patient controlled analgesia: a rational basis for choice? British Journal of Anaesthesia 59: 1328P–1329P, 1987

    Google Scholar 

  • Owen H, Plummer JP, Szekely S, Cushnie J, Mather LE. Varying the variables of patient-controlled analgesia II: concurrent infusion. Anaesthesia 44: 11–13, 1989b

    Article  PubMed  CAS  Google Scholar 

  • Patwardhan RV, Johnson RF, Hoyumpa JRA, Sheehan JJ, Desmond PV, et al. Normal metabolism of morphine in cirrhosis. Gastroenterology 81: 1006–1011, 1981

    PubMed  CAS  Google Scholar 

  • Portenoy RK, Moulin DE, Rogers A, Inturrisi CE, Foley KM. IV infusion of opioids for cancer pain: clinical review and guidelines for use. Cancer Treatment Reports 70: 575–581, 1986

    PubMed  CAS  Google Scholar 

  • Runciman WB, Mather LE. Effects of anaesthesia on drug disposition. In Feldman et al. (Eds) Mechanisms of action of drugs in anaesthetic practice, pp. 87–122, Edward Arnold, London, 1987

    Google Scholar 

  • Runciman WB, Myburgh JA, Upton RN. Pharmacokinetics and pharmacodynamics in the critically ill. Ballière’s Clinical Anaesthesiology 4: 271–303, 1990

    Article  Google Scholar 

  • Säwe J. High dose morphine and methadone in cancer patients: clinical pharmacokinetic considerations of oral treatment. Clinical Pharmacokinetics 11: 87–106, 1986

    Article  PubMed  Google Scholar 

  • Säwe J, Hansen J, Ginan C, Hartvig P, Jacobssen PA, et al. Patient controlled dose regimen of methadone for chronic cancer pain. British Medical Journal 282: 771–773, 1981

    Article  PubMed  Google Scholar 

  • Säwe J, Kager L, Svensson JO, Rane A. Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation. British Journal of Clinical Pharmacology 19: 495–501, 1985

    Article  PubMed  Google Scholar 

  • Scott JS. Obstetric analgesia. American Journal of Obstetrics and Gynecology 106: 7, 1970

    Google Scholar 

  • Sjostrom S, Jamsen A, Hartvig P. Patient-controlled analgesia with extradural morphine or pethidine. British Journal of Anaesthesia 60: 358–366, 1985

    Article  Google Scholar 

  • Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics of intravenous and intramuscular morphine. Clinical Pharmacology and Therapeutics 24: 52–59, 1978

    PubMed  CAS  Google Scholar 

  • Jamsen A, Sjostrom S, Hartvig P. The Uppsala experience of patient controlled analgesia. In Foley & Inturrisi (Eds) Advances in pain research and therapy, Vol. 8, pp. 325–332, Raven Press, New York, 1986

    Google Scholar 

  • Jucker GJ. Pharmacokinetic and pharmacodynamic models. In Benadetti et al. (Eds) Advances in pain research and therapy. Vol. 14, pp 181–201, Raven Press, New York, 1990

    Google Scholar 

  • Urquhart ML, Klapp K, White PF. Intravenous versus subcutaneous hydromorphone for patient-controlled analgesia. Anesthesiology 67: 231A, 1987

    Article  Google Scholar 

  • Varvel JR, Shafer SL, Hwang SS, Coen PA, Stanski DR. Absorption characteristics of transdermally administered fentanyl. Anesthesiology 70: 928–934, 1989

    Article  PubMed  CAS  Google Scholar 

  • Vickers MD. Clinical trials of analgesic drugs. In Harmer et al. (Eds) Patient controlled analgesia, pp. 42–54, Blackwell Scientific Publications, Oxford, 1985

    Google Scholar 

  • White PF. Alternative routes for patient-controlled analgesia in the management of acute pain. In Ferrante et al. (Eds) Patient controlled analgesia, pp. 223–227, Blackwell Scientific Publications, Cambridge (Mass), 1990

    Google Scholar 

  • Yaksh JL. Opioid receptor systems and the endorphins: a review of their spinal organization. Journal of Neurosurgery 67: 157–176, 1987

    Article  PubMed  CAS  Google Scholar 

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  1. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Harlan F. Hill &  Laurence E. Mather

  2. Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia

    Harlan F. Hill &  Laurence E. Mather

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  1. Harlan F. Hill
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  2. Laurence E. Mather
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Hill, H.F., Mather, L.E. Patient-Controlled Analgesia. Clin. Pharmacokinet. 24, 124–140 (1993). https://doi.org/10.2165/00003088-199324020-00003

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