Opioid Intravenous Anesthetics

The administration of opioids in the perioperative period is not without the concern of overdose. The major signs of overdose with opioids are miosis, hypoventilation, and coma. If the patient becomes severely hypoxemic, mydriasis can occur. Airway obstruction is a strong possibility because the skeletal muscles become flaccid. Hypotension and seizures can also occur. The treatment for an opioid overdose is mechanical ventilation and the slow titration of naloxone. Consideration must always be given to the fact that some patients who become overdosed with an opioid may indeed be already physically dependent. Naloxone can precipitate an acute withdrawal syndrome.²

Meperidine Hydrochloride

Meperidine (Demerol) was discovered in 1939 by Eisleb and Schauman. Because it is chemically similar to atropine, it was originally introduced as an antispasmodic agent and was not used as an opioid anesthetic agent until 1947. The main action of this drug is similar to morphine; it stimulates the subcortical mu receptors, which results in an analgesic effect. Meperidine is approximately one tenth as potent as morphine and has a duration of action of 2 to 4 hours. The onset of analgesia is prompt (10 minutes) after subcutaneous or intramuscular administration. All pain, especially visceral, gastrointestinal, and urinary tract, is satisfactorily relieved. This drug causes less biliary tract spasm than morphine; however, in comparison with codeine, meperidine causes greater biliary tract spasm. It produces some sleepiness but causes little euphoria or amnesia. Meperidine increases the sensitivity of the labyrinthine apparatus of the ear, which explains the dizziness, nausea, and vomiting that sometimes occur in ambulatory patients.^2,4

This opioid may slow the rate of respiration, but the rate generally returns to normal within 15 minutes after intravenous injection. The tidal volume is not changed appreciably. In equivalent analgesic doses, meperidine depresses respiration to a greater extent than does morphine. Some authors have noted that meperidine can release histamine from the tissues. Occasionally, urticarial wheals form over the veins where meperidine has been injected. The usual treatment is discontinuation of the use of meperidine and, if the reaction is severe, administration of diphenhydramine (Benadryl). Diphenhydramine further sedates the patient, however, and should be administered only if truly warranted.

Meperidine in therapeutic doses does not cause any significant untoward effects on the cardiovascular system. When this drug is administered intravenously, it usually causes a transient increase in heart rate. With intramuscular administration, no significant change in heart rate is observed. One of the major concerns with this drug is orthostatic hypotension, probably caused by meperidine’s interference with the compensatory sympathetic nervous system reflex. After administration of meperidine, a patient should be repositioned slowly in a “staged” approach to avoid any possibility of hypotension.

Meperidine is generally metabolized in the liver; less than 5% is excreted unchanged by the kidneys. However, because of a toxic metabolite of meperidine, patients who are administered this drug may have seizures.² Meperidine is partially metabolized to normeperidine, a metabolite that has some analgesic effects, but, more important, it lowers the seizure threshold and can induce central nervous system (CNS) excitability. Meperidine probably should not be administered to elderly patients because renal dyfunction may occur and the elderly have less tolerance to normeperidine.

Because of its spasmolytic effect, meperidine is the drug of choice for biliary duct, distal colon, and rectal surgery. It offers the advantages of little interference with the physiologic compensatory mechanisms, low toxicity, smooth and rapid recovery, prolonged postoperative analgesia, excellent cardiac stability in patients at poor risk, and ease of detoxification and excretion.^2,4,5 Meperidine has also been shown to decrease postoperative shivering. Currently, meperidine is used most often with procedures and not typically for long-term pain management because of the effects of normeperidine over time. Some hospitals have removed meperidine from the hospital formulary because of the adverse side effects.

Morphine

Morphine, one of the oldest known drugs, has only recently been used as an opioid intravenous anesthetic agent. Alkaloid morphine is from the phenanthrene class of opium. The exact mechanism of action of morphine is unknown. In humans, it produces analgesia, drowsiness, changes in mood, and mental clouding. The analgesic effect can become profound before the other effects become severe and can persist after many of the side effects have almost disappeared. With direct effect on the respiratory center, morphine depresses respiratory rate, tidal volume, and minute volume. Maximal respiratory depression occurs within 7 minutes after intravenous injection of the drug and 30 minutes after intramuscular administration. After therapeutic doses of morphine, the sensitivity of the respiratory center begins to return to normal in 2 or 3 hours, but the minute volume does not return to a preinjection level until 4 or 5 hours have passed.

The greatest advantage of morphine is the remarkable cardiovascular stability that accompanies its use. It has no major effect on blood pressure, heart rate, or heart rhythm—even in toxic doses—as long as hypoxia is avoided. Morphine does, however, decrease the capacity of the cardiovascular system to adjust to gravitational shifts. This effect is important to remember because orthostatic hypotension and syncope can easily occur in a patient whose care necessitates a position change. This phenomenon is primarily the result of the peripheral vasodilator effect of morphine. Therefore, a position change for a patient who has received morphine should be accomplished slowly with constant monitoring of the patient’s vital signs.

Morphine can cause nausea and vomiting, especially in ambulatory patients, because of its direct stimulation of the chemoreceptor trigger zone. The emetic effect of morphine can be counteracted with opioid antagonists and phenothiazine derivatives such as prochlorperazine (Compazine), dexmedetomidine (Precedex), or the 5-HT₃ receptor antagonist ondansetron (Zofran). Histamine release has been noted with morphine, and morphine also causes profound constriction of the pupils, stimulation of the visceral smooth muscles, and spasm of the sphincter of Oddi.^5–7

Morphine is detoxified by conjugation with glucuronic acid. Ninety percent is excreted by the kidneys, and 7% to 10% is excreted in the feces via the bile.²

Morphine is used in the balanced or nitrous-opioid technique with nitrous oxide, oxygen, and a muscle relaxant, although fentanyl is also commonly used. This technique is useful for cardiovascular surgery and other types of surgeries in which cardiovascular stability is necessary. The patient may arrive in the PACU still narcotized from morphine with an endotracheal tube in place. Mechanical ventilation for 24 to 48 hours is usually warranted. Morphine may or may not be supplemented during the time of ventilation. This type of recovery procedure facilitates a pain-free state and maximum ventilation of the patient during the critical phase of recovery. Morphine can also be used to provide basal narcosis when regional anesthesia is used.

In the PACU, morphine is an excellent drug for the control of postoperative pain. When given intravenously, this drug has a peak analgesic effect in approximately 20 minutes with a duration of approximately 2 hours. With intramuscular administration, the onset of action is approximately 15 minutes with a peak effect attained in 45 to 90 minutes and a duration of action of approximately 4 hours.

Methadone

Methadone was introduced in the late 1930s in Germany and in the 1940s in the United States. The drug was originally introduced to help treat chronic pain, opioid abstinence syndromes, and heroin addiction. It has seen a resurgence in popularity for clinical use in the PACU for pain relief.

Methadone undergoes slow metabolism and is high in lipid solubility, which makes it longer lasting than morphine-based drugs, with a duration of action up to 24 hours that allows for less frequent dosing. It is a good drug for treating chronic pain, especially in patients who are thought to have a propensity for drug dependence. Methadone can be administered orally and intravenously; when administered intravenously at a dose of 20 mg, methadone produces postoperative analgesia that lasts more than 24 hours.

The actions of this synthetic opioid agonist resemble morphine; side effects include depression of ventilation, miosis, constipation, and biliary tract spasm. Clinically, the sedative and euphoric actions of methadone appear to be less than those produced by morphine.⁵

Hydromorphone

Hydromorphone (Dilaudid), which is a derivative of morphine, was developed in Germany in the 1920s and released to the mass market in the late 1920s. The drug has a renewed popularity for the PACU and can be administered intravenously, intramuscularly, rectally, or orally. The drug profile with regard to its analgesia and side effects is similar to morphine. Hydromorphone is recommended for patients in renal failure because of its virtual lack of active metabolites after its breakdown in the liver. It has a high solubility and a rapid onset of action and appears to have less troublesome side effects and dependence liability profile compared with morphine. Because of its high lipid solubility, hydromorphone can be administered via epidural or spinal for a wide area of anesthesia compared with Duramorph.²

Hydromorphone, like all opioids, is a CNS depressant and has actions and side effects similar to morphine. Its depressant effects can be enhanced with beta-blockers and alcohol. The duration of action of this drug is approximately 2 hours, with a peak action in approximately 30 minutes with intravenous administration.

Fentanyl

Janssen and colleagues introduced a series of highly potent meperidine derivatives that were found to render the patient free of pain without affecting certain areas in the CNS.⁸ Fentanyl (Sublimaze) appeared to be of special interest. With regard to analgesic properties, fentanyl is approximately 80 to 125 times more potent than morphine and has a rapid onset of action of 5 to 6 minutes and a peak effect within 5 to 15 minutes. The analgesia lasts 20 to 40 minutes when administered intravenously. Via the intramuscular route, the onset of action is 7 to 15 minutes; the analgesia usually lasts 1 to 2 hours. When fentanyl is administered as a single bolus, 75% of the drug undergoes first-pass pulmonary uptake. That is, the lungs serve as a large storage site, and this nonrespiratory function of the lung (see Chapter 12) limits the amount of fentanyl that actually reaches the systemic circulation. If the patient receives multiple doses of fentanyl via single injections or infusion, the first-pass pulmonary uptake mechanism becomes saturated, and the patient has a prolonged emergence because of increased duration of the drug. Consequently, during the admission of the patient to the PACU, the postanesthesia nurse must determine the frequency and amount of intraoperative fentanyl administration. Patients who have received a significant amount of fentanyl via infusion or titration should be continuously monitored for persistent or recurrent respiratory depression. In addition, fentanyl has been implicated in what is called a delayed-onset respiratory depression. In some patients, a secondary peak of the drug concentration in the plasma occurs approximately 45 minutes after the apparent recovery from the drug. This syndrome can occur when some of the fentanyl becomes sequestered in the gastric fluid and then recycles into the plasma in approximately 45 minutes. Therefore, in the PACU, all patients who have received fentanyl should be continuously monitored for respiratory depression for at least 1 hour from the time of admission to the unit.²

Fentanyl can be administered during surgery at three different dose ranges depending on the type of surgery and the desired effect. For example, the low-dose range of 2 to 20 mcg/kg attenuates moderately stressful stimuli. The moderate dose range is 20 to 50 mcg/kg and strongly obtunds the stress response. The megadose range of as much as 150 mcg/kg blocks the stress response and is particularly valuable when protection of the myocardium is critical.⁴

Fentanyl shares with most other opioids a profound respiratory depressant effect, even to the point of apnea. Rapid intravenous injection can provoke bronchial constriction and resistance to ventilation caused by rigidity of the diaphragmatic and intercostal muscles. This is commonly called the fixed chest syndrome, which can occur when any potent opioid analgesic is administered too rapidly via the intravenous route. Should this syndrome occur, intravenous subclinical administration of succinylcholine (15 to 25 mg) relieves the rigidity of the chest wall muscles. When succinylcholine is administered for this purpose, the perianesthesia nurse should be prepared to ventilate the patient’s lungs until the skeletal muscle relaxant properties of succinylcholine subside.

Table 22.2

Example of Conversion of Dosage Calculations from Milligrams to Micrograms

Milligrams	Micrograms	Milliliters of Fentanyl (50 mcg/1mL)
0.025	25	0.5
0.05	50	1.0
0.10	100	2.0
0.15	150	3.0
0.20	200	4.0
0.25	250	4.5
0.50	500	10.0
1.00	1000	20.0

Fentanyl, unlike most opioids, has little or no hypotensive effects and usually does not cause nausea and vomiting. Because of its vagotonic effect, it may cause bradycardia, which can be relieved with atropine or glycopyrrolate. Fentanyl can be reversed with the opioid antagonist naloxone, which also reverses analgesia. Should fentanyl be reversed with naloxone in the PACU, the perianesthesia nurse should continue to monitor the patient for the possible return of respiratory depression, because the duration of the respiratory depression produced by the fentanyl may be longer than the duration of action of naloxone.

Fentanyl can be used alone in a nitrous-opioid technique. It also is used in the PACU in the form of a low-dose intravenous drip for pain relief; however, fentanyl is usually given slowly intravenously in the PACU for breakthrough pain (Table 22.2 for helpful calculation of milligram to microgram dosage information).

Sufentanil

Sufentanil is an analog of fentanyl and is approximately fivefold to sevenfold more potent than fentanyl. Anesthesia with sufentanil can be induced more rapidly with basically the same technique as that used for fentanyl without an increase in the incidence rate of chest wall rigidity. However, sufentanil can produce chest wall rigidity; therefore, if it is administered in the PACU, equipment for administration of oxygen with positive pressure and the skeletal muscle relaxant succinylcholine should be on hand. The incidence rate of hypertension with sufentanil is lower than with comparable doses of fentanyl. Bradycardia is infrequently seen in patients who receive sufentanil, and when high-dose sufentanil is used in combination with nitrous oxide-oxygen, the mean arterial pressure and cardiac output may be decreased. The recovery time from sufentanil from the time of injection is about the same as with fentanyl, because sufentanil is rapidly eliminated from tissue storage sites; consequently, the duration of action of sufentanil is about the same as with fentanyl. In addition, the incidence rates of postoperative hypertension, the need for vasoactive agents, and the requirements for postoperative analgesics are generally reduced in patients who are administered moderate or high doses of sufentanil in comparison with patients given inhalation agents. Of particular interest to the perianesthesia nurse is that sufentanil has an additive effect seen in patients who receive barbiturates, tranquilizers, other opioids, general anesthetics, or other CNS depressants. This effect is especially true of benzodiazepines because they can potentiate a profound hypotensive action. Therefore, when sufentanil is combined with any of these drugs, particular attention should be paid to any signs of decreased respiratory drive, increased airway resistance, or hypotension. Immediate countermeasures include maintenance of a patent airway with proper positioning of the patient, placement of an oral airway or endotracheal tube, and administration of oxygen. If indicated, naloxone should be used as a specific antidote for management of the respiratory depression. The duration of respiratory depression after overdose with sufentanil may be longer than the duration of action of the naloxone. Consequently, the patient should be constantly observed for the recurrence of respiratory depression even after the initial successful treatment with naloxone. Hypotension can be treated with reversal with naloxone; however, fluids and vasopressors may be indicated (see Chapter 11).⁴

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