Handbook of Clinical Anesthesia

Chapter 19


Opioid is an all-inclusive term that describes drugs (natural and synthetic) and endogenous peptides that bind to morphine receptors (Coda BA: Opioids. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 465–497). The term opioid includes drugs that are agonists, agonist-antagonists, and antagonists. Opiate is often used interchangeably with opioid but historically designates only drugs derived from opium (morphine, codeine). Narcotic is a nonspecific designation applicable to any drug that produces sleep.

  1. Endogenous Opioids and Opioid Receptors (Table 19-1)
  2. All of the endogenous opioids are derived from prohormones, and each of these precursors is encoded by a separate gene. Synthesis of endorphins is from a prohormone principally located in the anterior pituitary. Endogenous opioids bind to a number of opioid receptors to produce their effects.
  3. The expression of endogenous opioids and opioid receptors is not a static phenomenon.
  4. Acute inflammation up-regulates the expression of peripheral µand ∂-opioid receptors. Chronic inflammation is associated with a down-regulation of µ-opioid receptors.
  5. All opioid receptors appear to be coupled to G proteins, which regulate the activity of adenylate cyclase and subsequent ion channel conduction characteristics.


Table 19-1 Classification of Opioid Receptors and Actions










Slowed gastric emptying


Skeletal muscle rigidity
Possibly urinary retention
Biliary spasm





Prolactin turnover

Acetylcholine release




Slowed gastric emptying


Cardiovascular effects







Decreased ADH release













Possibly depression

Slowed gastric emptying

Possibly growth hormone release

Possibly urinary retention






Dopamine turnover



Unknown receptor and subtype






ADH = antidiuretic hormone.


  1. Pharmacokinetics and Pharmacodynamics
  2. Physicochemical propertiesof opioids influence both pharmacokinetics and pharmacodynamics (Table 19-2).
  3. To reach its sites of action (receptors on neuronal cell membranes in the central nervous system [CNS]), an opioid must cross the blood–brain barrier.
  4. The ability of opioids to cross the blood–brain barrier depends on properties such as molecular size, ionization, lipid solubility, and protein binding.
  5. The degree of ionization depends on the pKa of the opioid and the pH of the tissue (nonionized drugs are 1000 to 10,000 times more lipid soluble than the ionized form).
  6. The major plasma proteins to which opioids bind are albumin and alpha1-acid glycoprotein.
  7. Biotransformationand excretion are the principal mechanisms for elimination of opioids.
  8. Opioids are metabolized in the liver (conjugation, oxidative and reductive reactions) or hydrolyzed in the plasma (unique for remifentanil).
  9. With the exception of the N-dealkylated metabolite of meperidine and the 6- and possibly 3-glucuronides of morphine, opioid metabolites are generally inactive.
  10. Opioid metabolites, and to a lesser extent, parent compounds are excreted by the kidneys. The biliary system and gastrointestinal (GI) tract are less important routes of opioid excretion.

III. Morphine

Morphine mimics the effects of endogenous opioids by acting as an agonist at µ1- and µ2-opioid receptors throughout the body and is considered the agonist with which other µ agonists are compared (Tables 19-3 and 19-4).

  1. Analgesia
  2. Morphine analgesia results from complex interactions at a number of discrete sites in the brain, spinal cord, and under certain conditions, peripheral tissues, and involves bothµ1- and µ2-opioid effects.


Table 19-2 Physicochemical Characteristics and Pharmacokinetics of Commonly Used Opioid Agonists















Nonionized (pH, 7.4) (%)







Protein binding (%)







Clearance (mL/min)







Volume of distribution (steady state, L)







Elimination half-time (hr)








Table 19-3 Relative Potencies and Plasma Concentrations for Various Opioid Effects








Relative potencies







Analgesic dose (mg)







Minimum effective analgesic concentration (ng/mL)







Moderate to strong analgesia (ng/mL)







Decrease MAC 50% (ng/mL)







Surgical analgesia with 70% nitrous oxide (ng/mL)







Depression of ventilation threshold (ng/mL)







Ventilatory response to carbon dioxide decreased 50% (ng/mL)







Apnea (ng/mL)







Unconsciousness (not reliably achieved with opioids alone) (ng/mL)







MAC = minimum alveolar concentration; NA = not available.


Table 19-4 Effects of Opioid Agonists*

Central Nervous System (Brain and Spinal Cord)
Depression of ventilation (increased PaCO2 [decreased ventilatory response to CO2 because of brain stem depression] and decreased breathing rate and minute ventilation)
Nausea and vomiting (stimulation of the chemoreceptor trigger zone, especially in ambulatory patients; high doses of opioids depress the vomiting center and may overcome the chemoreceptor trigger zone stimulating effect)
Miosis (diagnostic of opioid administration)
Depressed cough reflex
Skeletal muscle rigidity
Myoclonus (may be confused with seizures)
Gastrointestinal Tract
Slowed gastric emptying
Increased tone of the common bile duct and sphincter of Oddi (reversed by nitroglycerin [as is angina] or naloxone [not angina]; can prevent visualization of contrast material in the duodenum, resulting in the erroneous conclusion that the common bile duct is blocked by a stone)
Genitourinary Tract
Urinary retention
Endocrine System
Antidiuretic hormone release
Autonomic Nervous System
Arterial and venous vasodilation (orthostatic hypotension)
Bradycardia (sympatholytic and parasympathomimetic mechanisms)
Histamine Release (morphine and meperidine are probably not mediated by opioid receptors)

*Similar for all opioid agonists, but the magnitude of effect of equianalgesic doses may differ.

  1. Supraspinal opioid analgesia originates in the periaqueductal gray matter, the locus ceruleus, and nuclei within the medulla and primarily involves µ1-opioid receptors.
  2. At the spinal cord level, morphine acts presynaptically on primary afferent nociceptors to decrease


the release of substance P. Morphine also hyperpolarizes interneurons in the substantia gelatinosa of the dorsal spinal cord to decrease afferent transmission of nociceptive impulses. Spinal morphine analgesia is mediated by µ2-opioid receptors.

  1. Peripheral analgesia produced by morphine is most likely attributable to activation of opioid receptors on primary afferent neurons, which occurs only when inflammation is present.
  2. The minimum effective analgesic concentration of morphine for postoperative pain relief is 10 to 15 ng/mL. (This is more likely to be maintained by patient-controlled analgesia than by intermittent intravenous [IV] or intramuscular [IM] injections; Table 19-3).
  3. Effect on Minimum Alveolar Concentration of Volatile Anesthetics
  4. The µagonists are used extensively in conjunction with nitrous oxide with or without a volatile anesthetic to produce “balanced anesthesia.”
  5. Morphine (1 mg/kg IV) administered with 60% inhaled nitrous oxide blocks the adrenergic response to surgical skin incision in 50% of patients (MAC-BAR).
  6. Neuraxial morphine may also decrease minimum alveolar concentration (MAC).
  7. Other Central Nervous System Effects.Morphine can produce sedation as well as cognitive and fine motor impairment, even at plasma concentrations commonly achieved during management of moderate to severe pain.
  8. Respiratory Depression
  9. Morphine and other µagonists produce dose-dependent ventilatory depression primarily by decreasing the response of the medullary respiratory center to carbon dioxide.
  10. Frequent periods of oxygen desaturation associated with obstructive apnea, paradoxical breathing, and slow respiratory rate may occur in patients who are sleeping and who receive morphine infusions for postoperative analgesia. Sleep apnea increases the risk of morphine-induced respiratory depression.
  11. Cardiovascular Effects
  12. In doses typically used for pain management or as part of balanced anesthesia, morphine has little


effect on blood pressure or heart rate and cardiac rhythm in supine normovolemic patients.

  1. Large doses may produce peripheral vasodilation (central sympatholytic activity), especially in patients with high sympathetic nervous system tone (congestive heart failure, severe trauma). Hypotension may reflect sympatholysis and histamine release.
  2. Morphine does not depress myocardial contractility but does produce bradycardia probably by both sympatholytic and parasympathomimetic mechanisms.
  3. In clinical anesthesia practice, opioids are often used for cardiac surgery to prevent tachycardia and decrease myocardial oxygen demand.
  4. Morphine (40 mg) suppresses several components of the inflammatory response to cardiopulmonary bypass.
  5. Morphine does not directly affect cerebral circulation as long as drug-induced depression of ventilation with retention of carbon dioxide (would produce cerebral vasodilation) is prevented by mechanical support of breathing.
  6. Disposition Kinetics.After IM administration of morphine, peak plasma concentration is seen at 20 minutes.
  7. Active Metabolites
  8. Morphine's major metabolic pathway is conjugation in the liver to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The importance of extrahepatic sites of glucuronidation (kidneys, lungs, GI tract) in humans is unknown.
  9. M6G possesses significant µ-receptor affinity and potent antinociceptive activity.
  10. Sensitivity of renal failure patients to morphine may reflect the dependence of M6G on renal excretion.
  11. Dosage and Administration of Morphine
  12. Morphine crosses the blood–brain barrier relatively slowly because of its hydrophilicity.
  13. Because of its delayed onset of action, morphine can be more difficult to titrate as an anesthetic supplement than the more rapidly acting opioids.
  14. Meperidine
  15. Analgesia and Effect on Minimum Alveolar Concentration of Volatile Anesthetics


  1. Meperidine's analgesic potency is about one tenth that of morphine's and is most likely mediated by µ-opioid receptor activation.
  2. Unlike morphine, meperidine's plasma concentrations correlate with its analgesic effects (Table 19-3).
  3. Meperidine is unique among the opioids in also possessing a weak local anestheticproperly, which is useful for neuraxial administration.
  4. Side effectsresemble those of morphine (Table 19-4).
  5. High doses of meperidine are associated with CNS excitement (seizures) and decreased myocardial contractility (hypotension).
  6. The increase in common bile duct pressure occurs to a lesser extent than with equianalgesic doses of morphine and fentanyl.
  7. Shivering.Meperidine (25–50 mg IV) is effective in decreasing postoperative shivering; equianalgesic doses of morphine and fentanyl are not effective. The observation that drugs other than opioids (e.g., clonidine, serotonic antagonists, propofol, physostigmine) reduce postoperative shivering suggest that a nonopioid mechanism may be involved.
  8. Disposition Kinetics(Table 19-2)
  9. After IV administration, meperidine plasma concentrations decrease rapidly.
  10. Meperidine is metabolized mainly in the liver by N-demethylation to form normeperidine, the principal metabolite, and by hydrolysis to form meperidinic acid.
  11. Active Metabolites.Normeperidine has pharmacologic activity and can produce signs of CNS excitation (daily doses >1000 mg increase the risk of seizures).
  12. Dosage and Administration of Meperidine(Table 19-3)
  13. Methadone

Methadone is a synthetic µ-opioid receptor agonist that possesses a long elimination half-time. The drug is most often used for long-term pain management (10 mg is similar to morphine) and in treatment of abstinence syndrome.

  1. Side effectsare similar in magnitude and frequency to those of morphine.
  2. Disposition Kinetics.Methadone is well absorbed after oral administration and reaches peak plasma concentration at 4 hours after oral administration.


  1. Dosage and Administration of Methadone.Patients with significant pain have no depression of respiration or level of consciousness.
  2. Fentanyl

Fentanyl and its related µ-opioid receptor analogs sufentanil and alfentanil are the most frequently used opioids in clinical practice. The clinical potency of fentanyl is 50 to 100 times that of morphine, and there is a direct relationship between plasma concentrations and analgesia (Table 19-3).

  1. Use in Anesthesia
  2. Plasma fentanyl concentrations decrease rapidly after a single IV injection, so the magnitude of MAC reduction varies depending on the time after fentanyl administration. (Computer-assisted continuous infusion provides a constant plasma concentration and associated decrease in anesthetic requirements.)
  3. Combining opioids with propofol rather than an inhaled anesthetic can produce general anesthesia (total IV anesthesia). Plasma concentrations of fentanyl and propofol that prevent responses to skin incision in 50% of patients have been determined.
  4. Fentanyl has been used as the sole drug for anesthesia (50–150 µg/kg IV or a stable plasma concentration in the range of 20–30 ng/mL) because hemodynamic stability is desirable for patients with heart disease.
  5. When administered rapidly intravenously, high doses of opioids can produce skeletal muscle rigidity.
  6. Combining opioids with other depressant drugs (nitrous oxide, benzodiazepines) changes the stable hemodynamic profile of the opioid alone, and hypotension can occur.
  7. Other Central Nervous System Effects
  8. The effect of fentanyl on intracranial pressure (ICP) is inconsistent with some reports showing an increase and others no change.
  9. Fentanyl has been associated with seizure-like movements (most likely myoclonus), but seizure activity is not present on the electroencephalogram.
  10. Fentanyl-induced pruritus often presents as facial itching but can be generalized (similar with sufentanil and alfentanil).


  1. Respiratory Depression
  2. Peak depression of ventilation occurs in about 5 minutes and parallels the plasma concentration and intensity of analgesia (Table 19-3).
  3. The magnitude of respiratory depression can be greatly increased when fentanyl is administered with another sedative drug such as a benzodiazepine.
  4. Airway Reflexes
  5. Similar to the volatile anesthetics, opioids depress airway reflexes elicited in response to laryngeal stimulation (placement of a laryngeal mask airway).
  6. Cough is the laryngeal reflex that is most vulnerable to depression by fentanyl.
  7. Cardiovascular and Endocrine Effects
  8. In clinical practice, high-dose fentanyl administration is associated with remarkable hemodynamic stability. (Combination with other anesthetic drugs may result in cardiovascular depression.)
  9. Hypertension in response to median sternotomy is the most common hemodynamic disturbance during high-dose fentanyl anesthesia.
  10. Unlike morphine and meperidine, which induce hypotension, at least partly by histamine release, high-dose fentanyl is not associated with significant histamine release.
  11. Smooth Muscle and Gastrointestinal Effects.Similar to morphine and meperidine, fentanyl increases common bile duct pressure. Fentanyl can cause nausea and vomiting, especially in ambulatory patients, and can delay gastric emptying.
  12. Disposition Kinetics(Table 19-2)
  13. Fentanyl's high lipid solubility allows it to cross biologic membranes rapidly (rapid onset) followed by redistribution to inactive tissue sites such as skeletal muscle and fat (short duration). High doses or prolonged administration of fentanyl can saturate redistribution sites, converting this drug to a long-acting opioid.
  14. Clearance of fentanyl is primarily by hepatic metabolism (N-dealkylation to norfentanyl and hydroxylation of both the parent compound and norfentanyl).
  15. A patient with respiratory acidosis will have a higher proportion of unbound (active) fentanyl.
  16. Dosage and Administration of Fentanyl(Table 19-3)
  17. Fentanyl can be used as a sedative/analgesic premedication when given a short time before induction of


anesthesia (25–50 µg IV or transmucosal delivery system for pediatric and adult patients). Respiratory depression can occur, emphasizing the need to monitor patients treated with these doses of fentanyl.

  1. Fentanyl is commonly used as an adjunct to induction drugs to blunt the hemodynamic response to laryngoscopy and tracheal intubation. Because fentanyl's peak effect lags behind the peak plasma concentration by 3 to 5 minutes, fentanyl should be administered about 3 minutes before initiating laryngoscopy.
  2. Perhaps the most common use of fentanyl and its derivatives is as an analgesic component of balanced general anesthesia (0.5–2.5 µg/kg IV as dictated by the intensity of the surgical stimulus or 2–10 µg/kg/hr as a continuous infusion).
  3. High-dose fentanyl (50–150 µg/kg IV) may be used as the sole anesthetic for cardiac surgery. (It may not provide total amnesia in healthy patients.)
  4. Fentanyl has been used as an analgesic in the management of acute and chronic pain. Both transdermal and transmucosal fentanyl delivery systems are effective for relief of cancer pain.

VII. Sufentanil

Sufentanil is a highly selective and potent (10 to 15 times that of fentanyl) µ-opioid receptor agonist that equilibrates rapidly between the blood and the brain.

  1. Use in Anesthesia
  2. Sufentanil, similar to other opioids, produces a dose-dependent decrease in the MAC of volatile anesthetics.
  3. In clinical practice, sufentanil is used as a component of balanced anesthesia and in high doses (10–30 µg/ kg IV) for cardiac surgery. (Similar to fentanyl, sufentanil does not completely block the hemodynamic response to noxious stimuli.)
  4. Other central nervous system effectsresemble those of fentanyl.
  5. Respiratory depressionresembles other µ-opioid receptor agonists and can be especially marked in the presence of inhaled anesthetics.
  6. Disposition Kinetics(Table 19-2)
  7. Sufentanil is highly lipid soluble and has pharmacokinetic properties that resemble fentanyl. Because of


its higher degree of ionization at physiologic pH and higher degree of plasma protein binding, its volume of distribution is somewhat smaller and its elimination half-time shorter than those of fentanyl. Obesity may increase the volume of distribution and prolong the elimination half-time of sufentanil.

  1. Clearance of sufentanil (similar to fentanyl) is rapid, primarily by hepatic metabolism (N-dealkylation and O-demethylation).
  2. Dosage and Administration of Sufentanil(Table 19-3)
  3. Sufentanil (similar to fentanyl) is most often used as a component of balanced anesthesia or in high doses for cardiac surgery (≤50 µg/kg IV).
  4. Doses in the range of 0.3 to 1.0 µg/kg IV given 1 to 3 minutes before laryngoscopy can be expected to blunt hemodynamic responses to tracheal intubation.
  5. For maintenance of balanced anesthesia, sufentanil can be administered in intermittent doses (0.1–0.5 µg/kg IV) or as a continuous infusion (0.3–1.0 µg/kg/hr IV).

VIII. Alfentanil

Alfentanil is a µ-opioid receptor agonist with a potency approximately 10 times that of morphine and one fourth to one tenth that of fentanyl. In contrast to fentanyl and sufentanil, the duration of even very large doses of alfentanil is brief, necessitating its administration by continuous infusion if a sustained effect is desired.

  1. Nausea and Vomiting.Clinical comparisons between alfentanil and sufentanil or fentanyl and nitrous oxide reveal a similar incidence of nausea and vomiting.
  2. Disposition Kinetics(Table 19-2)
  3. Alfentanil pharmacokinetics differ from fentanyl and sufentanil with respect to pK (alfentanil 6.8 and all other opioids above 7.4). This results in 90% of unbound plasma alfentanil being unionized at a plasma pH of 7.4. This property, together with moderate lipid solubility, enables alfentanil to rapidly cross the blood–brain barrier (with a blood–brain equilibration half-time of 1.1 minutes versus >6 minutes for fentanyl and sufentanil) and accounts for its rapid onset of action.


  1. Alfentanil has a smaller volume of distribution than fentanyl, which is a result of its lower lipid solubility and high protein binding (about 92%, mostly to α1-acid glycoprotein).
  2. Plasma alfentanil concentrations decrease rapidly (90% of an administered dose has left the plasma by 30 minutes) because of rapid distribution to tissues. After a single IV dose, redistribution is the most important mechanism for recovery, but after a very large dose, repeated small doses, or a continuous infusion, elimination are a more important determinant of the duration of alfentanil's effects.
  3. Clearance of fentanyl is only half that of fentanyl, but because its volume of distribution is four times smaller than fentanyl's, more alfentanil is available to the liver for metabolism (cirrhosis slows elimination of alfentanil). Alfentanil undergoes N-dealkylation and O-demethylation in the liver to form inactive metabolites.
  4. Dosage and Administration of Alfentanil(Table 19-3)
  5. Because of its rapid onset of action, alfentanil has been used for the induction of anesthesia (120 µg/kg IV produces unconsciousness in 2.0 to 2.5 minutes but may also be associated with skeletal muscle rigidity).
  6. With 2.5 mg/kg of propofol, an alfentanil dose of 10 µg/kg appears optimal for laryngeal mask insertion but is accompanied by apnea for about 2 minutes.
  7. Remifentanil

Remifentanil is an ultra short-acting µ-receptor opioid agonist that is unique among the opioids in that it contains a methyl ester side chain that is susceptible to hydrolysis by blood and tissue esterases. (It is ultrashort acting because of metabolism rather than redistribution.)

  1. Analgesiaproduced by remifentanil 1.5 µg/kg IV and alfentanil 32 µg/kg IV is similar in magnitude and duration (about 10 minutes).
  2. Use in Anesthesia
  3. The rapid onset and brief duration of action of remifentanil suggest that this opioid may be suitable for induction of anesthesia, yet a high incidence of skeletal muscle rigidity and purposeless movements have been described.


  1. At doses above 1 µg/kg IV, brief increases in blood pressure and heart rate occur, but histamine release does not occur.
  2. Pediatric patients require twice as much remifentanil as adults (0.15 µg/kg/min vs. 0.08 µg/kg/min) when it is used with propofol for total IV anesthesia.
  3. Recovery from remifentanil is rapid with return of spontaneous ventilation in 2 to 5 minutes, but the disadvantage is that patients may require analgesics soon after remifentanil is discontinued.
  4. The rapid onset and brief duration of remifentanil make this opioid suitable for combination with other injected drugs (propofol) to provide total IV anesthesia.
  5. Remifentanil produces dose-dependent nausea and vomiting similar to those of other short-acting µ-opioid agonists.
  6. Remifentanil is frequently administered with propofol to provide total IV anesthesia. Fixed infusion rates or computer-controlled systems, or target-controlled infusions, that provide target plasma concentrations may be used.
  7. As with other opioids, higher rates of respiratory depression occur when propofol is combined with remifentanil.
  8. Disposition Kinetics(Table 19-2)
  9. The key structural feature of remifentanil is the ester side chain that is susceptible to hydrolysis by blood and tissue esterases, resulting in rapid metabolism (elimination half-time, 10–20 minutes).
  10. Because the short duration of action is attributable to metabolism rather than redistribution, remifentanil should be less likely to accumulate with repeated dosing or prolonged infusion.
  11. Pharmacokinetic parameters of remifentanil are unchanged by hepatic or renal disease. Nevertheless, patients with hepatic disease appear to be more sensitive to remifentanil-induced respiratory depression.
  12. Advanced age is associated with a decrease in clearance and volume of distribution of remifentanil as well as an increase in potency.
  13. Dosage and Administration of Remifentanil.Because of its short duration of action, remifentanil is best


administered as a continuous IV infusion in combination with another anesthetic drug to produce general anesthesia.

  1. Induction Dosage, Intubation, and LMA Placement.The most common remifentanil-based regimen for anesthetic induction and laryngoscopy consists of remifentanil 0.5 to 1.0 µg/kg IV administered over 60 seconds plus propofol 1 to 2 mg/kg IV followed by remifentanil infusion of 0.25 to 0.5 µg/kg/min IV (with or without midazolam premedication).
  2. Maintenance of General Anesthesia
  3. In combination with 70% nitrous oxide, remifentanil 0.6 µg/kg/min IV is generally adequate. (There is a wide range of infusion rates.)
  4. A disadvantage of remifentanil related to its short duration of action is that patients may experience substantial pain on emergence from anesthesia.
  5. Monitored Anesthesia Care
  6. Remifentanil can be used as an adjunct for sedation or analgesia during regional anesthesia (0.5–1.0 µg/kg/min IV), for block placement (retrobulbar block preceded by remifentanil 1.0 µg/kg IV 90 seconds before the block), and as part of monitored anesthetic care (colonoscopy).
  7. The dose requirement for remifentanil for sedation and analgesia is decreased when the opioid is combined with midazolam (as much as 50%) or propofol.
  8. The risk of excessive depression of ventilation or development of chest rigidity after a bolus dose of remifentanil can be minimized by injecting the dose over 30 seconds.
  9. Partial Agonists and Mixed Agonist–Antagonists (Table 19-5)

The partial agonist and mixed agonist–antagonist opioids are synthetic or semisynthetic compounds that are structurally related to morphine. These drugs are characterized by binding activity at multiple opioid receptors and differential effects (agonist, partial agonist, antagonist) at each receptor type. The major clinical use of these drugs is the provision of postoperative analgesia, but they have also been used for intraoperative sedation, as adjuncts


during general anesthesia, and to antagonize some of the effects of µ receptor agonists.

Table 19-5 Receptor Effects and Relative Potencies of Opioid Agonists–Antagonists


µ Receptor

K Receptor

Relative Potency*

Analgesic Dose (mg)


Partial agonist

Partial agonist




Partial agonist

Partial agonist




Partial agonist

Possibly an antagonist



*Morphine's relative potency is 1.

  1. Nalbuphine
  2. The modest ability of this drug to decrease MAC (8% vs 65% for morphine) suggests that nalbuphine may not be a useful adjunct for general anesthesia.
  3. Analgesia (mediated by Kand µ receptors) and associated depression of ventilation (mediated by µ receptors) produced by nalbuphine have a ceiling effect. Nalbuphine has been used to antagonize the ventilatory depressant effects of µ agonists while still providing analgesia by K receptor stimulation.
  4. Butorphanol
  5. This drug has partial agonist activity at µ and Kopioid receptors (similar to nalbuphine). Compared with nalbuphine and similar drugs, butorphanol has a pronounced sedative effect, which is probably mediated by K receptors.
  6. Increases in intrabiliary pressure do not occur, and this drug may be effective in treatment of postoperative shivering.
  7. Butorphanol is indicated for sedation as well as treatment of moderate to severe postoperative pain.
  8. Buprenorphine
  9. Buprenorphine is a highly lipid-soluble thebaine derivative that is 25 to 50 times more potent than morphine. Slow dissociation from µ receptors can lead to prolonged effects that are not easily antagonized by naloxone.


  1. Unlike nalbuphine and butorphanol, buprenorphine does not seem to possess agonist activity at Kreceptors. (It may act as an antagonist at these receptors.)
  2. Opioid Antagonists (Naloxone and Naltrexone)
  3. Naloxoneis a pure antagonist at µ, K, and ∂-opioid receptors.
  4. In clinical practice, naloxone is administered to antagonize opioid-induced respiratory depression and sedation.
  5. Because opioid antagonists reverse all opioid effects, including analgesia, naloxone should be carefully titrated (20–40 µg IV produces peak effects in 1 to 2 minutes) to avoid producing sudden, severe pain in postoperative patients.
  6. Sudden, complete antagonism of opioid effects can cause hypertension, tachycardia, ventricular cardiac dysrhythmias, and pulmonary edema.
  7. Pulmonary edema can occur in the absence of heart disease and is thought to reflect centrally mediated catecholamine release causing acute pulmonary hypertension.
  8. Naloxone precipitates opioid withdrawal symptoms in opioid-dependent individuals.
  9. Because naloxone has a short duration of action (1 to 4 hours), depression of ventilation may recur if large systemic doses of opioids or long-acting opioid agonists or neuraxial opioids have been administered. When prolonged depression of ventilation is anticipated, an initial loading dose of naloxone followed by a continuous IV infusion (3–10 µg/kg/hr) can be used.
  10. Naltrexoneis a long-acting oral antagonist of opioid effects.

XII. Use of Opioids in Clinical Anesthesia (Tables 19-6 and 19-7)

  1. Opioids are used alone or in combination with other drugs, such as sedatives or anticholinergics, as pharmacologic preoperative medication.
  2. Intraoperatively, opioids are administered as components of balanced anesthesia or alone in high doses.


Table 19-6 Clinical Uses of Opioids

Induction of anesthesia (sole drug or adjuvant)
Blunt hemodynamic responses to noxious stimulation (alfentanil has the most rapid blood–brain equilibration time)
Intraoperative analgesia
Postoperative pain relief (patient-controlled analgesia, neuraxial, parenteral)
Adjuvant to facilitate mechanical ventilation and tolerance to tracheal tube

  1. Fentanyl and its derivatives sufentanil and alfentanil are the opioids most often used as supplements to general anesthesia. (They are more easily titrated than morphine because of their rapid onsets of action.)

Table 19-7 Dosage for Opioid Agonists in Elective Surgery in Adults

Anesthetic Phase





Premedication (µg)






With hypnotic (µg/kg)




0.5–1.0 or 0.25–0.5 µg/kg/min

With 60–70% N20 (µg/kg)





High-dose opioid (µg/kg)




2.5 or 2 µg/kg/min


Balanced anesthesia






   Infusion (µg/kg/min)





High dose opioid (µg/kg/min)





Transition to PACU(µg/kg/min)





Monitored Anesthesia Care

Intermittent bolus (µg/kg)





Infusion (µg/kg/min)





  1. P.287

Figure 19-1. Overlay of the fentanyl, alfentanil, and sufentanil recovery curves describing the time required for decreases of 20% (A), 50% (B), and 80% (C) from the maintained intraoperative effect site concentration after termination of the infusion.

  1. P.288

Figure 19-2. A simulation of the time necessary to achieve a 50% decrease in drug concentration in the blood after variable-length intravenous infusions of opioids.

  1. Important pharmacokinetic differences among opioids include volumes of distribution and intercompartmental (distributional) and central (elimination) clearances.
  2. The major pharmacodynamic differences among these opioids are potency and equilibration time between the plasma and the site of drug effect. (Brain–blood equilibration times are more rapid with alfentanil and remifentanil than with fentanyl or sufentanil.)
  3. The rate of recovery after a continuous infusion of any drug, including opioids, depends on the duration of the infusion as well as the magnitude of decline that is required (Fig. 19-1).

XIII. Context-Sensitive Half-Time

  1. The time required for the drug concentration in the central compartment (circulation) to decrease 50% and the influence of duration of the IV infusion on this time is defined as the context-sensitive half-time (Fig. 19-2).
  2. Context-sensitive half-time curves are theoretical predictions based on computer models. It is not known if a decrement of 50% provides the most clinically useful description of the rate of offset of opioid effects.

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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