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A Computer-Based System for Controlling Plasma Opioid Concentration According to Patient Need for Analgesia

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Summary

Microprocessor-controlled infusion pumps, which allow a patient to self-administer bolus doses of an analgesic to relieve pain, are becoming commonplace. While these patient-controlled analgesia (PCA) systems overcome the large interpatient variations in pharmacokinetics, they do not provide steady relief from pain since they rely on delivering a drug in small, incremental doses. To overcome this problem, the authors developed an algorithm and computer-pump system that allows patients to control their own plasma concentration of analgesic. This approach uses individually predetermined pharmacokinetic parameters to provide steady plasma opioid concentrations that can be increased or decreased by the patient in line with the need for more pain relief or fewer side effects. The control software uses a novel, recursive algorithm to compute the pump rates necessary to maintain constant plasma drug (e.g. morphine) concentrations at desired values and to reach a new steady concentration in response to patient requests. This report describes the mathematical approach to the problem of control of plasma opioid concentration, the application of this new drug delivery system to management of persistent pain in cancer patients undergoing bone marrow transplantation, and the magnitude of pharmacokinetic variability with morphine in this patient population. Results are presented from individual patients using this adjustable drug delivery system continuously for up to 2 weeks to control pain from oral mucositis.

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References

  • Akaike H. Fitting autoregressive models for prediction. Annals of the Institute of Statistical Mathematics 23: 243–247, 1969

    Article  Google Scholar 

  • Alvis MJ, Reves JG, Govier AV, Menkhans PG, Henling CE, et al. Computer-assisted continuous infusions of fentanyl during cardiac anesthesia: comparison to a manual method. Anesthesiology 63: 41–49, 1985

    Article  PubMed  CAS  Google Scholar 

  • Ausems ME, Stanski DR, Hug CC. An evaluation of the accuracy of pharmacokinetic data for the computer-assisted infusion of alfentanil. British Journal of Anaesthesiology 57: 1217–1225, 1985

    Article  CAS  Google Scholar 

  • Austin KL, Stapleton JV, Mather LE. Relationship between blood meperidine concentration and analgesic response: a preliminary report. Anesthesiology 53: 460–466, 1980

    Article  PubMed  CAS  Google Scholar 

  • Bauman TJ, Batenhorst RL, Graves DA, Foster TS, Bennett RL. Patient-controlled analgesia. Annals of Internal Medicine 20: 297–301, 1986

    Google Scholar 

  • Bennett RL. Patient-controlled analgesia for the control of postoperative pain: experience at the University of Kentucky. In Harmer et al. (Eds) Patient-controlled analgesia, pp. 149–155, Blackwell Scientific Publications, Oxford 1985

    Google Scholar 

  • Bennett RL, Batenhorst RL, Graves D, Foster TS, Griffen WO, et al. Drug use pattern in patient controlled analgesia. Anesthesiology 57: A210, 1982

    Article  Google Scholar 

  • Berkowitz BA, Ngai SH, Hempstead J, Spector S. The disposition of morphine in surgical patients. Clinical Pharmacology and Therapeutics 17: 629–635, 1975

    PubMed  CAS  Google Scholar 

  • Bovill JG, Sebel PS, Blackburn CL, Heykants J. The pharmacokinetics of alfentanil (R39209): a new opiate analgesic. Anesthesiology 57: 871–877, 1982

    Article  Google Scholar 

  • Chapko MK, Syrjala KL, Schilter L, Cummings C, Sullivan KM. Chemoradiotherapy toxicity during bone marrow transplantation: time course and variation in pain and nausea. Bone Marrow Transplantation 4: 181–186, 1989

    PubMed  CAS  Google Scholar 

  • Citron ML, Johnson-Early A, Boyer M, Krasnow SH, Hood M, Cohen MH. Patient-controlled analgesia for severe cancer pain. Archives of Internal Medicine 146: 734–736, 1986

    Article  PubMed  CAS  Google Scholar 

  • Citron M, Johnston-Early A, Fossieck BE, Krasnow SH, Franklin R, 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 

  • Colpaert FC. Long-term suppression of pain by narcotic drugs in the absence of tolerance development. Archives Internationales de Pharmacodynamie et de Thérapie 236: 293–295, 1978

    PubMed  CAS  Google Scholar 

  • Colpaert FC, Niemegeers JE, Janssen PAJ, Maroli AN. The effects of prior fentanyl administration and of pain on fentanyl analgesia: tolerance to and enhancement of narcotic analgesia. Journal of Pharmacology and Experimental Therapeutics 213: 418–424, 1980

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Dahlstrom B, Tamsen A, Paalzow L, Hartvig P. Patient controlled analgesic therapy: part IV. Pharmacokinetics and analgesic plasma concentrations of morphine. Clinical Pharmacokinetics 7: 266–279, 1982

    Article  PubMed  CAS  Google Scholar 

  • Fox JL, Lamson ML. RSTRIP: pharmacokinetic data stripping/least squares parameter optimisation, Micromath, Inc, 1986

  • Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed., Marcel Dekker Inc., New York, 1982

    Google Scholar 

  • Gourlay GK, Plummer SR, 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 

  • Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology 64: 322–327, 1986

    Article  PubMed  CAS  Google Scholar 

  • Harrison MJ. Prediction of infusion rates: computer study. British Journal of Anaesthesiology 64: 283–286, 1990

    Article  CAS  Google Scholar 

  • Hecker BR, Albert L. Patient-controlled analgesia: a randomized, prospective comparison between two commercially available PCA pumps and conventional analgesic therapy for postoperative pain. Pain 35: 115–120, 1988

    Article  PubMed  CAS  Google Scholar 

  • Hill HF. Pharmacokinetic tailoring of computer-controlled drug infusions. In Smith et al. (Eds) Pharmacodynamic research: current problems, potential solutions, pp. 158–166, Harvey Whitney Books, Cincinnati, 1988

    Google Scholar 

  • Hill HF, Chapman CR. Tailored infusion of opioids. In Benedetti et al. (Eds) Advances in pain research and therapy, vol. 14, Raven Press, New York, 1989

    Google Scholar 

  • Hill HF, Chapman CR, Kornell J, Sullivan K, Saeger L, 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, Mackie AM, Coda BA. Pharmacokinetically tailored opioid infusions for patient controlled analgesia: comparison of morphine and alfentanil. Pain (Suppl. 5): S269, 1990c

    Google Scholar 

  • Hill HF, Mackie AM, Jacobson RC. Pharmacokinetic aspects of patient-controlled analgesia. In Ferrante et al. (Eds): Recent advances in patient-controlled analgesia, pp. 214–222, Black-well Scientific Publications, Oxford, 1990b

    Google Scholar 

  • Hill HF, Saeger LC, Bjurstrom R, Donaldson G, Jacobson RC, et al. Steady-state infusion of opioids in human volunteers: I. Pharmacokinetic tailoring. Pain, in press, 1990d

    Google Scholar 

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

    Google Scholar 

  • Hill HF, Walter M, Saeger L, Sargur M, Sizemore W, et al. Dose effects of alfentanil in human analgesia. Clinical Pharmacology and Therapeutics 40: 178–186, 1986b

    Article  PubMed  CAS  Google Scholar 

  • Hoskin PJ, Hanks GW, Heron CW, Aherne GW, Chapman D. M6G and its analgesic action in chronic use. Clinical Journal of Pain 5: 199–201, 1989

    Article  PubMed  CAS  Google Scholar 

  • Hull CJ. The pharmacokinetics of opioid analgesics, with special reference to patient-controlled administration. In Harmer et al. (Eds) Patient-controlled analgesia, pp. 7–17, Blackwell Scientific Publications, Oxford, 1985

    Google Scholar 

  • Hull CJ. Opioid infusions for the management of postoperative pain. In Smith & Covino (Eds) Acute pain, pp. 155–179, Butterworths, London, 1985b

    Google Scholar 

  • Inturrisi CE, Colburn WA. Application of pharmacokinetic-pharmacodynamic modeling to analgesia. In Foley & Inturrisi (Eds) Advances in pain research and therapy, Vol. 8, pp. 441–452, Raven Press, New York, 1986

    Google Scholar 

  • Inturrisi CE, Portenoy RK, Max MB, Colburn WA, Foley KM. Pharmacokinetic-pharmacodynamic relationships of methadone infusion in patients with cancer pain. Clinical Pharmacology and Therapeutics 47: 565–577, 1990

    Article  PubMed  CAS  Google Scholar 

  • Inturrisi C, Portenoy R, Stillman M, Colburn W, Foley K. Hydromorphone bioavailability and pharmacokinetic pharmacodynamic (PK-PD) relationships. Clinical Pharmacology and Therapeutics 43: 162, 1988

    Google Scholar 

  • Kerr IG, Sone M, DeAngelis C, Iscoe N, MacKenzie R, et al. Continuous narcotic infusion with patient-controlled analgesia for chronic cancer pain to outpatients. Annals of Internal Medicine 108: 554–557, 1988

    PubMed  CAS  Google Scholar 

  • Kruger-Theimer E. Continuous intravenous infusion and multicompartmental accumulation. European Journal of Pharmacology 4: 317–324, 1968

    Article  Google Scholar 

  • Lehmann KA. Practical experience with demand analgesia for postoperative pain. In Harmer et al. (Eds) Patient-controlled analgesia, pp. 134–139, Blackwell Scientific Publications, Oxford 1985

    Google Scholar 

  • Lehmann KA. Patient-controlled intravenous analgesia for postoperative pain relief: issues in study design. In Max et al. (Eds) Design of analgesic clinical trials, Raven Press, New York, in press, 1990

    Google Scholar 

  • Martin RW, Hill HF, Yee HC, Saeger LD, Walter MH, et al. An open loop computer-based drug infusion system. IEEE Transactions on Biomedical Engineering BME 34: 158–166, 1987

    Article  Google Scholar 

  • Metzler CM, Weiner DL. PCNONLIN: software for the statistical analysis of nonlinear models (version 3.0), Statistical Consultants, Inc., Lexington 1989

    Google Scholar 

  • Nimmo WS, Todd JG. Fentanyl by constant rate i.v. infusion for postoperative analgesia. British Journal of Anaesthesiology 57: 250–254, 1985

    Article  CAS  Google Scholar 

  • Osborne R, Joel S, Trew C, Slevin M. Morphine and metabolic behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clinical Pharmacology and Therapeutics 47: 12–19, 1990

    Article  PubMed  CAS  Google Scholar 

  • Pasternak GW, Bodnar RJ, Clark JA, Inturrisi CE. Morphine-6-glucuronide, a potent mu agonist. Life Sciences 41: 2845–2849, 1987

    Article  PubMed  CAS  Google Scholar 

  • Peterson GM, Randall CTC, Peterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship of renal function and route of administration. European Journal of Clinical Pharmacology 38: 121–124, 1990

    Article  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 Reviews 70: 575–581, 1986

    CAS  Google Scholar 

  • Reilly CS, Wood AJJ, Wood M. Variability of fentanyl pharmacokinetics in man. Anaesthesia 40: 837–843, 1984

    Article  Google Scholar 

  • Robinson JO, Rosen M, Evans JM, Revill SI, David H, et al. Self-administered intravenous and intramuscular pethidine: a controlled trial in labor. Anaesthesia 35: 763–770, 1980

    Article  PubMed  CAS  Google Scholar 

  • Sandidge CH, Marvin JA, Heimbach DM. Patient controlled analgesia (PCA) in treating pain in burn patients. 19th Annual Burn Association Meeting Proceedings, A46, 1987

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

    PubMed  CAS  Google Scholar 

  • Tamsen A, Hartvig P, Fagerlund C, Dahlstrom B. Patient-controlled analgesic therapy: part II: Individual analgesic demand and analgesic plasma concentrations of pethidine in postoperative pain. Clinical Pharmacokinetics 7: 164–175, 1982

    Article  PubMed  CAS  Google Scholar 

  • Todd RD, Muldoon SM, Watson RL. Determination of morphine in cerebrospinal fluid and plasma by high performance liquid chromatography with electrochemical detection. Journal of Chromatography and Biomedical Applications 232: 101–110, 1982

    Article  CAS  Google Scholar 

  • Vaughan DP, Tucker GT. General derivation of the ideal drug input required to achieve and maintain constant plasma drug concentration: theoretical application to lignocaine therapy. European Journal of Clinical Pharmacology 10: 433–440, 1976

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • White PF. Use of a patient-controlled analgesia infuser for the management of postoperative pain. In Harmer et al. (Eds) Patient-controlled analgesia, pp. 140–148, Blackwell Scientific Publications, Oxford, 1985

    Google Scholar 

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Authors and Affiliations

  1. Division of Clinical Research, AB-122, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, Washington, 98104, USA

    Harlan F. Hill, Robert C. Jacobson, Barbara A. Coda & Adam M. Mackie

  2. Department of Anesthesiology, University of Washington, RN-10, Seattle, Washington, USA

    Harlan F. Hill, Robert C. Jacobson, Barbara A. Coda & Adam M. Mackie

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  1. Harlan F. Hill
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  2. Robert C. Jacobson
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  3. Barbara A. Coda
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  4. Adam M. Mackie
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Hill, H.F., Jacobson, R.C., Coda, B.A. et al. A Computer-Based System for Controlling Plasma Opioid Concentration According to Patient Need for Analgesia. Clin. Pharmacokinet. 20, 319–330 (1991). https://doi.org/10.2165/00003088-199120040-00006

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  • DOI: https://doi.org/10.2165/00003088-199120040-00006

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