Analgesics, Tranquilizers, and Sedatives

Receptor Physiology.

Opioid receptors are found throughout the peripheral and central nervous system as well as pituitary, adrenal, and immune cells. In the central nervous system, there are three main types of opioid receptors: mu (µ), delta (δ), and kappa (κ), each with subtypes resulting from posttranslational modifications. Ultimately, binding of an agonist to the opioid receptor results in hyperpolarization of the neuron and decreased action potential propagation. The highest density of receptors is in the substantia gelatinosa of the cerebral cortex and spinal cord, periaqueductal gray areas, thalamus, and hippocampus. Of these areas, laminae II through V of the substantia gelatinosa and the periaqueductal gray areas appear to have the highest concentration of µ-receptors and have the greatest impact on analgesia.

Morphine.

Morphine is the prototypic opiate agent. It has traditionally been used as the primary analgesic in the management of acute myocardial ischemia and for sedation in patients with underlying myocardial disease. Morphine has an onset time of action of 5 to 10 minutes and has a terminal elimination half-life (t _1/2β ) between 2 and 4.5 hours. Morphine is unique compared with other commonly used opioid agents in that it has relatively low lipid solubility ( Table 40.1 ). This results in lower penetration across the blood-brain barrier and significantly slower time to peak effect (20 to 30 minutes).

Morphine is metabolized by both the liver and the kidneys. Although the liver is responsible for the majority of its metabolism, 40% is metabolized by the kidneys. Owing to the high hepatic extraction ratio, morphine clearance can be significantly reduced in patients with shock or reduced hepatic blood flow. Morphine-3-glucuronide is the major metabolite, but it possesses much less opiate activity and has significant neuroexcitatory properties. In contrast, morphine-6-glucuronide accounts for roughly 10% of morphine metabolism and is more potent than its parent compound. In patients with renal failure, the accumulation of this metabolite can result in excess or prolonged respiratory depression. Thus morphine should be used with caution in patients with shock, renal failure, hepatic failure, or multiorgan dysfunction.

Morphine has distinct hemodynamic properties that make it advantageous in certain cardiac patients. Perhaps the most important of these is morphine's ability to decrease venous and arterial tone. It appears that the increase in venous capacitance produced by morphine is relatively greater than the decrease in arterial resistance. This effect on venous capacitance is dose related; large doses may result in hypotension. In some cardiac patients, this modest decrease in preload is desirable. In the dosages commonly used in the critical care setting, morphine has no direct effect on the inotropic state of the heart. However, morphine-induced histamine release resulting from rapid or large doses of morphine can induce a transient positive inotropic and chronotropic state. Overall, the net chronotropic effect of morphine is to slow the heart rate under normal conditions. The exact mechanism by which morphine achieves this action is not certain, but it is thought to involve both a stimulation of the central vagal nucleus and a direct depressive effect on the sinoatrial node.

Many of morphine's side effects are dose related and can be minimized by reducing the doses administered to patients. The most dangerous side effect of morphine is respiratory depression. All opiate agonists share the property of depressing ventilation; this is primarily accomplished by decreasing the central ventilatory response to carbon dioxide. This respiratory suppression may lead to progressive hypercapnia, carbon dioxide narcosis, and obtundation with apnea. High-risk patients—such as those with morbid obesity, obstructive sleep apnea, or advanced age—should receive additional monitoring for signs of excessive sedation and respiratory compromise when receiving opioids.

The central nervous system side effects of morphine and all opiates include drowsiness, lethargy, and potentially excessive sedation. All opioids may cause or exacerbate delirium in the elderly population and other at-risk patients. In addition to the direct central respiratory depression described previously, excessive sedation with morphine can worsen respiratory compromise by causing upper airway obstruction and obstructive apnea. Euphoria with morphine has been noted but is less common than with other opioids. Dysphoria can also occur. As in respiratory depression, the central depressant effects are dose related and progressive.

The other organ systems most commonly affected by morphine (or any opioid) are the gastrointestinal (GI) and genitourinary (GU) systems. Morphine has many GI effects, including nausea, emesis, constipation, generalized slowing of the GI tract, and spasm of the sphincter of Oddi. Morphine has been reported to cause urinary retention by increasing urethral sphincter and detrusor tone. Hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone is occasionally seen with the administration of large doses of morphine.

Morphine may cause the release of histamine, although true allergic reactions to morphine are quite rare. The release of histamine is from mast cells rather than basophils; the mechanism is nonimmunologic but not thoroughly understood. The release of histamine can lead to a flushing sensation, intense pruritus, hypotension, and tachycardia. When histamine-related hypotension occurs, treatment includes discontinuing morphine, ruling out other causes of anaphylactic or anaphylactoid type of reactions, administering intravenous fluids for hypotension, and administering histamine type 1 and type 2 blocking agents.

The main reason to administer intravenous morphine in the CICU is to produce analgesia and sedation, especially in the setting of acute myocardial ischemia or acute cardiogenic pulmonary edema. The acute venodilatory effects of intravenous morphine, combined with its analgesic and sedative properties, make it useful in cardiac patients. In contrast to fentanyl, morphine—with its long clinical duration and low lipid solubility—is best suited to administration by intermittent boluses rather than continuous infusion. Morphine may best be avoided in the hemodynamically unstable patient because it is more likely to induce hypotension than other opiates and in patients with multiorgan dysfunction owing to the risk of an excessively prolonged effect.

Hydromorphone.

Hydromorphone is a semisynthetic opioid that was introduced into clinical practice in 1926. Structurally very similar to morphine, hydromorphone is a hydrogenated ketone derivative of morphine; however, it is roughly 8 times more potent. Following intravenous administration, the onset of action is roughly 5 minutes, with maximal effect achieved at 20 minutes. Although it is still very water soluble, it is more fat soluble than morphine, resulting in a slightly faster onset of action and peak effect when compared to morphine. The analgesic effect of parenterally administered hydromorphone lasts roughly 3 to 4 hours in the absence of liver and renal failure. Hydromorphone is metabolized primarily in the liver to hydromorphone-3-glucuronide (H3G) and dihydroisomorphine glucuronide. Like morphine-3-glucuronide, H3G has neuroexcitatory properties. However, unlike morphine, hydromorphone does not have active metabolites, making it safer to use in patients with renal dysfunction.

The cardiovascular and hemodynamic effects of hydromorphone are not as well studied as morphine and fentanyl. However, it has proven to be hemodynamically well tolerated and is a common alternative to morphine for pain control in the ICU. Given its long duration of action and lack of metabolites, hydromorphone is suited for both intermittent bolus and continuous infusion. Unlike morphine, hydromorphone is not associated with histamine release and may have a lower frequency of nausea. The side effect profile is otherwise very similar to that of morphine, including respiratory depression, impairment of mental status, constipation, or general slowing of the GI tract.

Fentanyl.

Fentanyl and remifentanil are members of the phenylpiperidine class of opiate agents. In terms of analgesic properties, fentanyl is approximately 80 times more potent than morphine because of its greater affinity for the µ-opiate receptor. For many years, fentanyl has been used extensively for procedural sedation and in the operating room owing to its high potency, rapid onset, and short initial duration of action. Owing to these properties, it is now commonly used as an analgesic and sedative in the critical care setting.

Although fentanyl has similar elimination kinetics to morphine, fentanyl is approximately 40 times more lipid soluble than morphine, leading to significant differences in clinical effects. Its high lipid solubility allows rapid entry across the blood–brain barrier, resulting in a rapid onset and peak effect within minutes of intravenous administration. This also allows rapid redistribution away from the brain to inactive organ groups, such as muscle and adipose tissue. The redistribution is responsible for fentanyl's short clinical duration of action in bolus form. This rapid onset and brief clinical effect make it useful for procedural analgesia in the ICU. These pharmacokinetic properties also make fentanyl more suitable for continuous infusion than morphine. In addition, the dose can be easily titrated.

After prolonged infusions, fentanyl's duration of action becomes significantly prolonged. The actual t _1/2β of fentanyl is similar to morphine at 2 to 4.5 hours. As the total cumulative dose of fentanyl increases, the inactive tissues become saturated and the duration of fentanyl's clinical effects becomes progressively longer as the drug clearance then depends upon the much longer t _1/2β . This concept is known as context-sensitive half-time , in which the half-time of the drug's clinical effects depend upon the context of total duration of infusion. Fentanyl is metabolized primarily by the liver and to a lesser degree by the kidney without active metabolites of clinical significance.

When used in analgesic doses, fentanyl has minimal direct hemodynamic effects and no direct inotropic effects. However, fentanyl can cause hypotension through dose-dependent bradycardia thought to reflect direct stimulation of the central vagal nucleus by fentanyl. Fentanyl can cause hypotension indirectly by decreasing central sympathetic outflow. This effect is supported by the observation that patients with high basal levels of sympathetic tone, especially when they are hypervolemic, are more likely to become hypotensive when given fentanyl. It is important to note that the combination of synthetic opioids and benzodiazepines, especially midazolam, can cause significant decreases in blood pressure.

The side effect and toxicity profile of fentanyl are similar to morphine, with several exceptions. The pharmacokinetic properties of fentanyl can result in rapid apnea and oversedation if not used with caution; therefore this drug should be used only in a monitored setting. Fentanyl does not release histamine from mast cells in humans. It has been rarely reported to cause true anaphylactic reactions.

Few studies have formally addressed the role of fentanyl in the CICU. In comparison to morphine, fentanyl does not have the same vasodilatory effects that may be beneficial in the setting of myocardial ischemia or acute cardiogenic pulmonary edema. However, fentanyl's rapid kinetics, neutral hemodynamic profile, and lack of active metabolites make it useful for procedural analgesia and a better choice in patients with organ dysfunction or hemodynamic instability.