Chapter 5 Central Nervous System (2024)

KEY TERMS AND DEFINITIONS

LEARNING OBJECTIVES

After completing this chapter, you should be able to

1. Describe brain and spinal cord anatomy and physiology.

2. Describe common neurotransmitters and their actions in the central nervous system.

3. Identify local and general anesthetics and how each affects the central nervous system.

4. Define analgesia.

5. List opioid medications and differentiate them by drug class and route of administration.

6. Discuss the pharmacological effects and adverse effects of opioid medications.

The nervous system is the communication system through which electrical and chemical signals responsible for the conscious and unconscious functions of the human body are transmitted. The central nervous system (CNS) is composed of the brain and the spinal cord. The brain is the information-processing center for the body and resides within the skull. Different areas within the brain are responsible for a plethora of human function, ranging from language processing, memory, and personality, to movement, speech, and fine motor skills. The brain sends signals to the rest of the body to initiate movement and direction whether these are unconscious or conscious movements. The brain also processes the changing environment around the individual through interpretation of electrical signals from the rest of the body. It communicates signals to and from other parts of the organism via the nerves. The spinal cord is located in the spinal column, or backbone, and these nerves branch out to the rest of the body. The spinal cord helps to move signals back to the brain and to carry out actions dictated by the brain. A person’s emotional state is also determined by the brain and is mediated through a complex balance of neurotransmitters.

The CNS is an elaborate network of communicating cells and chemicals that serve as specific drug targets. Many different medications have their actions in the CNS, and these include anesthetics, analgesics, and other medications such as antidepressants or treatments for Alzheimer disease. This chapter introduces the basic structure and functions of the CNS and examines common medications that are used to modify certain processes in the CNS that lead to anesthesia, pain relief, and addiction.

ANATOMY AND PHYSIOLOGY OF THE CENTRAL NERVOUS SYSTEM

Within the skull, the brain is covered by three protective outer layers called meninges (see Figure 5-1). The meninges are located directly below the skull and protect the brain from injury, form a protective coating around it, and provide blood flow. The meninges also distribute cerebrospinal fluid (CSF) over the outer surface of the brain. The brain and spinal cord are floating in CSF, which is composed of glucose, protein, and water and is a clear color. The CSF is isolated from other areas outside of the body and is therefore considered sterile. It provides nutrients to the brain. The blood vessels that feed the brain and help produce CSF contain a row of specialized cells called the blood–brain barrier (BBB), which keeps foreign organisms and chemicals from entering the brain, while allowing nutrients and oxygen to enter the brain. Medications that have actions in the CNS generally need to “cross” the BBB to reach their desired target and exert their action. The need to penetrate the BBB dictates the way medications intended to act on the CNS are formulated. The BBB can be affected by certain inflammatory disease states that dysregulate the passage of certain substances to the brain. Sometimes, organisms can invade the meninges and make it through the BBB, leading to inflammation of the meninges called meningitis.

The brain is composed of many different structures. It is divided into two halves—“hemispheres”—connected by the corpus callosum, which enables the halves of the brain to communicate. The largest and most complex part of the brain is the cerebrum (or cerebral cortex) (see Figure 5-2). This is where the majority of reasoning, movement, and sensory information are processed. The cerebrum is divided into four different areas: frontal lobe, parietal lobe, temporal lobe, and occipital lobe. Each of these has unique functions. The frontal lobe deals primarily with reasoning, determining consequences to actions, attention, and other higher mental functions and is commonly characterized as the part of the brain responsible for personality. The parietal lobe is primarily concerned with motor and sensory activity. The temporal lobe helps with memories, hearing, speech, and language. The occipital lobe deals with vision. Other areas of the brain identified in the figure include the cerebellum, which is used for balance and motor movement; the brainstem, which is used for many of the automatic functions of the body such as breathing; the hypothalamus and pituitary gland, which secrete hormones; and the limbic system, which is responsible for emotions. The brain is a complex organ, and many areas and structures of the brain have overlapping functions. Just because a certain area of the brain is identified as related to a particular function does not mean that the function happens only in that part. All of the different brain regions and sections work together to help us navigate the world around us.

The functional unit of the brain is the neuron or nerve cell (see Figure 5-3). Neurons consist of different parts, each of which has its own function. The cell body of a neuron is called the soma. This is where proteins and neurotransmitters (described in Chapter 4) are made and where the nucleus resides. Branching directly off the soma are structures called dendrites. Dendrites receive information from other cells as transmitted by action potentials and the release of neurotransmitters. Axons are the part of the nerve that stretch away from the body of the nerve cell to carry signals to the next nerve (a little like the wires on a telephone pole). Axons are sometimes coated in a myelin sheath, or a layer of fat and protein (Figure 5-4). The myelin sheath protects the axon and increases the conduction of nerve impulses. The point at which the axon ends is a space called the synapse, or synaptic junction. At the other end of the synapse is the dendrite of another neuron. The synapse is where neurotransmitters are released for the action potential to send information to other neurons. There are also other cells present in the brain called glial cells, which provide a support function to the neurons.1

An action potential is a series of electrical and chemical impulses that travel along the neuron and activate other neurons. The action potential is an essential part of neuronal function as without action potentials one part of the brain would not be able to communicate with another part of the brain. The same is true for sensory neurons in the rest of the body; without action potentials, a person would not know that his or her hand was being burned.

The major function of the spinal cord is to send information to, and receive information from, the brain. The basic structure of the spinal cord can be seen in Figure 5-5. It is composed of meninges, CSF, neurons, and support cells just like the brain. Unlike the brain, however, the spinal cord has very long axons, which are the nerves in the peripheral nervous system (see Chapter 4) that enable the brain to receive sensory information such as pain and touch and send motor signals like “move your arm here.” As seen in Figure 5-5, the spinal cord is composed of gray matter and white matter. Each of these has a specific function: the white matter is where the motor and sensory neurons are located, and the gray matter is where the nerve cell bodies for the spinal cord are located.

The spinal cord is involved in all voluntary movement and some involuntary movements. The motor nerves projecting to the rest of the body from the spinal cord innervate muscles and end in the neuromuscular junction, a type of synapse that activates muscle instead of other neurons. If the neuromuscular junction is blocked by a medication, such as succinylcholine, this inhibits muscle functioning and causes paralysis.

The spinal cord is also involved in receiving sensory information from the body. There are two types of sensory pathways: the dorsal column-medial lemniscus pathway (or the posterior column-medial lemniscus pathway) and the anterolateral system. The dorsal column-medial lemniscus pathway deals with sensory information in the form of touch, proprioception, and vibration. Proprioception is the awareness of the relative position of neighboring parts of the body. The anterolateral system senses pain and temperature. The spinal cord’s role in pain perception allows it to serve as a target for anesthesia and delivery of pain medications.2

NEUROTRANSMITTERS

Neurotransmitters are chemicals produced by neurons in order for them to communicate effectively.1 They are stored in vesicles, or pouches, within neurons. Neurotransmitters are released into the synapse in response to an action potential. The neuron releasing the neurotransmitter is called the presynaptic neuron, whereas the neuron receiving the neurotransmitter is called the postsynaptic neuron. Neurotransmitters attach to receptors located on neurons. When a neurotransmitter is released from the presynaptic neuron then binds to receptors on the postsynaptic neuron this generates an action potential on the postsynaptic neuron.

Medications can enhance or diminish the actions of neurotransmitters. This is often accomplished by stimulating or blocking the receptors on the neurons with which the neurotransmitters interact. In general, medications that stimulate—or activate—receptors are called agonists. Agonists duplicate or enhance the actions of neurotransmitters. Medications that block—or inhibit—receptors are called antagonists. Medications that are receptor antagonists reduce the actions of neurotransmitters. Medications are often specific for certain neurotransmitters or receptors, allowing them to precisely affect only one neurotransmitter system.

Gamma-aminobutyric acid (GABA), an amino acid neurotransmitter, is the major inhibitory neurotransmitter of the CNS. This means that GABA generally decreases or slows actions across the CNS because of its restraining role in almost every neuronal circuit in the brain. There are two types of GABA receptors: GABA_A and GABA_B. Most medications that affect the GABA system interact with the GABA_A receptor. These medications enhance the inhibitory effects of GABA; therefore, they often produce sleep-promoting, anti-anxiety, and antiseizure effects. Examples of medications that promote the effects of GABA are benzodiazepines and barbiturates. Alcohol also promotes the inhibitory effects of GABA. Another neurotransmitter, glycine, is similar to GABA in its functioning, except it is found only in the spinal cord.

Glutamate, another amino acid neurotransmitter, is the major excitatory neurotransmitter of the CNS. As such, when glutamate is activated, it generally increases activity across the CNS because of its stimulating role in almost every neuronal circuit in the brain. A common receptor that is stimulated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is implicated in regulating learning and memory. Several classes of medications influence glutamate neurotransmission in the CNS. Several antiepileptic medications discussed in Chapter 6 reduce the excitatory actions of glutamate to produce their antiseizure effects. Memantine, a medication that blocks glutamate from binding to its NMDA receptor, is used to treat Alzheimer disease (see Chapter 6). The illicit substance phencyclidine (PCP) also blocks the NMDA receptor.

Acetylcholine is found in varying concentrations throughout the CNS. Acetylcholine activates muscarinic and nicotinic receptors (see Chapter 4), which deal with memory, reward, and learning. Although this neurotransmitter plays a significant role in the autonomic nervous system (in places like the heart, lungs, eyes, sweat glands, and gastrointestinal tract), acetylcholine is also found in the neuromuscular junction, where the neuron acts on the muscle to tell the muscle to contract. Acetylcholine is broken down in the synapse by the enzyme acetylcholinesterase. Several medications either promote or inhibit the effects of acetylcholine. Medications such as donepezil and rivastigmine, known as cholinesterase inhibitors, prevent the breakdown of acetylcholine. Because they increase the availability of acetylcholine for learning and memory, they are useful for the treatment of Alzheimer disease.

Dopamine is a catecholamine neurotransmitter that is found throughout the brain and deals with attention, reward response, movement, and hormone regulation. Dopamine exerts its actions through dopamine receptors, which include D₁, D₂, D₃, D₄, and D₅ receptors. Parkinson disease (Chapter 6) involves a relative lack of dopamine in areas of the brain that regulate movement; therefore, medications that stimulate dopamine receptors, such as levodopa and ropinirole, treat Parkinson disease. Conversely, schizophrenia (Chapter 7) involves high levels of dopamine activity in certain areas of the brain. Antipsychotic medications antagonize D₂ receptors and alleviate some of the symptoms of schizophrenia.

Norepinephrine (also called noradrenaline) and epinephrine (also called adrenaline) are catecholamine neurotransmitters. They activate many different types of receptors in the CNS and peripheral nervous system, including α₁, α₂, β₁, and β₂ receptors. In the CNS, these neurotransmitters have specific actions related to attention and alertness. Medications such as methylphenidate and atomoxetine that increase norepinephrine activity promote attention and alertness when used for attention-deficit/hyperactivity disorder.

Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter characterized as a “monoamine.” Although it is distributed throughout the CNS, it is concentrated in the frontal cortex, spinal cord, and limbic system. Serotonin regulates a number of activities in the CNS, including sleep, mood, anger, and appetite. It acts on serotonin receptors, of which there are more than a dozen different subtypes. Serotonin also plays a significant role in the gastrointestinal system. Serotonin and its actions are affected by many medications, including antidepressants (e.g., fluoxetine), antiemetics (e.g., ondansetron), antimigraine agents (e.g., sumatriptan), and illicit substances (e.g., lysergic acid diethylamide, or LSD), which are studied in Chapters 6 and 7.

Histamine is a chemical that has actions within the brain, especially at the hypothalamus, and throughout the body, playing key roles in the sleep/wake cycle and in digestion. Histamine acts on four different receptors: H₁, H₂, H₃, and H₄. The H₁ receptor subtype is found primarily in the CNS. Medications that antagonize H₁ receptors are also called antihistamines (e.g., diphenhydramine). These medications are used for allergic rhinitis, motion sickness, and even for insomnia. Gastric acid secretion is regulated, in part, by the H₂ receptor. Medications such as famotidine and cimetidine, commonly used for gastroesophageal reflux disease (GERD), are H₂ receptor antagonists. They decrease stomach acid secretion and improve GERD symptoms. Finally, pitolisant, an H₃ receptor antagonist, has been found to be helpful for the treatment of narcolepsy, a condition characterized by inordinate daytime sleepiness.

There are other neurotransmitters that play roles in the CNS, but they are not regularly affected by medications and, therefore, are not discussed here.

ANESTHETICS

Anesthetics are divided into two types: general and local. General anesthetics are used in surgery and produce general anesthesia, a reversible state in which the patient is unresponsive, does not respond to pain, and does not remember the time during which they were under general anesthesia. Inhaled and intravenous (IV) anesthetics are types of general anesthetics. Each has distinct properties (see Medication Table 5-1; Medication Tables are located at the end of the chapter).

Inhaled anesthetics are used in general anesthesia and are easily administered in the form of a gas, with the patient breathing in air to which the medication (anesthetic) has been added. The medical gas is mixed with a constant flow of oxygen and nitrous oxide, which is then inhaled through either a mask or a ventilator attached to the anesthesia machine. The machine enables the anesthesiologist to monitor the patient’s level of anesthesia and regulate the flow of medical gas through the ventilator. The inhaled anesthetics generally produce anesthesia very quickly. The original medication from this class is halothane. Halothane is a volatile general anesthetic that has been used in surgeries for many years. It can cause serious adverse effects, including heart and liver problems, and is no longer commercially available in the United States. Halothane has been replaced by newer, safer, and easier-to-use inhaled anesthetics like isoflurane (Forane), sevoflurane (Ultane), and desflurane (Suprane).

Intravenous anesthetics belong to various drug classes. Methohexital (Brevital) is a barbiturate, which works by increasing GABA transmission throughout the brain, enhancing its inhibitory action. Methohexital has a very rapid onset of action and a half-life of 2 to 3 hours, making it desirable for outpatient surgical procedures.

The most common side effects from IV barbiturates include injection site reactions, low blood pressure, and headache. Serious adverse effects include respiratory and cardiovascular depression.2

Propofol (Diprivan), a nonbarbiturate sedative, is the most commonly administered IV anesthetic. It is used widely for many surgeries, colonoscopies, other nonsurgical procedures, and intubated, mechanically ventilated patients. Propofol is advantageous for procedures where rapid onset of medication effects and quick return of baseline mental status is desired. It works similarly to barbiturates through potentiation of GABA but may have other mechanisms of action as well. Propofol can cause serious blood pressure reduction, and its use is avoided for patients who have preexisting hypotension. Propofol is a fat emulsion with a milky appearance and is available in many different-sized containers. While propofol preparations do contain an antimicrobial agent, they should be used immediately when opened and infusion completed within the time specified (usually 12 hours) to limit infection risk.2

Many hospitals restrict and monitor access to propofol since it has been misused in the past. This may lead to difficulties in keeping adequate supplies of the medication stocked in a restricted area (e.g., automated dispensing cabinet) in all locations of a hospital, as it is difficult to predict the amount of medication that each patient may require to maintain sedation. The onset of action of propofol is fast (less than 1 minute) with an induction dose of 1.5 to 2.5 mg/kg, and the clinical effects can last up to 2 hours from a bolus dose. The quick onset of propofol given as a bolus allows it to be used as an induction agent for sedation in rapid-sequence intubations. Many sites have rapid-sequence intubation kits that stock the 200 mg/20 mL vial for this reason. Propofol can also be used as a maintenance infusion at much lower doses (100 to 300 mcg/kg/min), but there is considerable inter- and intrapatient variability. For example, propofol is titrated to a desired level of sedation, and each patient may require a different dose of propofol to reach that desired level for reasons discussed below.2

Varying doses of propofol may be needed to keep a patient sedated, as the medication can accumulate in fat tissue and then “redistribute.” Redistribution occurs when a highly fat-soluble medication is deposited in fat tissue after prolonged exposure and, once administration of the medication stops, diffuses away from the fat tissue and reenters the circulation. At this point, the medication is continuing to perform its actions until it is removed from the body. Additionally, effects of other sedatives that the patient is receiving, such as opioid agonists, may necessitate alterations in the infusion rate. After prolonged infusion, propofol may accumulate in the fat tissue of a patient with obesity and prolong recovery time due to redistribution of the medication.

Adverse effects from propofol include hypotension, bradycardia, respiratory depression, injection site pain, involuntary muscle movements, hypertriglyceridemia, and pancreatitis. Rarely, patients who are receiving propofol for more than 48 hours and have additional risk factors may develop propofol-related infusion syndrome. This potentially fatal syndrome is characterized by many different symptoms, including, but not limited to, metabolic acidosis, bradycardia or tachycardia, renal failure, and hyperkalemia. If a patient develops persistent hypotension with propofol infusions, the medication may be changed to an alternative agent such as fentanyl. If the patient needs additional blood pressure support and requires the use of propofol, catecholamine infusions (e.g., norepinephrine) can be used. For transient decreases in blood pressure due to an initial bolus of propofol, patients may receive a bolus of an IV crystalloid fluid (e.g., normal saline, lactated Ringer’s) and potentially an IV push of a vasopressor, commonly phenylephrine.2

Another IV anesthetic is ketamine (Ketalar), which is classified as a dissociative anesthetic. The mechanism of action of this medication is similar to PCP, working as an NMDA receptor antagonist. However, this may not be the only mechanism through which anesthesia is achieved. The onset of action of ketamine is similar to other anesthetics but it has a slightly longer duration of action. The initial dose of ketamine is 0.5 to 2 mg/kg with an infusion dose of 0.25 to 0.35 mg/kg, followed by continuous infusion up to 1 mg/kg/hour. Unlike other anesthetics, ketamine has some analgesic properties. Ketamine is also given by other routes of administration, including the subcutaneous and intramuscular (IM) routes and intranasally as esketamine. Ketamine is utilized for other disease states such as acute agitation, procedural sedation, and refractory status epilepticus, whereas esketamine is used to treat major depressive disorder.2

Etomidate is an IV anesthetic that is commonly used for patients at an increased risk for hemodynamic instability during anesthesia, as it does not reduce blood pressure and increases cardiac output. Etomidate has a rapid onset of action and a half-life of about 3 hours, making it a good option for starting anesthesia at a dose of 0.2 to 0.6 mg/kg. Etomidate is commonly the anesthetic of choice in patients who have hypo- or hypertension, risk for increased intracranial pressures, and who are in need of sedation for rapid-sequence intubation. While etomidate does not affect the cardiovascular or respiratory systems, postoperative nausea and vomiting is significantly increased. Another adverse effect is the suppression of stress hormone release, leading to decreased cortisol concentrations in the blood and increased mortality.2

Local anesthetics are applied to a specific part of the body to block the nerves in that part of the body. They block all nerves, motor and sensory, in the localized area. These actions are reversible once the anesthetic is removed or metabolized, and the anesthetizing effects diminish over time. Local anesthesia is preferred when it is not necessary for the patient to lose consciousness during a procedure.3

Examples of local anesthetics include lidocaine, bupivacaine, mepivacaine, and tetracaine (Medication Table 5-2). They work by blocking the conduction of action potentials along the nerve and can be used in a variety of contexts, including surgery, dental work, and childbirth. The first medication discovered to have local anesthetic properties was cocaine which, due to the potential for misuse, is not commonly used for this purpose except in emergent situations to provide local vasoconstriction and anesthesia in epistaxis (nosebleed). Adverse effects of this drug class include local site reactions such as pain, redness, and tingling. Those administering local anesthetics must be mindful of the area that they are injecting into, as the volume of the medication itself may cause pain and pressure. Systemic adverse effects such as cardiac conduction abnormalities, bradycardia, seizures, and hypotension are rare, unless a large amount of medication is absorbed systemically. Many times, a local vasoconstrictor like epinephrine is administered along with the local anesthetic to prolong the action of the local anesthetic and prevent large amounts of systemic absorption. Metabolism of local anesthetics occurs in the region in which they are administered and are usually broken down by plasma esterases.3

For topical anesthesia, direct application of the local anesthetic on the desired place of action is often sufficient and desirable. This application would only affect the area to which it is applied and does not extend to the lower structures of the skin. If the local anesthetic is applied to mucus membranes such as the nose or mouth, then systemic absorption is possible, and the effects may be severe. Such absorption and accompanying adverse effects are not likely if the local anesthetic is used in appropriate amounts. Other areas for local anesthesia include entire nerve roots (nerve block) and specific spinal nerve block. These are useful for local surgical procedures. In such cases, the local anesthetics are administered to the desired site by injection. Topical anesthetics can be compounded together in standard products such as LET gel (lidocaine, epinephrine, and tetracaine) and EMLA cream (lidocaine and prilocaine eutectic mixture). Lidocaine 4% IV solution may also be utilized as a topical anesthetic for bronchoscopies and is administered to patients via nebulizer to decrease the pain associated with this procedure.3

Epidural anesthesia is the administration of a local anesthetic by injection into the epidural space in the spinal cord to block the spinal nerve roots, thus causing decreased sensation. This is performed in many surgeries but is used most commonly in childbirth. One advantage to using epidural anesthesia is the ability to place a catheter into the epidural space to administer a continuous dose of local anesthetic. This eliminates the need for repeated injections into the epidural space. In patients who have pain, opioids can be administered with the local anesthetic into the epidural space to give even longer lasting pain relief. Even in patients who are postoperative, the combination of an opioid and local anesthetic administered in the epidural space may be enough to provide adequate pain relief.3

ANALGESICS

Analgesia is also known as pain relief, and medications used for this purpose are called analgesics. Analgesics are effective for both acute and chronic pain. Pain can come from a variety of sources, such as an injury, cancer, or even nerve pain from diabetes mellitus. A commonly accepted precept is that pain should be treated using the simplest dosage regimens and the most effective treatments for the patient’s pain. Pain can be rated subjectively by the patient on a 0 to 10 scale, with 0 being no pain and 10 being the worst pain imaginable. The PQRSTU assessment is another tool available to characterize a patient’s pain. It includes P (palliative—what makes the pain better or worse), Q (quality—describe the pain), R (radiation—where is the pain and does it radiate), S (severity—rate pain severity), T (temporal—when did the pain start and how long has it been ongoing), and U (you—how are other aspects of health, such as sleep, mood, and general well-being). Some objective measurements like grimacing, increased heart rate and blood pressure, and favoring a limb can be used, but they are likely absent in a patient with chronic pain.

Several routes of administration are available for analgesics, including oral, IV, IM, rectal, transdermal, buccal, and intranasal. Route of administration is determined by various patient characteristics, but the oral route is preferred for most. Some notable exceptions include patients who cannot take oral medication or when immediate relief of pain is needed.4

Analgesics include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Acetaminophen and NSAIDs are covered in more depth in Chapter 13, so the focus of this section will be opioid analgesics.

Opioid analgesics can be grouped by their chemical structures into several different classes: phenanthrenes, phenylpiperidines, diphenylheptanes, and benzomorphans. Opioids may also be grouped by their mechanisms of action: opioid agonists, opioid antagonists, mixed opioid agonists-antagonists, and opioid partial agonists. Opioid analgesics interact with opioid receptors, which include mu (µ), kappa (κ), and delta (δ) receptors.4 Opioid agonists work by stimulating opioid receptors in the brain and spinal cord, modulating (usually reducing) the impulses from the pain receptors in the body and providing pain relief. Opioid partial agonists also stimulate opioid receptors and provide pain relief. To their advantage, the partial agonists have a lower risk of respiratory depression than the full agonists. Mixed opioid agonists-antagonists are rarely used in practice today. Opioid antagonists block opioid receptors; therefore, they do not provide pain relief. They reverse the effects of opioid agonists and partial agonists. Naloxone and other opioid antagonists are described in more detail below.

Opioid analgesics can differ from one another in several important ways. Opioids differ by potency. Some are highly potent and useful for severe pain, whereas others are less potent and better for moderate pain. Opioids also differ by mechanism of action. In addition to interacting with opioid receptors, several of these medications have additional actions. For example, tramadol inhibits the reuptake of serotonin and norepinephrine, and methadone antagonizes NMDA receptors. Opioids differ in their pharmaco*kinetic profiles, including the duration of analgesia that a dose of each medication provides. A comparison of opioid analgesics can be found in Medication Table 5-3.

Clinicians are often tasked with converting one opioid analgesic to a different opioid analgesic. Equianalgesic dosing charts are available to assist with these dosing conversions. These dosing charts often use morphine as the reference standard. Equianalgesic dosing assists the clinician with calculating the equivalent dose between formulations (e.g., IV morphine to oral morphine) or when converting to a different opioid (e.g., morphine to hydromorphone). After the new dose is calculated, some sources recommend reducing the calculated dose by 25% or more to avoid adverse effects such as excessive sedation. This comparison calculation is reflected in Medication Table 5.3 in the column labeled “Equianalgesic Dose.”

The most frequently employed dosing strategy for opioid agonists in the treatment of acute pain is around-the-clock dosing. This method has been shown to be very effective if the medication is titrated appropriately, by starting with the initial dose of the opioid agonist and then increasing or decreasing based on pain control and adverse effects. If the opioid agonist is given only on an as-needed basis, patients may not get adequate pain control due to the varying blood concentrations of the opioid agonist. For chronic pain, the most useful strategy is a basal-bolus-type dosing strategy. This means that there is a long-acting (8 to 12 hours) opioid agonist used for around-the-clock pain control in addition to an as-needed medication for breakthrough pain. Usually, these two medications are the same opioid agonist. For example, a patient may use extended-release morphine sulfate every 12 hours for basal pain control and then use immediate-release morphine for breakthrough pain as needed every 3 to 4 hours. If a consistent pattern of increased use of the as-needed medication is noted, then this amount of medication can be added to the basal (long-acting) pain control, with a goal to eliminate the necessity for as-needed use of opioid agonists. One important note about opioid analgesics is that opioid agonists have no maximum effective dose; their dose is limited only by adverse effects. Conversely, tramadol, tapentadol, and opioid partial agonists have maximum doses.

The regular use of opioid analgesics can result in tolerance and physical dependence. Tolerance is defined as needing larger doses of medication to achieve the same effect that occurred when first starting the medication. Physical dependence is defined as the occurrence of withdrawal symptoms upon abrupt reduction of dose or discontinuation of the drug. Opioid withdrawal symptoms (e.g., muscle aches, diarrhea, anxiety) may also result from the administration of an opioid antagonist medication, as discussed later on. Both of these phenomena, tolerance and physical dependence, are expected with long-term, daily use of opioids and are different from addiction. Addiction is a behavioral pattern characterized as a lack of control over—and compulsive use of—drugs despite negative consequences from use.5 While tolerance and physical dependence may be present in patients with opioid addiction, the rate of addiction among those who are prescribed opioids for pain relief is small. Many factors influence a patient’s risk for addiction, including genetics, social factors, and psychological factors. (Addiction is more thoroughly addressed in Chapter 7.) Pseudoaddiction is a phenomenon that occurs when a patient’s pain is undertreated. Patients appear to have symptoms of addiction, but these symptoms resolve once the patient’s pain is adequately managed.

Opioid analgesics can cause a number of adverse effects. Opioids cause sedation or drowsiness. Tolerance develops to the sedating effects of opioids, and sedation should dissipate with time. Constipation is a common adverse effect that may not resolve with time. Many options are available to treat opioid-induced constipation, including stimulant laxatives. The release of histamine may contribute to the development of rash and pruritis (itching), and this must be distinguished from an allergic reaction. Management of other adverse effects may be achieved by using the lowest possible dose for the shortest amount of time. Other CNS depressants, such as benzodiazepines or alcohol, should not be used along with opioids as the concurrent use increases the risk of respiratory depression. Major adverse effects of opioid medications are listed in Table 5-2.

Patient-controlled analgesia (PCA) is a commonly utilized pain management strategy for patients within a hospital setting and is also prescribed for outpatients suffering from chronic pain. It is initiated in patients requiring high doses of pain medication who need continuous and breakthrough coverage for pain. In institutional settings, it is often prepared in the form of an IV bag or epidural infusion or provided as a commercially manufactured container compatible with the technology in use, and administered with an automated pump programmed to provide a continuous infusion of pain medication and bolus doses. In outpatient settings, the pumps are frequently much smaller, to be worn or implanted, and epidural administration is more common.

The automated pump technology includes a button that the patient uses to self-administer a premeasured dose of opioid analgesia for breakthrough pain, using preset parameters for dose and frequency. Only a prespecified amount of medication is administered with each button press, and the patient is only able to use the button a certain number of times per hour. The period between allowable doses is commonly referred to as a “lock out period.” A PCA pump also includes a continuous infusion of a basal dose of analgesic. This method of administration results in better pain control and the patient feeling empowered. Knowing the number of patient-administered doses (or bolus doses) given helps clinicians determine the adjustments that need to be made to the basal infusion rate, and the amount and frequency of bolus doses. Very close monitoring of certain parameters such as respiratory and heart rate, blood pressure, pulse oximetry, and alertness is needed to ensure the safety of this approach. PCA is generally avoided for patients who are unconscious or unable to provide themselves bolus dosing, as this could lead to inappropriate dosing by family members and others based on their perception of the patient’s pain.4

Opioid antagonists, such as naloxone and naltrexone, block the effects of opioid analgesics. If a patient taking opioid analgesics has developed physical dependence, the administration of an opioid antagonist will precipitate opioid withdrawal symptoms. Therefore, opioid antagonists are administered only in specific circ*mstances. Naltrexone is a long-acting opioid antagonist used to treat patients with either opioid or alcohol addiction. Naloxone, an opioid antagonist with a more immediate onset and shorter duration of action, is used to reverse life-threatening situations of intentional or unintentional opioid overdose.

When administered promptly, naloxone can prevent opioid overdose–related deaths. It does not reverse overdoses caused by other substances (e.g., benzodiazepines, cocaine). Symptoms of opioid intoxication include slow or shallow breathing, drowsiness or coma, blue lips or fingertips, and slow heart rate. Naloxone reverses opioid-induced respiratory depression. It can be administered by IV, IM, or subcutaneous injection or by intranasal administration. Depending on route of administration, naloxone may start to work in as little as 2 to 5 minutes. Because naloxone is short acting (i.e., duration of approximately 30 to 120 minutes), several doses may be required to reverse the effects of longer-acting opioid analgesics.6 While individual state laws differ, most have expanded naloxone access in the community setting (e.g., dispensing naloxone without a prescription under a physician collaborative practice agreement). The intranasal formulation is often distributed in the community setting due to ease of administration. Because it is a “bystander-administered” medication, all individuals with access to it (e.g., patient, family members, caregivers) require overdose prevention education, instructions on how to administer the specific naloxone product dispensed, and instructions for responding to an overdose situation.

Responding to an opioid overdose begins with attempting to wake the individual by calling his or her name and by firmly rubbing in the middle of the individual’s chest (i.e., sternal rub). Emergency services (i.e., 911) should be contacted. It is important to ensure nothing is in the individual’s mouth or throat that can affect breathing. After these steps, naloxone can be administered, and rescue breathing provided if the individual is not breathing. Naloxone doses are repeated as indicated. If the individual begins breathing, the individual should be placed on his or her side in the recovery position to prevent aspiration. Someone should stay with the individual until emergency medical services arrive.7

SUMMARY

The CNS is a complex organization of neurons and neurotransmitters that serve as useful medication targets. There are many different neurotransmitters that act on various systems in the brain and spinal cord. Neurotransmitters serve as unique medication targets that can assist with anesthesia and analgesia. Anesthetics are useful for surgery, pain control, and minor procedures. General anesthetics can be administered IV or inhaled, each having different utility in various areas of medicine. Among the most common of these is propofol, which has many characteristics that make it unique. Local and topical anesthetics are utilized for targeted application during simple surgical procedures. Opioid analgesics are among the medications most commonly prescribed for pain and share many similar properties. Opioids can be given by multiple routes of administration. Patients requiring continuous infusions of opioid pain medications and in need of additional doses for breakthrough pain may qualify for patient-controlled analgesia.

REVIEW QUESTIONS

1. Explain the function of meninges and how the blood–brain barrier is important to medication therapy.

2. Describe the roles of common neurotransmitters, such as dopamine, serotonin, and GABA, and list medications that affect each neurotransmitter.

3. What is anesthesia and why is it important?

4. How do addiction, pseudoaddiction, physical dependence, and tolerance differ?

5. Which adverse effects are common among opioid agonist medications?

FURTHER READING

MEDICATION TABLES