Medical Pharmacology: Advanced Opioid Actions on the Cardiovascular System

Medical Pharmacology Chapter 13 Opioids: Advanced Topics

Influence of Opioids on Cardiovascular Dynamics¹

¹Hemodynamic responses to painful/noxious stimulation can be completely suppressed by the action of potent volatile anesthetics.
- The difficulty in this approach is that the amount of a volatile anesthetic needed to suppress such hemodynamic responses would also be sufficient to result in significant hypotension.
- Accordingly, opioids may be used to provide greater hemodynamic stability, suppressing hemodynamic responses to pain.
  - The proposition that high-does opioids representing the primary/only anesthetic results in hemodynamic stability remains controversial.
  - Nevertheless, the role of opioids as an adjunct to other agents is well established as is the ability of opioids to suppress hemodynamic responses to events commonly occurring intraoperatively.
- Excursion from a stable hemodynamic profile can be associated with anesthesia induction, intubation, as well as events occurring during surgery.
  - The qualitative and quantitative aspects of these excursions can be influenced by other factors which include:
    - Extent of β-adrenergic receptor blockade as well as the possibility of Ca²⁺ channel blockade
    - Preoperative status of ventricular function
    - Hydration state of the patient
    - Administration of premedication
    - Presence or absence of patient awareness.
- ¹The specific opioid used to modify hemodynamic excursions is also likely to have an effect.
  - This consideration is another example of lack of conclusive resolution in that some research indicates limited difference between fentanyl and sufentanil when used as principal anesthetics and cardiac surgery; whereas other results suggest that sufentanil might provide better intraoperative hemodynamic management.
  - Sufentanil administration appears to limit the need for vasodilators during cardiopulmonary bypass procedures as well as during the post-bypass period and the post-operative period.

**"A comparison of morphine, fentanyl and sufentanil anesthesia for cardiac surgery: induction, emergence, and extubation"**
An example of the comparative opioid study in the context of cardiac surgery; one that considers induction emergence and extubation is noted below in the work of Sanford et al. (1986). This study compared anesthetic doses of morphine (n = 10), fentanyl (n=9) and sufentanil (n=9) in a group of patients undergoing cardiovascular surgery. The opioid was administered after induction and took into consideration the EEG as well as cardiovascular signs indicative of anesthesia depth. Opioid comparisons included the following parameters: Times for anesthesia induction Return of consciousness Return of spontaneous ventilation Return event with cardiovascular status Extubation. Using a test for significance in which p < 0.05, the following statistically significant shorter times for sufentanil compared to fentanyl or morphine reported as mean +/- standard error of the mean ( SEM) or reported as follows: Induction: (15 +/- 2.3 minutes, 5.9 +/- 0.7 minutes, 3.0 +/- 0.2 minutes for morphine, fentanyl, and sufentanil respectively. Return of consciousness: morphine 19.7 +/- 34.4 minutes, fentanyl 62.3 +/- 70.9 minutes, sufentanil 17 +/- 8.7 minutes. Return of acceptable and stable cardiac status: morphine 587.3 +/- 139.3 minutes, fentanyl 537.9 +/- 144.8 minutes, sufentanil 173.7 +/- 56.8 minutes. Extubation: morphine 1121.3 +/- 61.8 minutes, fentanyl 1005.7 +/- 77.7 minutes, sufentanil 533.3 +/- 67.8 minutes. The authors concluded that sufentanil administered in the dosage range of 19 g/kg will allow for more rapid induction as well as earlier anesthesia merchants and faster extubation of patients when compared with either morphine or fentanyl. Reference: Sanford, TJ, NT Smith, D Dec-Silver and WK Harrison, A comparison of morphine, fentanyl and sufentanil anesthesia for cardiac surgery: induction, emergence, and extubation Anesthesia & Analgesia, Vol 65, 259-266, 1986

DISCLAIMER

This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information. Medical or other information thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.

¹Bailey, PL, Egan, TD, Stanley, TH, "Intravenous Opioid Anesthetics", in Anesthesia 5th edition, Miller, R.D., editor, Churchill Livingstone, Philadelphia, 2000, 273-377 (references secondarily sourced from this primary reference are noted below in the indented references)
- ^1aLowenstein, E, Hallowell P, Levine FH et al.: Cardiovascular response to large doses of intravenous morphine in man.N. Engl J Med 281:13 89, 1969
- ^1b Stanley, TH, Webster LR; Anesthetic requirements and cardiovascular effects of fentanyl-oxygen and fentanyl-diazepam-oxygen anesthesia in man. Anesth Analg 51:901, 1972.
- ^1c Arens, JR, Benbow, BP, Ochsner JL et al: Morphine anesthesia for the aorto-coronary bypass procedures. Anesth Analg 57: 411, 1978
- ^1d Stanley, TH, Gray NJ, Staford W. et al: The effects of high-dose morphine on fluid and blood requirements in open-heart operations. Anesthesiology 38:536, 1973.
- ^1e Stoelting, RK, Gibbs PS, Creasser CW et al: Hemodynamic in ventilatory response to fentanyl, fentanyl-droperidol, and nitrous oxide in patients with acquired valvular heart disease. Anesthesiology 42:319, 1975.
- ^1f Bowdle, TA, Ward, RJ: Induction of anesthesia with small doses of sufentanil or fentanyl: Dose versus EEG response, speed of onset and thiopental requirement. Anesthesiology 70:26, 1989
- ^1gHecker BR, Lake CL, DiFazio CA et al: The decrease of the minimum alveolar anesthetic concentration produced by sufentanil in rats. Anesth Anal 62:987, 1983.
- ^1hGoldstein,A: Opiate receptors. Life Sci. 14:615, 1974.
- ¹ⁱSnyder SH: Opiate receptors in the brain. N Engl. J Med to 96:266, 1977.
- ^1jMayer, DJ, Wolfle, TL, Akil H et al: Analgesia from electrical stimulation in the brainstem of the rat. Science 174:13 51, 1971.
- ^1kFields, HL: Brainstem mechanisms of pain modulation: Anatomy and physiology. In Herz, A (ed): Opioids II: Handbook of Experimental Pharmacology. Berlin, Springer-Verlag, 1993, p.3.
- ^1lKissin I, Vinik HR, Castillo R et al:Alfentanil potentiates midazolam-induced unconsciousness in subanalgesic doses. Anesth Analg 71:65, 1990
- ^1mMcEwan AI, Smith C, Dyar O et al: Isoflurane minimum alveolar concentration reduction by fentanyl. Anesthesiology 78:864, 1993.
- ¹ⁿBailey, PL, Wilbrink J, Zwanikken P et al: in Anesthetic induction with fentanyl. Anesth. Analg 64:45, 1985.
- ^1oHeier, T, Steen, PA: Assessment of anesthesia depth.Acta Anaesthesiol Scand 40:10 87, 1996.
- ^1pSebel PS Lang E Rampil IJ White PF Cork R Jopling M Smith NT Glass PSA Manberg A multicenter study of bispectral electroencephalogram analysis for monitoring anesthetic effect Anesth. Analg. 84(4) 1997 891-899.
- ^1qJones, JG: Use of evoked responses in the EEG to measure depth of anesthesia. In Lunn J, Rosen M (eds): Consciousness, Awareness and Pain and General Anesthesia. Boston, Butterworth, 1987, p 99.
- ^1rEgan TD, Minto CF, Hermann DJ et al: Remifentanil versus alfentanil: Comparative pharmacokinetics and pharmacodynamics. Anesthesiology 84: 821, 1996.
- ^1sKalkman CJ, Rheineck AR, Bovill JG: of high-does opioid anesthesia on posterior tibial nerve somatosensory cortical evoked potentials: Effects of fentanyl, sufentanil, and alfentanil J Cardiothorrac Anesth 2:758, 1998.
- ^1tAdler, LJ, Fyuulai F, Diehl D, Mintun, M, Winter, PM, Firestone, L Regional brain activity changes associated with fentanyl analgesia elucidated by positron emission tomography. Anesth Analg 1997; 84:120-126.
²Coda, BA, "Opioids" in Clinical Anesthesia, 4th edition, Barash, PG, Cullen, BF, Stoelting, RK, editors, Lipincott Williams & Wilkins, Philadelphia, 2001, 345-375
- 2a Thorpe, DH: Opiate structures and activity: a guide to underlying opioid actions. Anesth Analg 63:143, 1984.
³Gottschalk, A and Smith DS, New Concepts in Acute Pain Therapy: Preemptive Analgesia, American Family Physician, May, 2001 http://www.aafp.org/afp/20010515/1979.html
- First figure redrawn with permission by Gottschalk and Smith from: Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg 1993;77:1049.
- Second figure redrawn with permission by Gottschalk and Smith from: Woolf CJ, Chong MS. Preemptive analgesia--treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:368.
⁴Dickenson, AH Spinal cord pharmacology of pain. Br. J. Anaesth. 75: 193, 1995. (references secondarily sourced from this primary reference are noted below in the indented references)
- ^4aBattaglia, G, Rustioni A. Coexistence of glutamate and substance P. and dorsal root ganglion cells of the rat and monkey. Journal of Comparative Neurology 1988; 277:302-312.
- ^4bHaley, JE, Sullivan, AF, Dickenson, AH. Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rent. Brain Research 1990; 518:218-222.
- ^4cSchiable, HG, Grubb BD, Neugebauer, V, Oppmann M. The effects of NMDA antagonists on neuronal activity in cat spinal cord evoked by acute inflammation in the knee joint. European Journal of Neuroscience, 1991; 3:981-991.
- ^4dWoolf CJ, Thompson, SWN. The induction and maintenance of central sensitization is dependent on N--methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury hypersensitivity states. Pain 1991; 44:293-299.
- ^4eMao, J, Price DD, Hayes, RL, Lu, J, Mayer DJ, Frank H. Intrathecal treatment with dextrophan or ketamine publicly reduces pain-related behaviors in a rat model of peripheral mononeuropathy. Brain Research 1993; 605:164-168.
- ^4fPrice, DD, Mao, J, Mayer DJ. Central neural mechanisms of normal in abnormal pain states. In: Fields, HL, Lebeskind, JC, eds. Progress in Pain Research and Management. Seattle:IASP Press, 1994; 61-84.
- ^4gRogawaki MA. Therapeutic potential of excitatory amino acid antagonists; channel blocks and 2,3 benzodiazepines. Trends in Pharmacological Sciences 1993; 14:325-331
- ^4hEide PK, Jorum E, Stubhaug, A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-D-aspartate receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994; 58:347-354.
- ⁴ⁱPrice DD, Mao J, Frenk H, Mayer, DF. Central neural mechanisms of normal in abnormal pain states. In:Fields HL, Lebeskind JC, eds. Progress in Pain Research and Management. Seattle:IASP Press, 1994; 61-84.
- ^4jBesse, D, Lomabard, MC, Zajac, JM, Roques, BP, Besson, JM Pre- and and postsynaptic distribution of mu, delta, and kappa opioid receptors in the superficial layers of the cervical dorsal horn of the rat spinal cord, Brain Research 521 (1-2), June 1990 pp 15-22.
- ^4kKangrga I and Randic M Outflow of endogenous aspartate in glutamate from the rat spinal dorsal horn in vitro by activation of low-and high-threshold primary afferent fibers. Modulation by mu-opioids Brain research 553, 2, July 1991,pp. 347-352.
⁵Substantia Gelatinosa Image: Courtesy of The Digital Slice of Life, a cooperative project with the Slice of Life office, KUED Media Solutions, and the Knowledge Weavers Project.
Ross, AF, Gomez, MK, Tinker, JH "Anesthesia for Adult Cardiac Procedures in Principles and Practice of Anesthesiology, 2nd edition, Longnecker, DE, Tinker, JH, Morgan, GE, eds, Mosby, St. Louis, 1998, pp. 1659-1698.
⁶Two-dimensional & Three Dimensional Images courtesy of CORD Center for Opioid Research and Design http://www.opioid.umn.edu/
⁷Jaffe, CC, Stewart, WB, Lynch, PJ, Hines, S., Cranial Nerves, Yale University School of Medicine, Center for Advanced Instructional media, (c) 1998 http://info.med.yale.edu/caim/cnerves/contents.html
⁸Kauffman, AM & Patel M, Center for Cranial Nerve Disorders http://www.umanitoba.ca/cranial_nerves/trigeminal_neuralgia/manuscript/index.html
⁹Chakrabarti, S, Oppermann, M Gintzler AR Chronic morphine induces the concomitant phosphorylation and altered Association of multiple signaling proteins: A novel mechanism for modulating cell signaling PNAS 98 (7) 4009, 2001
¹⁰Brookoff, D Chronic Pain: 1. A New Disease? Hospital Practice July, 2000 http://www.hosppract.com/issues/2000/07/brook.htm
¹¹Protein Structure Study Guide http://www.princeton.edu/~actin/chm543_info.html#Study%20guide%201
¹²MRC Center for Synaptic Plasticity, University of Bristol, used with permission for non-commercial applications
¹³Breeze AL, Harvey, TS, Bazzo, R, Campbell ID Solution structure of Human Calcitonin Gene-Related Peptide by H NMR and Distance Geometry with Restrained Molecular Dynamics Biochemistry 30:575-582 (1991)
¹⁴Heish, JC, Carr, DB "Choosing a Therapeutic Approach: Opioids" in The Massachusetts General Hospital Handbook of Pain Management (Borsook D, LeBel, AA, McPeek, B, eds) Little, Brown and Company, Boston, 1996, pp 47-75.
¹⁵Anwari, J. S. & Iqbal, S. (2003)Antihistamines and potentiation of opioid induced sedation and respiratory depression. Anaesthesia 58 (5), 494-495
- ^3aGustafsson LL, Schildt B, Jacobsen KJ. Adverse effects of extradural and intrathecal opiates: Reports of a nationwide survey in Sweden. British Journal of Anaesthesia 1982; 54:479-486.
- ^3bBrockways MS, Nobel DW, Sharwood-smith GH, McClure JH. Are found respiratory depression after extradural fentanyl. British Journal of Anaesthesia 1990; 64:243-245.
- ^3cHolmstrom, B, Rawal N, Axelsson K, Nydahl P. Risk of catheter migration during combined spinal epidural block. Percutaneous epiduroscopy study. Anesthesia and Analgesia 1995; 80:747-753.
¹⁶Yli-Hankala,A Will enough isoflurane during surgery replace morphine after surgery? Acta Anaesthesiologica Scandinavica Volume 47 Issue 7 Page 785 - August 2003)
- ¹⁷Gurman GM, Weksler N, Steiner O, Popescu M, Avinoah E, Porath A. The influence of cortical electrical activity level during general anaesthesia on the severity of immediate postoperative pain in the morbidly obese. Acta Anaesthesiol Scand 2003; 47:804-8
¹⁷Soliman E Legatt, AD Somatosensory Evoked Potentials: General Principles eMedicine, http://www.emedicine.com/neuro/topic640.htm, 8/2001.
¹⁸Black, S, Sloan T., SOMATOSENSORY (SSEP) AND MOTOR EVOKED POTENTIALS (MEP) THE SOCIETY FOR NEUROANESTHESIA AND CRITICAL CARE - 1998 ANNUAL MEETING http://analgesic.anest.ufl.edu/anest2/mahla/snacc/eps/