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¹Opioids

• Overview

  •  Advantages for use in preoperative medication:

    1. Absence of myocardial depressant effects

    2. Alleviate the preoperative pain

    3. Management of discomfort associated with invasive monitor insertion

    4. Management of pain which may be associated with establishing regional anesthesia

  • Preoperative opioids may limit or eliminate the need for supplemental analgesics during the early postoperative phase

    • Pain experienced by lightly anesthetized patients may cause CNS changes that exacerbate pain postoperatively. 

      •  For example, in support of this hypothesis, a higher opioid concentration is required for suppression of C-fiber activation if pain has caused previous C-fiber activity

  • Generally,  in the absence of preoperative pain there may be no compelling reason to include a narcotic for preoperative anesthetic medication.  

    • On the other hand, opioid administration to patients experiencing preoperative pain not only relieves pain but also may induce a euphoric state.

• Commonly used opioids for premedication

  • Most commonly used: morphine and meperidine (Demerol)

    •  Morphine:

      • intramuscular injection; good absorption with peak plasma levels obtained in about 45-90 minutes

      • intravenous administration: the effects occur more rapidly, usually within 20 minutes

    •  Meperidine (Demerol):

      • Relative to morphine intramuscular injection yields a less predictable time to onset

  • One advantage of including morphine as part of preoperative medication:

    • Morphine tends to suppress tachycardic responses to surgical stimulation during volatile anesthetic administration

• Contexts for opioid administration:

  • Intramuscular: appropriate for nitrous oxide-opioid anesthesia

  • Intravenous administration:  appropriately administered immediately before induction (fentanyl (Sublimaze) is a good choice in this application)

  • Pain associated with regional anesthesia or associated with invasive monitoring catherization or even large intravenous lines may justify treatment with preoperative opioids.  

    • As would be expected for many agents, dosage reduction may be required for the elderly patient.  

    • Elderly patients may have reduced pain sensitivity that may exhibit an enhanced analgesic response to the opioid

  • Occasionally preoperative opioids are administered in advance of a nitrous oxide-opioid anesthesia plan -- the rationale is that previous opioid administration allows the anesthesia provider to gauge the  patients ensuing intraoperative opioid response. 

    • For postoperative pain, preoperative opioids may be employed; however, it is probably preferable to either provide administration in the recover room setting or perhaps most appropriately provide IV opioids during the emergence

    • Preoperative opioid administration may lower anesthetic requirements

    • For facemask induction, opioids may be used in combination with other agents-in this case opioid-mediated respiratory depression may decrease ventilation during spontaneous breathing which will reduce the rate of inhalational drug uptake. (the circumstance might arise if for some reason intravenous induction agents may not be used)

      • In this eventuality, the anesthesia provider may have to control ventilation, overcoming opioid-induced respiratory depression

•  Adverse Effects:

  • Minimal cardiovascular effects are noted, except for high-dose meperidine (Demerol)

  •  Respiratory depression: associated with reduced responsiveness to CO₂ (medullary respiratory center depression)

    • Even low-opioid doses reduce carotid body hypoxia responsiveness -- accordingly, anesthesia providers may wish to administer supplemental oxygen for those patients receiving opioids as premedication

      • The problem of using opioid agonist-antagonist agents, which cause reduced respiratory depression, is that they also are less effective analgesic drugs.  Also, these partial agonists may cause dysphoria (instead of the more expected euphoric response), a condition and not desirable in the preoperative time frame -- or probably any other time frame

  • Orthostatic hypotension secondary to peripheral vascular smooth muscle relaxation: 

    • Opioids prevent the expected compensatory peripheral vascular vasoconstriction.  

    • This effect is in addition to opioid- promoted histamine release that tends to cause a hypotensive reaction. 

    • The hypotensive  response will be more profound in patients who are hypovolemic. 

    • Hypotensive reactions can be avoided by ensuring that patients remained supine following opioids (and other) premedication agents.

  •  Nausea and vomiting: These effects are frequently associated with opioid administration, possibly occurring as a result of stimulation of the medullary chemoreceptor trigger zone or vestibular apparatus stimulation leading to motion sickness.

    • The likelihood of nausea and vomiting may be reduced by placing the patient in a recumbent position; however, the use of opioids because of their tendency to cause nausea and vomiting perhaps should be avoided in the same-day outpatient setting or if the surgical procedure's themselves are likely to cause nausea and vomiting (i.e. some gynecological and opthalmological surgeries)

  •  Delayed gastric emptying, which is associated with nausea symptoms, has two important consequences-(1) altered absorption rate for orally-administered agents and (2) and increased risk of pulmonary aspiration

  • Opioids may also cause smooth muscle constriction (biliary spasm (choledochododenal sphincter spasm, i.e. sphincter of Oddi)).  Manifestation consists of an upper right quadrant pain secondary to smooth muscle constriction

    • Patients with biliary tract disease should perhaps not receive opioids.  

    • Also pain associated with biliary spasm, e.g. caused by an opioid, may be difficult to distinguish from angina particularly since pain from either angina or biliary spasm would be relieved by smooth muscle relaxation due to sublingual nitroglycerin. 

    • Opioid-induced pain, however, would be relieved by administration of a pure opioid antagonist such as naloxone (Narcan) or naltrexone (ReVia) or possibly glucagon.  These drugs would not reverse true anginal pain.

    • Meperidine (Demerol) is less likely than morphine to cause biliary tract spasm.

  •  Pruritis-probably secondary to histamine release; 

    • Accordingly opioids may cause flushing and dizziness.  

    • Since opioids are miotic agents, pinpoint pupils may occur.

• Specific agents:

  • Morphine:- dosage (5-15 mg, IM Route of Administration)

    • Well absorbed following IM administration

    • Time to onset: 15-30 minutes with peak effect at about 45-90 minutes with total duration of action as long as about four hours

      • With intravenous usage, significant, peak effects occur within about 20 minutes

    • Side reactions as noted for the opioid group in general, including ventilation depression; orthostatic hypotension as well as nausea and vomiting secondary to effects on the chemoreceptor trigger zone (CTZ) or on the vestibular apparatus

    • Reduction in GI motility

    • Preoperative use of morphine reduces cardioacceleration associated  with surgical stimulation and volatile anesthetic agents

  • Meperidine (Demerol) dosage:  (50-150 mg, IM Route of Administration)

    • Less potent compared to morphine (about 10% as potent)

    • Route of Administration: oral or parenteral

    • Single dosage effect duration: 2-4 hours with intramuscular injection providing a variable time to peak effect and duration

    • Elimination: mainly through hepatic metabolism

    • Cardiovascular effects: positive chronotropic effect secondary to antimuscarinic drug effects.

  • Fentanyl (Sublimaze):dosage-1-2 ug/kg intravenous for preoperative analgesia

    • Alternative Routes of Administration:

      • Oral (transmucosal) fentanyl (Sublimaze)-- 5-20 ug/kg [used in children and adults to diminish preoperative anxiety and pain)

        • Transmucosal fentanyl (Sublimaze) is associated with a high incidence of preoperative gastrointestinal disturbance (nausea and vomiting) typically at doses > 15 ug/kg:  Therefore, transmucosal fentanyl (Sublimaze) at these dosages is not recommended for patients < 6 years of age

    • Fentanyl (Sublimaze) issues:

      • Significant respiratory (ventilation) depression

      • Significant bradycardia

      • Fentanyl (Sublimaze) plus benzodiazepines may result in unwanted synergistic effects requiring close observation

      • Histamine release is NOT associated with fentanyl (Sublimaze)

      • Fentanyl (Sublimaze) administration does not cause myocardial depression

  • Agonist-antagonist agents

    • These drugs, e.g. pentazocine (Talwain), butorphanol (Stadol), nalbuphine exhibit reduced respiratory depression compared to pure opioid agonists; however, these drugs also have comparatively limited analgesic effects.

    • These partial agonist, given preoperatively, reduce the efficacy of pure opioid agonist given postoperatively to control postoperative pain.  Partial agonist  administration can in fact limit or reverse analgesia caused by the presence of the pure agonist

• ⁴Side effect incidence following preoperative opioid administration: [1 hr following dosage]-- original citation: Forest, W.H., Brown, B.W. et al.: "Subjective responses to six common preoperative medications", Anesthesiology 47:241, 1977.

  • Morphine (5-10 mg):

    • Dry mouth 80%

    • Slurred speech 33%

    • Dizziness 15%

    • Nausea 7%

    • Relaxation 20%

  • Meperidine (Demerol) (50-100 mg):

    • Dry mouth 85%

    • Slurred speech 45%

    • Dizziness 20%

    • Nausea 12%

    • Relaxation 25%

• ¹Antihistamines:

  • Overview:

    • ¹Occasional use for preoperative medication due to sedative and antiemetic characteristics.  For example meperidine (Demerol) + promethazine (Pherergan) produces additive sedation without enhancing the likelihood of nausea/vomiting or respiratory depression.

  • Specific applications:

    • Purpose of premedication -- prevention of intraoperative allergic reactions for those patients who have a history of chronic atopy (predisposition towards hypersensitivity reactions) or who will be undergoing a procedure associated with allergic reaction such as a radiographic studies requiring the use of a dye.

      • For these applications diphenhydramine (Benadryl) [0.5-1 mg/kg orally) may  be combined with H₂ receptor antagonist (blocker).  An example of an H₂ receptor antagonist would be cimetidine (Tagamet) [4-6 mg/kg]. 

      • The combination of an H₁ blocker (diphenhydramine (Benadryl)) and the H₂ antagonist (cimetidine (Tagamet)) reduces the likelihood of physiological responses to endogenous histamine release.

      • An additional agent, a steroid such as prednisone (Deltasone) (50 mg orally every six hours for the 24-hour period preceding the surgical procedure) may be helpful in combination with the above antihistamines.

      • Despite the use of these agents preoperatively, allergic reactions may still occur and may have to be managed intraoperatively

    • Other applications for histamine receptor blockers:  reduction of gastric acid secretion

      • Mechanism: blockade of histamine-receptor mediated gastric acid secretion by selective, competitive inhibition; as a consequence gastric pH increases

      • No reliable effect on gastric fluid volume or emptying time

      • Probably appropriate as premedication for patients with aspiration pneumonia risk.  Routine use is probably not appropriate.

        • Patient groups probably at increased pulmonary aspiration risk:

          • Parturients

          • Morbidly obese patients

          • Patients with esophageal reflux symptoms

          • "Difficult airway" patients

      • For patients undergoing elective surgery,  costs associated with preventing a single serious pulmonary aspiration complication may preclude routine use of H₂ blockers (this conclusion follows from  the very low likelihood of pulmonary aspiration and and serious morbidity in this patient group)-- also note that these drugs would not be expected to be 100% effective anyway.

      • Several doses are likely more effective for increasing gastric pH compared to single preoperative dose

      • Important reminder: Use of medications, such as H₂ receptor antagonists, to reduce aspiration risk is much less important than proper anesthetic technique which ensures for the correct placement of cuffed tracheal tubes

    • Specific medications:

      • Cimetidine (Tagamet),  reduces acid secretion responses to histamine, caffeine, hypoglycemia, gastrin

        • Route of Administration: oral or parenteral

        • Dosage: 150-300 mg (obese patients may require larger doses)

        • Such administration (oral) 60-90 min preceding surgery increases gastric acid pH to > 2.5 in most patients; however gastric fluid volume is not significantly altered.

          • [recall that in adults: possibly, relatively high-risk of pulmonary complications if aspiration volume when gastric fluid volume is > 25 ml with a pH < 2.5)

        • Concerning neonatal effects:

          • Probably limited since, although cimetidine (Tagamet) crosses placental barrier, studies resolved no difference between use of 30 ml of antacid 1-3 hours prior to the surgery and cimetidine (Tagamet) (300 mg) 1-3 hours before the procedure, with respect to neonatal neurobehavorial scores

        • Duration of action: 3-4 hours

        • Prominent side effect: inhibition of hepatic mixed-function oxidase enzyme system (cytochrome P450 system): consequence-

          • Half-life prolongation for drugs including diazepam (Valium), theophylline, propranolol (Inderal), lidocaine (Xylocaine)

          • Serious cardiovascular side effects may occur following rapid IV administration particularly  in critically ill patients (these effects include arrhythmias, hypotension, and cardiac arrests)

      • Ranitidine (Zantac), six times as potent as cimetadine in inhibiting gastric acid secretion

        • Ranitidine (Zantac) compared to cimetidine (Tagamet):

          • Longer acting

          • increased relative potency is reflected in a lower dosage range (50-200 mg)

        • Dosage:

          • Oral -- 50-200 mg

          • Parenteral: 50-100 mg (gastric fluid pH will increase within about our)

          • Duration of action: may last as long as 9 hr, suggesting that for very long cases premedication with ranitidine (Zantac) may reduce aspiration pneumonia is risk during emergence/tracheal tube extubation

        • Side effects: probably fewer CNS or cardiovascular side effects compared to cimetidine (Tagamet);smaller inhibitory effect on cytochrome P450 system than observed with cimetidine (Tagamet)

      • Famotidine (Pepcid)

        • Generally similar to cimetidine (Tagamet) and ranitidine (Zantac) however with a longer elimination  half-life

        • Dosage: (oral) 40 mg administered 1.5-3 hours preoperatively is likely effective in increasing gastric pH

      • Nizatidine (Axid): similar to the above agents in that 150-300 mg (oral) given about two hours before the procedure will reduce preoperative gastric pH

• ⁴Antacids: 

  • Overview: Antacids are exceedingly effective in increasing gastric fluid pH to > 2.5 when administered 15-30 minutes prior to anesthesia induction

    • An important factor in the affects the antacid efficacy is simply the extent of patient movement-with increased movement promoting more complete antacid mixing with the gastric fluid

  • Concerns associated with inhalation of gastric fluid containing antacids:

    • If aspiration does occur and gastric fluid containing antacid particulates is inhaled a possible significant inflammatory reaction may ensue which can cause significant pulmonary dysfunction.  

      • This possibility is an argument in favor of nonparticulate antacids such as sodium citrate (0.3 M) which also is effective in raising gastric fluid pH to  > 2.5 without producing significant pulmonary complication should inhalation of fluids occur. 

      • Pulmonary complications can include pulmonary edema and arterial hypoxemia.

  • Special advantages of antacids compared to H₂ receptor blockers: 

    • Administration of an antacid immediately increases gastric pH, without the lag time associated with histamine receptor blockers. 

    • The antacids, however, may increase gastric fluid volume, although this effect should not be interpreted as to discourage antacid use and is more likely to occur after repeated doses (such as during labor) and especially if opioids have been given which themselves delay the gastric emptying

  • As noted earlier for the receptor blockers, antacids need not be routinely used, but rather used for those selected patients who appear to have a higher risk for pulmonary aspiration.

    • ³Rationale: A large percentage of patients will exhibit gastric fluid volumes > 0.4 ml/kg  with a pH < 2.5 (about 3/4 of pediatric patients and about half of adult out-patients qualify)

      • However the likelihood of aspiration turns out to be very low.  

        • In one study of about 40,000 anesthetic procedures in children, aspiration was noted only four times (2 occasions intraoperatively and two occasions postoperatively).  [Tiret, L., Nivoche, Y, Hatton, F, et al:  Complications related to anesthesia in infants and children:  a prospective surbey of 40,240 anaesthetics.  Br J. Anaesth 1988:  61: 263]

        • In a separate study involving retrospective assessment of 185,000 procedures, 83 aspiration occurrences were noted resulting in an incidence rate of about 1 in 2000.  [Olsson, GL, Hallen, B.  Pharmacological evacuation of the stomach with metoclopramide.  Acta Anesth Scand, 1982; 26, 417]

          • For most of these cases (68 out of 83), other factors which would be expected to delay gastric emptying were noted. Therefore, an approach that involves routine premedication to avoid aspiration pneumonitis is difficult to support; however identification of risk factors IS important.

      • ³Risk factors for aspiration pneumonitis-- causative factors for gastric emptying delay:

        • Elevated intracranial pressure

        • Obesity

        • Gastritis or ulcer history

        • Emergency abdominal surgery

        • Pregnancy

        • Emergency surgery

        • Pain/stress

        • Elective upper abdominal surgery

      • ³Patients who should receive aspiration prophylaxis: (Table 34-6)

        • Anticipated challenging airway intubation

        • Emergency surgical patients

        • Trauma patients

        • Patients exhibiting reduced level of consciousness which may be caused by head trauma or drug overdosage

          • Intestinal obstruction

          • Elevated intracranial pressure due to mass effects or edema

          • Impaired laryngeal reflexes which could be caused by Shy-Drager syndrome (autonomic data), amyotrophic lateral sclerosis (Lou Gehrig's disease), vocal cord paralysis, stroke, bulbar palsy 

            • Bulbar palsy: bulbar refers to the lower brain stem, i.e. cranial nerves 7-12; palsy refers to weakness -- Therefore bulbar palsy refers to weakness of muscles controlled by cranial nerves 7-12.  

              • Manifestations could include difficulty in speaking, swallowing, coughing as well as difficulty with facial expressions. 

              • Bulbar palsy, therefore, may be manifestation of a number of diseases including Lou Gehrig's disease, stroke, or inflammatory disease.

          • Obesity

          • Ulcer disease including previous surgeries such as partial  gastrectomy or vagotomy the latter of which  would lead to gastroparesis due to the absence of cholinergic tone following nerve section. 

          • Hiatal hernia and reflux 

            • hiatal hernia -- definition: A hiatal hernia could be defined as a condition in which a portion of the stomach pushes through the diaphragm into the chest cavity. This condition is relatively common affecting about 15% of the population (U.S.) 

            • Reflux and hiatal hernias-- The size of the hiatal hernia predicts the likelihood of symptoms.  For large hernias the symptoms are almost always associated with gastro-esophageal reflux disease or GERD

              • GERD occurs because the hernia itself interferes with the lower esophageal sphincter which usually prevents gastric acid from refluxing into the esophagus.  GERD can occur in the absence of a hernia.

            • Gastric acid typically does not reflux into the esophagus for a couple of reasons 

              • (1) because the diaphragm muscle wraps around the region of the lower esophageal sphincter.  Therefore both the diaphragmatic muscle and the lower esophageal muscle contribute to blocking regurgitation.  In the presence of a hiatal hernia, says the lower esophageal sphincter is no longer in the region the diaphragm, the diaphragmatic pressure component is lost, making regurgitation more likely. T

              • he second reason (2) is that normally the esophagus enters the stomach at an angle, a fairly sharp angle, with a thin piece of tissue at this location forming a "valve". 

              • When the stomach protrudes through the diaphragm in hiatal hernia, the sharpness of the angle between the esophagus and stomach is significantly reduced with the concurrent reduction in the ability of the valve to prevent regurgitation.

          • Pregnancy

          • Upper abdominal surgery

          • Abdominal ascites/tumor

          • ³Gastric paresis (paralysis) caused by other sources including dialysis or diabetes

      • ³Choice of agents for prophylaxis of expected aspiration:

        • For trauma patients, sodium citrate (30 ml-raises the pH of gastric fluid already present); ranitidine (Zantac) by IV administration at a dosage of 50 mg; metoclopramide (Reglan), 20 mg by IV administration to facilitate gastric emptying.

        •  For preparation of elective surgery patients who have a difficult airway:

          • Ranitidine (Zantac) orally administered at a dosage of 150 mg at 7 p.m. and in the morning of surgery; metoclopramide (Reglan) at a dosage of 20 mg administered orally in the morning of surgery;  glycopyrrolate (Robinul),0.2 mg by IV administration to reduce secretions in support of fiberoptic bronchoscopy

• Proton pump inhibitors:

  • Overview:

    • Parietal cells H⁺ ion secretion depends on a H⁺,K⁺-ATPase pump-- promoting H⁺ K⁺ exchange

      • H+,K+-ATPase located in apical membraneto and tubulovesicular apparatus of parietal cells

      • Luminal surface of the membrane enzyme: exposed to gastric luminal acid

  • Specific drugs:

    • Omeprazole (Prilosec)

      • Dosage (adult):

        • Intravenous dosage is 40 mg administered 30 minutes prior to induction

        • The oral dose range is between 40 and 80 mg administered between 2 and 4 hours before the procedure

      • Mechanism of action: Omeprazole (Prilosec) and lansoprazole (Prevacid) bind "irreversibly" to the proton pump.  This action result in an extended duration of action, since new protein must be synthesized to reestablish proton secretion function.

      • Duration of action: The effect on gastric pH may be as long as 24 hours with variable effects on gastric volume (omeprazole (Prilosec))

.

• ¹Preoperative Medication in Basis of Anesthesia, 4th Edition, Stoelting, R.K. and Miller, R., p 119- 130, 2000) 

• Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives; Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc., 1996, pp. 364-367.

• ³Sno E. White The Preoperative Visit and Premedication in Clinical Anesthesia Practice pp.  576-583 (Robert Kirby and Nikolaus Gravenstein, eds) W.B.  Saunders Co., Philadelphia, 1994

• ⁴John R. Moyers and Carla M. Vincent Preoperative Medication in Clinical Anethesia, 4th edition (Paul G. Barash, Bruce. F. Cullen, Robert K. Stoelting, eds) Lippincott Williams and Wilkins, Philadelphia, PA, 2001

• ⁵Kathleen R. Rosen and David A. Rosen, "Preoperative Medication" pp. 61-70 in  Principles and Procedures in Anesthesiology (Philip L. Liu, ed) J. B. Lipincott Company, Philadelphia, 1992