Action potential

a series of electrical and chemical impulses that travel along the neuron and activate other neurons.


a behavioral pattern characterized as lack of control over and compulsive use of drugs despite negative consequences from use.


relieving or reducing pain.


a condition during which a patient forms no new memories, is unconscious, cannot move, and does not respond to pain.

Blood–brain barrier

specialized cells in the blood vessels of the meninges, which keep foreign materials (e.g., microorganisms, medications) from entering the brain.


organ at the center of the central nervous system.

Central nervous system

composed of the brain and spinal cord; relays and interprets motor and sensory information, as well as higher-order functions such as memory and reasoning.

General anesthetics

medications, administered by inhalation or intravenously, that produce anesthesia.

Local anesthetics

medications applied or administered to a specific part of the body to block the nerves in that part of the body.


outer layers of the brain that protect it; located below the skull.


nerve cell; functional unit of the brain.

Physical dependence

a condition characterized by the occurrence of withdrawal symptoms on abrupt reduction or discontinuation of a drug.

Spinal cord

enclosed within the vertebral column; transmits nerve impulses from the brain to the rest of the body.


the need for larger doses of medication to achieve the same effect that occurred when first starting the drug.


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.


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.


Meninges—the different layers of meninges from skull down to brain.

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.


General brain structures. A. Different lobes of the cerebrum; B. cross-section of the brain with various structures identified.

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


Synapse—a synapse between two nerve cells with dendrite and cell body.


Axon with myelin sheath.

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.


Spinal cord—general spinal cord structures.

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 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: GABAA and GABAB. Most medications that affect the GABA system interact with the GABAA 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.


Mr. Jones is a patient in the intensive care unit (ICU). He was admitted for a case of severe pneumonia. He is currently being sedated (a deep sleep, but not full anesthesia) because he is on a mechanical ventilator to aid in the treatment of his pneumonia. Patients who are on mechanical ventilation need to be sedated to prevent normal breathing from interfering with the ventilator. Breathing is a process that happens involuntarily in patients with intact neurological function and the only way to prevent the brain from automatically breathing is through a medically induced deep sleep.


What purpose might sedation have for a patient on a mechanical ventilator?


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).

TABLE 5-1.

Drug Enforcement Administration Controlled Substance Schedules



Example Medications

Special Order Form Required


No current medical use; high abuse potential; no data for safety under medical supervision

3,4-methylenedioxymethamphetamine (MDMA, or “ecstasy”)


Lysergic acid diethylamide


Yes, for research purposes only


Medical use; high abuse potential; abuse of the drug or other substance may lead to severe psychological or physical dependence












Medical use; abuse potential is less than schedules I and II; abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence





Sodium oxybate




Medical use; abuse potential is low relative to schedule III; abuse of the drug or other substance may lead to limited physical or psychological dependence


Benzodiazepines (alprazolam, clonazepam, diazepam)


Nonbenzodiazepine sedative/hypnotics (eszopiclone, zaleplon, zolpidem)





Medical use; abuse potential is low relative to schedule IV; abuse of the drug or other substance may lead to limited physical or psychological dependence

Cough syrups containing a small amount of codeine

Diphenoxylate with atropine




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).

Practice Point

When stored in the pharmacy, inhaled anesthetics are typically shelved in an area designated for medications utilized in operating rooms.

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

Practice Point

Propofol should be accounted for when calculating total parenteral nutrition (TPN) since it provides 1.1 kcal/mL of lipid nutrition. In addition, triglycerides should be monitored while a patient is receiving a prolonged infusion of propofol.


Patients who are allergic to soy or egg products should not receive propofol.

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


Mr. Jones is receiving propofol (Diprivan) for sedation. On the last delivery this morning at 0600, the pharmacy technician left an entire carton of the 50-mL bottles there, which should have lasted until tomorrow. It is 1800 and the nurse is calling for an additional supply. Why might Mr. Jones be in need of more propofol?


LOOK-ALIKE/SOUND-ALIKE—Diprivan (propofol) and Diflucan (fluconazole) have been the subject of confusion.

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


Propofol is not compatible with many other IV infusions and should not be administered in the same IV line as other medications or blood products.

Practice Point

Propofol may be administered with lidocaine, a local anesthetic, to prevent injection site pain.

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


Ketamine is a CIII controlled substance and has been used illicitly. Hence, it may be stored in a special location in the hospital pharmacy. Adverse effects from ketamine include hallucinations, vivid dreams, hypertension, tachycardia, increased muscle movements, and respiratory depression.

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


Mr. Jones is admitted to the ICU for new-onset heart failure. He requires the placement of a Swan-Ganz catheter (pulmonary artery catheter) which is used to closely monitor heart function in patients with heart failure. When the Swan-Ganz catheter is being placed into a large vein, patients can experience significant pain at the site. Which local anesthetic should be used and how should it be administered?

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

TABLE 5-2.

Adverse Effects of Opioid Agonists

Body System

Adverse Effects

Central nervous system

Euphoria, drowsiness, withdrawal (upon abrupt discontinuation)

Circulatory system

Orthostatic hypotension

Digestive system

Nausea, vomiting, constipation

Genitourinary system

Urinary retention, sexual dysfunction

Integumentary system

Rash, pruritus (itching)

Respiratory system

Decreased respiratory rate


Many injectable local anesthetics are available in multiple strengths and as preparations with varying concentrations of epinephrine already added. Pharmacy technicians must be sure not only to choose the correct agent, but also the correct strength, as well as noting whether or not an epinephrine-containing preparation has been ordered (and, if so, in what strength). Local anesthetics used for spinal administration (e.g., epidural) must always be preservative-free and labeled MPF (methylparaben preservative-free).

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


Mrs. Smith presents to the emergency department following a motor vehicle accident. After conducting a physical assessment, the prescriber writes a prescription for an opioid analgesic for the patient’s severe, acute pain.


What opioid analgesic options are available for the treatment of acute pain? What are the differences in drug class and mechanism of action between different opioid 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 pharmacokinetic 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.”


LOOK-ALIKE/SOUND-ALIKE—Tramadol (an analgesic) and Trazodone (an antidepressant) have been confused.


Careless drug abbreviations can cause errors. Morphine sulfate should never be abbreviated as MS or MSO4. This can be confused with other medications, such as magnesium sulfate (MgSO4).

Practice Point

Opioid analgesics are listed by the Drug Enforcement Administration (DEA) as controlled substances. Controlled substances can produce physical and psychological dependence. Therefore, they may be stored in a locked cabinet or other special location within the pharmacy. The DEA has different categories, or schedules, of controlled substances (Table 5-1). A special form, DEA 222, is used to order CII controlled substances, which can only be acquired by DEA registrants.

Practice Point

Constipation is a common opioid analgesic adverse effect (Table 5-2). Unlike other adverse effects, such as sedation, tolerance does not develop to constipation. Therefore, patients will often require a stimulant laxative (e.g., senna) to take in addition to the opioid medication.


Mrs. Smith arrives at the outpatient pharmacy with two opioid prescriptions. The prescriber has written prescriptions for oxycodone immediate-release 5 mg by mouth every 6 hours as needed and oxycodone extended-release 10 mg by mouth every 12 hours. Why might a prescriber order two different dosage forms and strengths of the same opioid medication?

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.

Practice Point

Many patients may experience a rash and pruritus (itching) when taking opioid analgesics. This may not be a true allergy unless it is associated with shortness of breath, severe low blood pressure, or other anaphylactic-type reactions. These pseudoallergic reactions are common with opioids, caused by histamine release, and can be treated by giving the patient an antihistamine. With true allergic reactions, an opioid from a different drug class should be chosen (Medication Table 5-3). The patient should be monitored closely.

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.

Practice Point

Most states have implemented electronic prescription drug monitoring programs. These databases track controlled substances dispensed by pharmacies, including opioid medications. Prescription drug monitoring programs help to identify prescriber or pharmacy “shopping” by patients. They are an important tool to identify inappropriate prescribing patterns, improve opioid prescribing, and protect at-risk patients.

Practice Point

Methadone and buprenorphine are used to treat opioid use disorder (opioid addiction). They reduce overdose-related deaths, HIV and hepatitis C infection risk, and criminal behavior. While methadone can be dispensed by a community pharmacy for pain relief, only licensed methadone clinics can legally dispense it for opioid use disorder. Buprenorphine can be dispensed by a community pharmacy for opioid use disorder; however, prescribers must first complete special training to prescribe it for addiction treatment. Once the training is complete, the prescriber is issued an additional DEA registration number. This “X” series DEA number must be present on the prescription when it is presented at the outpatient pharmacy.

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

Practice Point

Patient-controlled analgesia contains narcotic pain medication and, in institutional settings, must be delivered directly to the nurse. It is commonly locked within the smart pump technology to prevent misuse and diversion.


Along with the oxycodone prescriptions, the prescriber also orders intranasal naloxone for Mrs. Smith. The pharmacist trains Mrs. Smith and her spouse on the proper use of intranasal naloxone. What type of medication is naloxone? What is the purpose behind providing naloxone to patients taking opioid analgesics?

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 circumstances. 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

Practice Point

Naloxone is available in several formulations and can be administered intranasally or by IM, IV, or subcutaneous injection (Medication Table 5-4). Dosing and administration vary among naloxone formulations. Family members and caregivers require education regarding how to administer naloxone during an opioid emergency. Instructions for use should be provided with the specific naloxone product. Educate all individuals to be familiar with where naloxone is stored in the household in case of emergency and to periodically check the expiration date and replace naloxone if needed.


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.


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    Patel HH, Pearn ML, Patel PM, Roth DM. General anesthetics and therapeutic gases. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2018:387404.

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    Catterall WA, Mackie K. Local anesthetics. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2018:405420.

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    Substance Abuse and Mental Health Services Administration. SAMHSA Opioid Overdose Prevention Toolkit. Accessed October 24, 2021.


  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?


  • Becker DE, Reed KL. Local anesthetics: Review of pharmacologic considerations. Anesth Prog. 2012;59(2):90102.

  • Vearrier D, Grundmann O. Clinical pharmacology, toxicity, and abuse potential of opioids. J Clin Pharmacol. 2021;61(2 Suppl):S70S88.



Intravenous Anesthetics6

Generic Name (pronunciation)

Brand Name

Available Preparations


Induction Dose (IV)


Induction Dose Duration (minutes)



Methohexital (meth oh HEKS i tal)


500, 2,500 preservative-free injectable solution



Anesthesia, procedural sedation

Immediate onset of action

Used for intracarotid testing (Wada test)

Etomidate (e TOM i date)




General anesthesia, procedural sedation, rapid-sequence intubation

Used in Cushing syndrome

Propofol (PROE po fole)

Diprivan, Fresenius Propoven, Propofol-Lipuro

100 mg/10mL

200 mg/20 mL

1,000 mg/100 mL, 500 mg/50 mL (Preservative free available)



General anesthesia, sedation for mechanically ventilated ICU patients, sedation and regional anesthesia

Avoid in patients with egg and soy allergy

Contains 1.1 kcal/mL

Ketamine (KEET a meen)


10, 50, 100 injectable solution

Prefilled IV syringe: 50 mg/5 mL



Procedural sedation, rapid-sequence intubation, analgesia/sedation/agitation, depression, status epilepticus, chronic pain

Can be administered by intravenous, intramuscular, subcutaneous, intranasal, or intraosseous means


Local Anestheticsa,6

Generic Name (pronunciation)

Brand Name

Available Preparations

Onset of Action (minutes)

Duration of Anesthesia (hours)



Bupivacaine (byoo PIV a kane)

Marcaine, Sensorcaine

Injectable formulations (available with and without preservatives):

0.25%, 0.5%, 0.75% (without epinephrine)

0.25%, 0.5%, 0.75% (with epinephrine 1:200,000)




Surgery, dental procedures, obstetrics (includes nerve block and epidural)

Available in preservative-free dextrose injection for spinal anesthesia

Bupivacaine (Liposomal) (byoo PIV a kane lye po SO mal)


Suspension, injection:



Up to 72

Local postsurgical analgesia

Single-dose infiltration or nerve block

Lidocaine (LYE doe kane)

Xylocaine, LidaMantle, Lidoderm, others

Injection: 0.5%, 1%, 1.5%, 2%, 4% (with and without epinephrine; with and without preservatives—MPF)

Topical: solution, ointment, cream, lotion, gel, patch in various strengths



Injection: nerve block, IV administration

Topical: skin, anorectal area, oral area, many others; sterile preparations for ophthalmic use, nebulized inhalation for bronchoscopy

Also used to treat life-threatening cardiac arrhythmias

Mepivacaine (me PIV a kane)

Carbocaine, Polocaine

Injection only: 1%, 1.5%, 2%, 3% with and without preservatives—MPF



Peripheral nerve block, obstetrics (includes epidural), infiltration, dental procedures, pain management

Ropivacaine (roe PIV a kane)


2 mg/mL (10 mL, 20 mL, 100 mL, 200 mL)

5 mg/mL (20 mL, 30 mL, 100 mL, 200 mL)

7.5 mg/20 mL, 10 mg/mL (10 mL, 20 mL)



Surgical anesthesia, epidural for labor pain, postoperative pain management

Reduced toxicity compared to bupivacaine

Tetracaine (TET ra kane)

Altacaine, others

Injection: 0.5%, 1%, 2%, 20 mg for reconstitution

Ophthalmic, mouth/throat solution, ointment


10–20 minutes

Injection: spinal anesthesia

Topical products: local anesthesia, pain relief

Not used with epinephrine

MPF = methylparaben free


Pronunciations have been adapted with permission from USP Dictionary of USAN and International Drug Names (USP Dictionary) © 2022.


Opioid Analgesics6

Generic Name (pronunciation)

Brand Name


Duration of Analgesia (hours)

Equianalgesic Dose (mg)


Drug Class: Phenanthrenes

Mechanism of Action: Opioid Agonists

Codeine (KOE deen)





Often combined with acetaminophen (Tylenol with codeine #3)

Hydrocodone (hye droe KOE done)

Zohydro ER




Often combined with acetaminophen (Lorcet, Norco, Vicodin)

Hydromorphone (hye droe MOR fone)






7.5 (oral)

1.5 (IV)

More potent than morphine; IM administration is not recommended

Morphine (MOR feen)

MS Contin, Roxanol, others






30 (oral)

10 (IV)

The standard opioid to which other opioids are generally compared

Oxycodone (oks i KOE done)

Oxycontin, others




Often combined with acetaminophen (Percocet)

Oxymorphone (oks i MOR fone)




More potent than morphine

Drug Class: Phenanthrenes

Mechanism of Action: Partial Opioid Agonists

Buprenorphine (byoo pre NOR feen)

Buprenex, Butrans, Belbuca Sublocade, Subutex



IM, sublingual



0.3 (IV)

Topical formulation (patch) applied once every 7 days; other formulations (Subutex, Sublocade) used to manage opioid addiction

Drug Class: Phenanthrenes

Mechanism of Action: Opioid Agonists-Antagonists

Butorphanol (byoo TOR fa nole)





2 (IV)

Rarely used; only opioid available as an intranasal formulation

Nalbuphine (NAL byoo feen)




10 (IV)

Rarely used

Drug Class: Phenylpiperidines

Mechanism of Action: Opioid Agonists

Fentanyl (FEN ta nil)

Actiq, Duragesic, Subsys, others






0.125 (IV)

Topical formulation (patch) not for acute pain; other similar drugs include sufentanil and remifentanil

Meperidine (me PER i deen)






300 (oral)

100 (IV)

Less commonly used for analgesia than other drugs; may cause seizures, especially in patients with poor kidney function

Drug Class: Diphenylheptanes

Mechanism of Action: Opioid Agonists

Methadone (METH a done)

Dolophine, Methadose






Used for analgesia; also used to manage opioid addiction; high doses may require heart rhythm monitoring

Drug Class: Miscellaneous

Mechanism of Action: Opioid Agonists

Tramadol (TRA ma dole)





Inhibits reuptake of norepinephrine and serotonin; increases risk of seizures

Tapentadol (ta PEN ta dol)





Inhibits reuptake of norepinephrine; increases risk of seizures


Representative Emergency Opioid Antagonists6

Generic Name (pronunciation)

Brand Name


Dose (mg)

Instructions for Use

Naloxone (nal OKS one)

Narcan, others




0.4–2, up to 10

Remove cap from vial and uncover needle; insert needle into vial and pull back on plunger; administer 0.4–2 mg by injection; administer additional doses every 2–3 minutes if needed; evaluate for other causes of respiratory depression if no response following administration of 10 mg total

Naloxone (nal OKS one)



2, 4

Tilt the individual’s head back and support the neck with one hand; using other hand, insert the nozzle into either nostril; press the plunger firmly to administer a single spray into one nostril; administer additional doses every 2–3 minutes if needed, alternating nostrils, using a new device each time

Naloxone (nal OKS one)




Tilt the individual’s head back and support the neck with one hand; using the other hand, insert the nozzle into either nostril; press the plunger firmly to administer a single spray into one nostril; administer additional doses every 2–3 minutes if needed, alternating nostrils, using a new device each time

Naloxone (nal OKS one)





Preferably administered by individuals 12 years and older; administer into anterolateral thigh by IM or subcutaneous injection; may be injected through clothing if needed; administer additional doses every 2–3 minutes if needed using a new device each time