Medical Pharmacology Chapter 13 Opioids: Advanced Topics

¹Intravenous Opioid Anesthetics:  Pruitus and Other Topics

•  The occurrence of opioid-induced pruritus is well established; however, the mechanism remains to be elucidated. 

  • Histamine release does not appear to be the cause, given that certain opioids that do not promote histamine release still cause pruritus. 

  • Allergic reactions in the presence of drug solution preservatives also do not account for this phenomenon.

¹Opioids: Some Therapeutic Actions

• ¹Ventilation: One consequence of pain/anxiety may be respiratory alkalosis secondary to increased spontaneous ventilation. 

  • Hyperventilation can also follow from some brainstem disorders. 

  • Management of hyperventilation is provided by opioids by means of reducing both pain and central ventilatory drive. 

  • Postoperative respiratory dysfunction can follow from inadequate pain relief. 

  • Opioid analgesic treatment can enhance synchronous breathing with a reduction in voluntary muscle tone, ultimately improving dynamic total respiratory compliance in awake but mechanically ventilated patients in the ICU setting. 

    • Of course, the caveat is that large doses of opioids can reduce pulmonary compliance (increased rigidity) as well as in directly impair ventilation.

• ¹Anti-cough: (antitussive)

  • Central mechanisms are responsible for opioid-induced antitussive effects.  

    • In about half of patients receiving IV bolus fentanyl, sufentanil and alfentanil can initiate brief coughing episodes, possibly due to a pulmonary chemoreflex mediated by C-fiber receptors.

    • This cough reflex following opioid injection is not affected by atropine pretreatment, though suggesting a mechanism other than a vagal one. 

    • Opioid-induced cough could occur by stimulation of "Ericsson" receptors associated with tracheal smooth muscle. 

    • Pretreatment using inhalational - adrenergic agonists decreases the likelihood of   IV opioid injection-induced cough.

• ¹Suppression of upper airway, tracheal and lower respiratory tract reflexes: 

  • This type of reflex suppression although well accepted is not associated with and elucidated mechanism.

• ¹Opioid-induced suppression of somatic and autonomic reactions associated with endotracheal intubation:

  • Opioid administration permits endotracheal intubation without "bucking" or coughing, syndromes that can lead to hypoxemia, hemodynamic instability, hypercarbia and other pathophysiological conditions. 

  • Reduced lung volume is associated with bucking and this reduced lung volume along with disturbances in ventilatory pattern can result in nonphysiological gas exchange. 

  • Coughing and bucking on emergence might be expected in those patients who received a potent inhalational agent but did not receive opioids. 

  • Utilization of opioids, that is proper utilization, can lead to patient awakening without such problems even if the endotracheal tube remains in place.

• ¹Bronchomotor tone: opioids may prevent increased bronchomotor tone. 

  • These agents also are helpful in managing dyspnea and other respiratory manifestations associated with asthma and congestive heart failure. 

    • Fentanyl, which exhibits antihistaminergic, antiserotonergic, as well as antimuscarinic effects may be more effective than morphine for managing patients with asthma or bronchospastic disorders. 

    • Suctioning-induced tracheobronchial stimulation can induce a pulmonary vasoconstrictive response which may be prevented or reduced by opioids.

¹Opioids: Adverse Effects and Non-Therapeutic Effects

• ¹One of the prominent effects of opioids is respiratory depression.

  • Opioid receptors have been found at high concentration in the number of sites in the brain, including the nucleus solitarius, nucleus retroambigualis, and nucleus ambiguus. 

  • Opioid induced respiratory effects are mediated by specific chemosensitive brain regions. 

  • Opioids also prevent normal physiological function in pontine and medullary respiratory centers.

(The Digital Slice of Life is a cooperative project with the Slice of Life office, KUED Media Solutions, and the Knowledge Weavers Project.  http://medlib.med.utah.edu/kw/) (links not active)

Attribution:  Dr. Al Ferguson, Queen's University at Kingston

• ¹-opioid receptors are stimulated by opioids, resulting dose-dependent respiratory depression by means of direct action on brain-stem respiratory centers. 

  • CO₂ stimulatory effects on ventilation are diminished by opioids and in accordance with this finding, ventilatory slope and occlusion pressure responses to CO₂ are diminished with minute ventilatory responses to increases in PaCO₂ exhibit curve shifting to the right. 

  • The apneic threshold and resting end-tidal PCO₂ are increased by opioids

• ¹Hypoxic ventilatory drive is attenuated by the opioids with carotid body chemoreception and hypoxic drive also blunted or eliminated even by low, analgesic opioid doses. 

  • The increased respiratory drive associated with increasing airway resistance is also reduced by opioids. 

  • The dose-dependent reduction in spontaneous respiratory rate allows opioid titration to effect in the anesthetized patient. 

    • On the other hand, the extent of opioid-induced respiratory depression cannot be reliably judged by only observing respiratory rate, particularly in the postoperative environment.

    • Elimination of spontaneous respiration by the opioids is not necessarily associated with loss of consciousness; therefore, individuals receiving high-dose opioids may be responsive to verbal commands even those which request that they breathe.

• ¹Opioid-induced influences on respiratory rhythm and pattern include the following changes:

  • Irregular and/or periodic breathing

  • Expiratory delay

  • Respiratory pausing

  • Alteration in tidal volume (decreased or increased)

• ¹Onset of respiratory depression following opioid administration:

  • Peak onset of respiratory depression following morphine (analgesic dose level) is slower than that observed following comparable fentanyl doses (the proportionality is about 30 minutes versus about seven minutes). 

    • Explanation for this difference references the lower lipid solubility associated with morphine.

      • Lower lipid solubility is responsible for morphine plasma concentrations in onset of action being nearly the same following IV versus IM administration. 

      • In the immediate postoperative timeframe, the use of morphine as an IV analgesic is therefore perhaps not the best choice.

  • Duration of respiratory depression

    • Small doses of morphine induce a respiratory depression that typically lasts longer than that observed following an equipotent fentanyl dose.

    • Another comparison involves IV fentanyl versus meperidine. 

      • In that case IV fentanyl (100 and 200 g/70kg) administration induces respiratory depression that does not last as long as and equipotent meperidine dose (65-75 mg/70kg). 

        • In the same study, faster onset in peak effect following fentanyl was noted, compared to meperidine.  The shorter onset include recovery associate with fentanyl compared to morphine and meperidine does not obviate the observation that small doses (2g/kg) induces respiratory depression that lasts for a rather longtime (> one hour).  By contrast, sufentanil (0.1-0.4 g/kg) administration results in shorter-lasting respiratory depression but longer-lasting analgesia compared to fentanyl (1-4 g/kg).

  • Initial postoperative respiratory depression  is typically not observed when fentanyl (4-8 g/kg) is administered during induction; however, there's a possibility of significant respiratory depression noted five or more hours later. 

    • With higher doses of fentanyl (50-100g/kg) persistent respiratory depression may require ventilatory support for 6-18 hours. 

      • With intermediate dose levels (20-50 g/kg) the possibility of the need of postoperative mechanical ventilation should be considered.

• ¹Recovery of respiratory function

  • Alfentanil and sufentanil are associated with a more rapid recovery of respiratory function compared to fentanyl, at least with fentanyl, a possible explanation at the molecular level is the more rapid dissociation of alfentanil from the receptor compared to other agents. 

    • This more rapid dissociation has been interpreted to possibly explain a decrease likelihood of respiratory depression.

  • With remifentanil, independent of dosage, and a residual effects dissipate extremely rapidly (5-15 minutes) following discontinuation of administration.

¹Factors that Influence Opioid-Induced Respiratory Depression

• ¹Duration and magnitude of respiratory depression following opioid administration can be influenced by a number of factors.

  • Factors that increase magnitude  and/or duration of opioid-induced respiratory depression include:

    • dose

    • Intermittent bolus (by contrast to continuous infusion)

    • Brain penetration/drug delivery

      • Distribution ( cardiac output)

      • Un-ionized fraction (respiratory alkalosis)

    • Reuptake from the brain (interoperative respiratory alkalosis)

    • Clearance (hepatic blood flow for example inter-abdominal surgery)

    • Secondary peaks in plasma opioid concentrations (reuptake of opioid from muscle, lung, fat, intestine reservoir)

    • Ionized opioid receptor site (postoperative respiratory acidosis)

    • Sleep

    • Age

    • Metabolic alkalosis

• ¹Sleep:

  • Opioids potentiate the normal right shift of the PaCO₂-alveolar ventilation curve, observed during non-REM sleep. 

  • Respiratory, cognitive, and hemodynamic anomalies are probably responsible for the hypoxemia associated with sleep postoperative (several days). 

  • Natural sleep as well as morphine reduce the thoracic component of breathing with limited effect on the diaphragmatic component. 

  • Tonic and phasic upper airway muscle activity associated with breathing is also impair by sleep; this effect may be problematic one patients have an opioid-based anesthetic in the context of surgery which is associated with limited postoperative pain. 

    • In this eventuality, seemingly normal breathing while awake can transition to inadequate breathing during sleep.  For those patients with impaired abdominal breathing or problems with their airway function (e.g.in significantly obese patients or in patients who exhibit sleep apnea), opioid analgesics may increase the probability of adverse respiratory events.

• ¹Age:

  • Anesthetic and respiratory depressant effects of opioids are more apparent in older patients. 

    • Furthermore, older patients exhibit a higher opioid blood concentration as corrected for weight.  

    • More frequent incidences of apnea, periodic breathing is well as obstruction following morphine has been reported in older patients relative to young adults.

      • In neonates again with weight adjustment, morphine administration causes a greater degree of respiratory depression relative to the adult patient. 

      • This effect is probably due to a more ready penetration by morphine into the neonatal brain due to the underdeveloped blood-brain barrier. 

        • The sensitivity of morphine to the extent of blood brain barrier development is probably due to its relatively low intrinsic lipid-solubility  which would normally be limiting. 

        • By contrast, neonatal patients are not more sensitive to other more lipid-soluble opioid such as fentanyl, sufentanil, or meperidine; the intrinsic lipid solubility then would be more important than the status of the blood-brain barrier.

• ¹Effects of other drugs administered concurrently:

  • Opioid-induced respiratory depression would be in hand/prolonged if opioid administration is associated with administration of other CNS the presence which would include potent inhaled anesthetics, barbiturates, benzodiazepines, or ethanol.

    • Bradypnea are apnea can be induced by these drug interactions which depress ventilatory responses to hypercarbia and/or hypoxia.

    • Examples of agents which DO NOT enhance bradypnea or apnea in this setting include droperidol, scopolamine, and clonidine.

    • This conclusion was reached by noting that these agents do not increase fentanyl or other opioid-induced respiratory depression.

• ¹Pain:

  • Respiratory depression may be influenced by pain and/or surgically-induced pain; however, some clinical research findings have not supported this assertion. 

    • (1) some postsurgical breathing patterns are not influenced by the level or type of pain relief. 

    • (2) sevoflurane-induced sedation that causes ventilatory response depression to hypoxemia is not reversed by acute pain.

• ¹Opioids and  Tolerance:

  • Some degree of acute tolerance to respiratory depression secondary to opioid administration can be noted rapidly. 

    • However, a longer period, perhaps one half-year of opioid exposure may be required to detect significant tolerance to respiratory-depressant opioid action on hypoxic ventilatory responses. 

    • Complicating the consideration is the observation that cross-tolerance to the respiratory depression action of differing opioids may be unpredictable and incomplete.

  • Abnormal physiological renal function can translate to abnormal opioid activity duration. 

    • This result occurs despite the conclusion that opioid action is mainly ended by redistribution and hepatic metabolism. 

    • The general idea is that greater respiratory depression can follow from the accumulation of morphine/meperidine/metabolites in the renal insufficiency case.

  • Postoperative respiratory depression following fentanyl (10 and 25 g/kg)  may be prolonged and enhanced by hypocapnic hyperventilation. 

    • The opposite consequence is associated with interoperative hypercarbia.  These results may be explained by the following:

    1. Increase brain opioid transfer to the brain would be expected with increased uncharged fentanyl (un-ionized)  associated with the hypocarbic state

    2. By contrast, increased removal may occur secondary to decrease cerebral blood flow with the hypocarbic state.

    3. Another factor might be reduced hepatic clearance secondary to reduced cardiac output with attenuated hepatic blood flow.

• 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 and 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/