Chapter 7 Opioids
Pharmacokinetics
7. What are the potency, time of onset, and duration of action of opioids dependent on? How rapid is the effect-site equilibration time of morphine relative to the other opioids?
8. What is the latency time to peak effect of opioids (i.e., bolus front-end kinetics) after a bolus injection?
9. How is the time to steady-state concentration after starting a continuous infusion defined and measured? How is remifentanil different from other opioids when used as a continuous infusion?
10. What is context-sensitive half-time (CSHT)? What are some clinical implications of the CSHT?
Pharmacodynamics
Adverse effects
12. What are the effects of opioids on the cardiovascular system?
13. What are the effects of opioids on ventilation?
14. What are the effects of opioids on the central nervous system?
15. What are the effects of opioids on the thoracoabdominal muscles? How can they be treated?
16. What are the effects of opioids on the gastrointestinal system?
17. What are the effects of opioids on the genitourinary system?
18. What is the mechanism by which opioids are thought to cause nausea and vomiting?
Special populations
Unique features of individual opioids
27. How does the onset time of morphine compare with the other opioids? What are some potential drawbacks of the administration of morphine?
28. How does fentanyl compare with morphine with regard to its effect-site equilibration time? What is the potency of fentanyl relative to morphine?
29. What are some routes for the administration of fentanyl?
30. How are the effects of fentanyl terminated? How does the context-sensitive half-time of fentanyl compare with other opioids?
31. What are some systemic clinical effects associated with the administration of fentanyl?
32. What are some clinical uses of fentanyl in anesthesia practice?
33. How does sufentanil compare with the other opioids with respect to its effect-site equilibration time and its context-sensitive half-time?
34. What is the potency of sufentanil relative to morphine?
35. What are some systemic clinical effects associated with the administration of sufentanil?
36. How does alfentanil compare with the other opioids with respect to its effect-site equilibration time and its context-sensitive half-time?
37. What are some clinical uses of alfentanil?
38. How does remifentanil compare with the other opioids with respect to its effect-site equilibration time and its context-sensitive half-time?
39. What is the potency of remifentanil relative to morphine?
Answers*
Structure activity relationships
1. Opioids that are commonly used in anesthesia practice include morphine, meperidine, fentanyl, sufentanil, alfentanil, and remifentanil. The only clinically significant opioids that occur naturally and are derived from the poppy plant are papaverine, codeine, and morphine. Papaverine lacks any opioid activity. Morphine is considered the prototype opioid with which all other opioids are compared. (115, Figure 10-1)
Mechanism of action
2. Opioids exert their effects through their agonist actions at the opioid receptors. Opioids bind to the opioid receptors in the ionized state. After an opioid binds to a receptor, there are at least two mechanisms by which opioids alter the activity of the cell. The main action of opioids appears to be through the interaction with G-proteins, resulting in inhibition of the activity of adenylate cyclase and increasing potassium conductance. This ultimately results in hyperpolarization of the cell and leads to a suppression of synaptic transmission. The second mechanism by which opioids may produce their effect is through the interference of calcium ion intracellular transport in the presynaptic cells. This results in interference with the release of neurotransmitters from the presynaptic cell and again suppresses synaptic transmission. Neurotransmitters that are affected by this mechanism of action of opioids include acetylcholine, dopamine, norepinephrine, and substance P. (116, Figure 10-2)
3. Opioid receptors are located in various tissues throughout the central nervous system and exert their therapeutic effects at multiple sites. They inhibit the release of substance P from primary sensory neurons in the dorsal horn of the spinal cord, mitigating the transfer of painful sensations to the brain (spinal analgesia). Opioid actions in the brainstem modulate nociceptive transmission in the dorsal horn of the spinal cord through descending inhibitory pathways. Opioids probably change the affective response to pain through actions in the forebrain (supraspinal analgesia). Three classical opioid receptors have been identified: μ, κ, and δ. More recently, a fourth opioid receptor, ORL1 (also known as NOP), has also been identified, but its function is quite different from that of the classical opioid receptors. Although the existence of opioid receptor subtypes (e.g., μ1, μ2, etc.) has been proposed, it is not clear from molecular biology techniques that distinct genes code for them. The responses evoked by opioid agonists at the μ receptor include spinal and supraspinal analgesia, ventilatory depression, gastrointestinal effects (nausea, vomiting, and ileus), and sedation. The responses evoked by agonists at the delta receptor include the modulation of the μ receptor. The responses evoked by agonists at the κ receptor were almost the same as the μ receptor but lacked any ventilatory depression effect. (116-117, Table 10-2)
4. Endorphins and enkephalins are endogenous neurotransmitters that normally bind to and activate opioid receptors. (Table 10-2)
Metabolism
5. Opioids are transformed and excreted by different metabolic pathways. Codeine is a prodrug and its metabolite, morphine, is the active compound. Codeine is partly metabolized by O-demethylation into morphine, a metabolic process mediated by the liver microsomal isoform CYP2D6. Genetic variation in the metabolic pathway of codeine can drastically alter its clinical effects. Patients who lack CYP2D6 because of deletions, frame shift, or splice mutations (i.e., approximately 10% of the white population) or whose CYP2D6 is inhibited (e.g., patients taking quinidine) do not benefit from codeine even though they exhibit a normal response to morphine.
Morphine is metabolized by hepatic conjugation and subsequent excretion by the kidney. Morphine has a high hepatic extraction ratio (first pass effect), when administered orally, which decreases its effect significantly than when injected intravenously. The hepatic first pass effect of orally administered morphine also results in high morphine-6-glucuronide levels.
Alfentanil, fentanyl, and sufentanil are also metabolized by liver microsomal enzymes. Liver metabolism is unpredictable for alfentanil, and less so for fentanyl and sufentanil. The primary enzyme responsible for alfentanil biotransformation, CYP3A4, has significant individual variability. Remifentanil is a very short-acting drug because of de-esterification (i.e., ester hydrolysis) by nonspecific plasma and tissue esterases to an inactive metabolite. (118, 124, 125, Figure 10-10)
6. Opioids are cleared principally by hepatic metabolism. Morphine is the only opioid that possesses an active metabolite. About 10% of the metabolism of morphine is to the active metabolite morphine-6-glucuronide. Morphine-6-glucuronide has analgesic and ventilatory depressant effects and is eliminated by renal excretion. It is more potent at the μ receptor than morphine and has a similar duration of action. Care must be taken when administering morphine to patients with renal failure because the elimination of the active metabolite of morphine may be prolonged. Morphine’s principal metabolite, morphine-3-glucuronide, is inactive. (124)
Pharmacokinetics
7. The potency of an opioid is related to its affinity for the opioid receptor. The time of onset, or effect-site equilibration time, and duration of action of an opioid are related to its lipid solubility and degree of ionization at physiologic pH. A greater lipid solubility and greater nonionization allow for quicker crossing of the blood-brain barrier, quicker access to the central nervous system to exert its effects, and quicker redistribution to inactive tissue sites. For example, morphine has relatively low lipid solubility and is only 10% to 20% nonionized at physiologic pH, accounting for its relatively prolonged effect-site equilibration time. (118, Figure 10-3)
8. The latency time to peak effect (bolus front-end kinetics) of common intravenous opioids (morphine, fentanyl, sufentanil, alfentanil, and remifentanil) after administering a bolus is influenced by the opioid’s ionization and lipid solubility. Opioids that are un-ionized and unbound, and have high lipid solubility rapidly equilibrate to the effect site. The time on peak effect is also influenced by the amount of drug administered in the initial bolus. The offset of effect after bolus injection is also called bolus back-end kinetics. (118-119)
9. The time required to reach steady state after starting an opioid infusion is defined as the time required to achieve steady-state effect-site concentrations (i.e., infusion front-end kinetics). It is important to understand the clinical relevance of administering a continuous opioid infusion. First, the time required to approach steady-state effect-site concentrations can be very long, often longer than a surgical procedure. To achieve final steady-state concentrations more rapidly, a bolus can be administered before the infusion is started. Additionally, opioid concentrations will increase slowly for many hours after an infusion is started and continued at a constant infusion rate. Because remifentanil rapidly equilibrates to the effect site, it is an exception to this general rule. For this reason, remifentanil is often chosen for total intravenous anesthesia (TIVA). (118)
10. The context-sensitive half-time (CSHT) is defined as the time required for a 50% decrease in drug concentration after stopping a steady-state infusion. The CSHT predicts the termination of drug effect or “infusion back-end” kinetics. It has many clinical utilities. First, for most drugs, the CSHT changes with the length of the infusion time that it has been infused. After a short duration of infusion, the predicted back-end kinetics for the various drugs do not differ much (remifentanil is an exception). But if the duration of infusion is increased, the CSHTs will vary for the different opioids. Second, clinically shorter- or longer-acting drugs should be chosen depending on the duration of opioid effect acceptable after discontinuing it. Finally, the shapes of these curves are not the same if a different degree of concentration decline (20% or an 80% decrease) is required. (118-119)
Pharmacodynamics
Therapeutic effects
11. Opioids appear to be highly effective for the relief of pain that arises from the viscera, skeletal muscles, and joints, by acting at spinal and brain μ receptors. Other clinical effects of morphine include euphoria, sedation, and altered mentation. Opioids also suppress the cough reflex via the cough centers in the medulla. (120)
Adverse effects
12. There are several mechanisms by which the administration of opioids may result in hypotension. These include histamine release, centrally mediated decreases in sympathetic tone, vagal-induced bradycardia, and direct and indirect venous and arterial vasodilation. For example, morphine may result in hypotension primarily due to histamine release or through centrally mediated decreases in sympathetic tone. The release of histamine is most likely to accompany the administration of morphine when high doses of morphine are administered rapidly. The effects of morphine on blood pressure may manifest clinically only as orthostatic hypotension in the supine, normovolemic patient. The hypotension associated with the administration of morphine may also occur due to vagal stimulation. Hypertension may accompany the administration of opioids secondary to inadequate dosing of the opioid or to the ill-timed administration of the opioid relative to the stimulus inducing the increase in blood pressure. (121, Figure 10-4)
13. All the μ receptor agonist opioids produce a dose-dependent depression of ventilation. This is reflected by an increase in the resting PaCO2, an increase in the apneic threshold, a decrease in the responsiveness to the ventilatory stimulant effects of carbon dioxide, and a decrease in the hypoxic ventilatory drive. The administration of opioids also affects the rate of breathing and the tidal volume. The respiratory rate is typically slowed and insufficiently compensated by an increase in the tidal volume. Consequently, the minute ventilation is decreased. The mechanism by which these effects of opioids on ventilation occur is thought to be through the direct depression of the medullary ventilatory centers. (120-121)
14. The administration of opioids results in several central nervous system effects. Opioids are unable to produce a dose-related general depression of the central nervous system typical of other general anesthetics. Instead, opioids have a ceiling effect that is not overcome by increasing the administered dose of opioids. Opioids do contribute to the MAC of anesthesia delivered and decrease the amount of volatile agent required to achieve a given anesthetic depth. Opioids are not considered to be true anesthetics, however, because of their inability to reliably produce unconsciousness even in high doses. Finally, the administration of opioids causes miosis through its cortical inhibition of the Edinger-Westphal nucleus. (122)
15. The administration of opioids can result in increased thoracoabdominal muscle tone, which may result in chest wall stiffness. This “stiff-chest” syndrome can interfere with ventilation. Although the exact mechanism for this muscle rigidity is not known, it appears to occur most frequently when rapid, large boluses of fentanyl congeners are initially administered. Termination of the rigidity to allow for ventilation can be accomplished through the administration of a neuromuscular blocking drug or an opioid antagonist such as naloxone. Prophylaxis against this muscle rigidity can be achieved through the administration of a priming dose of a nondepolarizing neuromuscular blocking drug and the slow, intermittent administration of opioid. (121)
16. Among the several effects opioids have on the gastrointestinal system are effects on gastrointestinal motility, gastric emptying, and biliary smooth muscle tone. Opioids increase tone and decrease propulsive motility in both the small and large intestines. Opioids also increase the gastric emptying time through both central and peripheral effects of the opioid. Centrally, this effect is mediated by the vagus nerve. Peripherally, binding of an opioid to the opioid receptors in the myenteric plexus and cholinergic nerve terminals inhibits the release of acetylcholine at these nerve terminals. Opioids also increase pyloric sphincter tone, further contributing to a delay in gastric emptying. Opioids can cause spasm of biliary smooth muscle, increasing biliary duct pressure. Opioids also increase the tone of the sphincter of Oddi. In patients receiving intraoperative cholangiograms, approximately 3% of patients who have been administered opioids have opioid-induced spasm of the sphincter of Oddi. Together these can result in an increase in intrabiliary pressure that may manifest as biliary colic or mimic angina pectoris in the awake patient. The clinician can distinguish between opioid-induced biliary colic pain and myocardial ischemia through the administration of naloxone. Naloxone can relieve the pain of biliary colic, but it has no effect on the pain caused by myocardial ischemia. Glucagon also reverses biliary spasm due to opioids. Nitroglycerin has resulted in pain relief in both circumstances, making diagnosis difficult. (121-122)
17. Opioids can decrease bladder detrusor tone and increase the tone of the urinary sphincter. This may lead to urinary retention in some patients, particularly in males, when the opioid is administered intrathecally or epidurally. When this occurs there may be the need to catheterize the patient’s bladder to drain it. These effects are in part centrally mediated, although peripheral effects are also likely given the widespread presence of opioid receptors in the genitourinary tract. (122)
18. There are several mechanisms by which opioids are thought to cause nausea and vomiting. The primary mechanism appears to be through the direct stimulation of the chemoreceptor trigger zone in the area postrema on the floor of the fourth ventricle in the brain. In addition to this, opioids also increase gastrointestinal secretions, decrease gastrointestinal tract motility, and prolong gastric emptying time. (121)
19. Both administered and endogenous (e.g., endorphins) opioids depress cellular immunity. For example, opioids have been shown to inhibit the transcription of interleukin-2 in activated T cells. The different opioids may differ in the mechanism and extent of their immunomodulatory effects. Some possible adverse outcomes due to the impairment of cellular immunity may include impaired wound healing, perioperative infections, and cancer recurrence. These effects are not completely understood. (122)
Drug interactions
20. A pharmacokinetic drug interaction is one in which the administration of a drug influences the concentration of another administered drug. An example of this occurs when opioids are administered concurrent with a continuous propofol infusion. Opioid concentrations may be higher when administered with a continuous propofol infusion than they are when the same dose is administered alone. This may be due in part to the hemodynamic changes induced by propofol. (122)
21. A pharmacodynamic drug interaction is one in which the administration of a drug influences the effect of another administered drug. The most common and most important pharmacodynamic drug interaction of opioids is its synergistic effect when administered with sedatives. Opioids also synergistically reduce the minimum alveolar concentration (MAC) when administered with volatile anesthetics. The reduction in the MAC of anesthesia can be substantial, by up to 75% or more. (122)
Special populations
22. With the exception of remifentanil, the liver is the organ primarily responsible for the metabolism of opioids. The anhepatic phase of orthotopic liver transplantation is the only situation in which opioid concentrations may accumulate. Other than that, liver failure is usually not severe enough to have a major impact on opioid concentrations. Clinically, patients with severe liver disease, such as those with hepatic encephalopathy, may be more sensitive to the sedative effects of opioids. (122-123)
23. Kidney failure may have clinical effects on opioid administration, depending on the opioid. Kidney failure has major clinical relevance when administering morphine and meperidine. Two metabolites of morphine, morphine-3-glucuronide and morphine-6-glucuronide (M3G and M6G), are excreted via the kidney. Indeed, nearly half of morphine conversion to M3G and M6G also happens in the kidney. M3G is inactive, but M6G is an analgesic whose potency approaches that of morphine. Life-threatening respiratory depression can develop in patients with renal failure administered morphine due to very high levels of M6G.
Normeperidine is the main metabolite of meperidine and is excreted through the kidney. Normeperidine has analgesic and excitatory central nervous system effects. Increasing levels of CNS toxicity of normeperidine include anxiety, tremulousness, myoclonus, and frank seizures. Therefore, normeperidine accumulation is of particular concern in patients with renal failure. For most other opioids, kidney failure has minimal clinical importance. Remifentanil, which is metabolized through ester hydrolysis, is not affected by kidney disease. (123, Figure 10-7).
24. Gender may have an influence on opioid pharmacology. Morphine is more potent in women, but has a slower onset of action. (123)
25. Age has an important influence on opioid pharmacology. For example, fentanyl is more potent in the older patient. Pharmacokinetic changes, decreases in clearance and central distribution volume in older patients, play a lesser role. Pharmacodynamic differences are primarily responsible for the decreased dose requirement in older patients (> 65 years of age). Doses of opioids, including remifentanil, should be decreased by at least 50% or more in elderly patients. (123, Figure 10-8)
26. The clearance of opioids appears to be more closely related to lean body mass, such that obese patients do not require as high a dose as would be suggested by their total body weight. For this reason lean body mass should be used to calculate the dose of opioid administered. Pharmacokinetic simulations used to calculate the remifentanil dosage based on total body weight (TBW) or lean body mass (LBM) in obese and lean patients showed dramatically higher concentrations of opioids when TBW was used in obese patients. (124, Figure 10-9)
Unique features of individual opioids
27. Morphine is the opioid with which other opioids are compared. The onset time of morphine is slower than the other opioids given its high degree of ionization and its low lipid solubility. Some potential drawbacks of the administration of morphine include its active metabolite, the histamine release it causes, and the potential for “stacking” of subsequent doses in patients in pain due to its slow onset time. (124-125)
28. Fentanyl administered intravenously has a more rapid onset and shorter duration of action than morphine. This reflects its greater lipid solubility. The effect-site equilibration time of fentanyl is about 6.5 minutes. Its shorter duration of action is also reflective of its rapid redistribution to inactive tissue sites, leading to a rapid decrease in the plasma concentration of fentanyl. Fentanyl is 75 to 125 times more potent than morphine. (Figure 10-3)
29. Fentanyl can be administered numerous ways. In addition to the intravenous route, transdermal, transmucosal, transnasal, and transpulmonary routes are all effective routes for the administration of fentanyl. The oral transmucosal delivery of fentanyl citrate results in a faster achievement of higher peak levels than when the same dose is swallowed. (125)
30. The effects of fentanyl are terminated through its redistribution to inactive tissue sites followed by its metabolism by the liver. High intravenous doses of fentanyl or a continuous intravenous infusion can lead to saturation of the inactive tissue sites. This may result in prolonged redistribution, prolonged elimination, and prolonged pharmacologic effects of the drug. The cumulative drug effects during continuous intravenous infusions of fentanyl, sufentanil, alfentanil, and remifentanil have been compared. Alfentanil and remifentanil do not seem to produce clinically significant cumulative drug effects, and awakening appears to be prompt with minimal lingering side effects when compared with fentanyl. (118, Figure 10-3)
31. The administration of fentanyl is associated with a decrease in heart rate. The administration of fentanyl alone leads to little change in systemic blood pressure, whereas its administration after a benzodiazepine may lead to decreases in blood pressure. There are also synergistic effects between fentanyl and benzodiazepines on ventilatory depression and sedation. (121-122)
32. Clinical uses of fentanyl in anesthesia practice include perioperative analgesia, the induction and maintenance of anesthesia, the inhibition of the sympathetic nervous system response to direct laryngoscopy or surgical stimulation, and preemptive analgesia. Opioids are most commonly used during the maintenance of anesthesia as a supplement to inhaled anesthetics. Opioids used in this manner are often administered in small intravenous boluses or as a continuous infusion. High doses of a narcotic, especially fentanyl or sufentanil, may be used as the sole anesthetic agent in patients who are unable to tolerate any effects of cardiac depression that inhaled anesthetics may produce. A disadvantage of an opioid-based anesthetic is the potential for patient awareness. (126)
33. Sufentanil has an effect-site equilibration time similar to fentanyl. Its context-sensitive half-time is less than that of alfentanil for infusions lasting less than 8 hours, but it is greater than that of remifentanil. (Figure 10-3)
34. Sufentanil is 500 to 1000 times more potent than morphine. It is the most potent opioid currently in use in anesthesia practice. (125)
35. Systemic clinical effects associated with the administration of sufentanil include depression of ventilation and bradycardia that appears to be greater than that produced by fentanyl. Sufentanil in large doses may result in thoracoabdominal muscle rigidity as well. (121)
36. Alfentanil has an effect-site equilibration time that is shorter than that of fentanyl and sufentanil, about 1.4 minutes. This is a result of its low pKa, which allows for about 90% of the drug to be nonionized and lipid soluble at physiologic pH. The context-sensitive half-time of alfentanil varies by as much as 10 times among individuals. This is believed to be due to individual variations in its metabolism. Even so, the context-sensitive half-time of alfentanil is considered to be short when compared with other opioids. (Figure 10-3, Table 10-1)
37. The rapid, short-acting effect of alfentanil makes it useful for situations in which the response to a single, brief, intense, noxious stimulus requires blunting. Examples include the response to direct laryngoscopy and endotracheal intubation, or the performance of a retrobulbar block. (126)
38. Remifentanil has an effect-site equilibration time of about 1.4 minutes, which is shorter than that of fentanyl and sufentanil, and about equal to that of alfentanil. The context-sensitive half-time of remifentanil is much shorter than that of the other opioids, approximately 4 minutes. It is also independent of the duration of the continuous infusion, which is unique to remifentanil among the opioids. The basis for this is its structure, which has an ester link. The ester link allows for hydrolysis in the plasma to inactive metabolites. This accounts for its rapid titratability, noncumulative effects, and rapid recovery. (Figure 10-3, 125)
39. Remifentanil is 250 times more potent than morphine. (125)
40. Like alfentanil, the unique pharmacokinetic profile of remifentanil makes it desirable in cases where the response to a brief, intense stimulus requires blunting. It can also be used as maintenance anesthesia when rapid recovery might be desired, as during an intraoperative wake-up test for the evaluation of motor nerve integrity during spine surgery. Likewise, a remifentanil infusion is commonly administered along with propofol for total intravenous anesthesia. When remifentanil is used as maintenance anesthesia, a longer-acting opioid may need to be administered before patient arousal for analgesia. (125-126)
Clinical application
Common clinical indications
41. Opioids have been used in different areas of anesthesia. Their main and oldest indication is postoperative analgesia. To increase the safety of opioid use for postoperative pain control they can be delivered by a patient-controlled analgesia (PCA) machine. They can be combined with other drugs and techniques to decrease pain as well. Another common indication of opioid use is for “balanced anesthesia.” With this technique, the opioids are primarily used for their ability to decrease MAC, thereby avoiding the direct myocardial depression and other untoward hemodynamic effects of the volatile anesthetics. Cardioprotection against ischemia (preconditioning) is another possible beneficial indication of opioids. Total intravenous anesthesia (TIVA) can be achieved when opioids are administered in combination with propofol infusions. This is another recent indication of opioids during anesthesia that may result in postoperative euphoria and less nausea and vomiting. (126)
Rational drug selection and administration
42. Pharmacokinetic differences between opioids are the main consideration in selecting them for appropriate purpose. All μ agonists are equally efficacious when given in equipotent doses. Among key elements when selecting an opioid for administration is the desired time of onset, the duration of effect, and potential side effects. Side effects for consideration include sedation and respiratory depression. (126-127)
