14.3: Opioid Agonists and Antagonists
By the end of this section, you should be able to:
- 14.3.1 Identify the characteristics of opioid agonist and antagonist drugs used to treat pain.
- 14.3.2 Explain the indications, actions, adverse reactions, and contraindications of opioid agonist and antagonist drugs used to treat pain.
- 14.3.3 Describe nursing implications of opioid agonist and antagonist drugs used to treat pain.
- 14.3.4 Explain the client education related to opioid agonist and antagonist drugs used to treat pain.
Opioid Agonists
Opioid agonist s have been in use for thousands of years. Opioids originated from the opium poppy, Papaver somniferum , from which naturally occurring opioids such as heroin, codeine, and morphine are derived. Since the discovery of the potent analgesic effects of these medications, other opioids have been developed, including hydrocodone and oxycodone. The term opiate strictly refers to agents that come from the opium poppy (e.g., heroin, morphine), but is often used interchangeably with the term opioid . Opioid agonists are some of the most potent analgesics available and are used for treatment of moderate to severe pain. However, opioids carry a risk for misuse and addiction that has led to one of the most notable public health crises to date, the opioid epidemic. Because of these risks, the DEA categorizes all opioids as controlled substances . Most opioids fall under the strict categorization of Schedule II (CII), meaning they have an acceptable medical use but are associated with a high risk for misuse and addiction.
Opioids produce many of their desired therapeutic effects and potentially life-threatening adverse effects via the opioid receptors, including the mu, delta, and kappa receptors. When activated, these receptors located throughout the CNS help modulate painful signals from peripheral tissues to alter pain perception and heighten the pain threshold. These same receptors are also known to cause many of the notable adverse effects of opioids, including the CNS and respiratory depression that can be seen in overdose. Opioid agonists also suppress the cough receptors in the brain and can be used as cough suppressants. However, due to the risk for misuse and addiction, opioid agonists are usually considered last-line treatments for cough.
Codeine
Codeine is one of the naturally occurring opioids derived from the opium poppy. It is most often given orally for mild to moderate pain. For codeine to be effective, it must be converted to morphine in the liver via the enzyme cytochrome P450 2D6 (CYP2D6). Because individuals may produce more or less CYP2D6, clients receiving codeine may experience unpredictable therapeutic and adverse effects. Clients who produce too little CYP2D6 (slow metabolizers) do not convert enough codeine into morphine and thus may not receive adequate analgesia. Clients producing many copies of CYP2D6 (rapid metabolizers) may convert too much codeine into morphine, causing enhanced analgesic effects and a greater risk for life-threatening respiratory depression. Due to this variability in client metabolism and potential risks, the American Academy of Pediatrics does not currently recommend codeine for use in children (Silva et al., 2021). Similarly, codeine should be used with caution in older clients .
Fentanyl
Fentanyl is a potent synthetic opioid that is frequently used intravenously to treat severe pain related to trauma or surgery. It is also available in patches to help provide long-lasting analgesia in clients with chronic pain conditions. Fentanyl is considered a synthetic opioid because it shares no chemical resemblance to naturally occurring opioids such as morphine, which means it can be a safe alternative for clients who have a documented morphine allergy. Because of its potency, fentanyl is often used by clients with opioid use disorders, and it has become a major contributor to opioid-related deaths in the past several years (National Institute on Drug Abuse, 2023).
Hydromorphone
Hydromorphone is a semisynthetic derivative of morphine, meaning it shares some chemical structure similarities with naturally occurring opioids. It is a potent analgesic and is most frequently used for cases of moderate to severe pain. Hydromorphone is available in both intravenous and oral forms, so it is frequently used for clients with severe pain both in and outside the hospital setting.
Meperidine
Meperidine is a synthetic opioid that is not routinely used as an analgesic. This is because it produces a toxic metabolite that can accumulate in older adults with poor renal function, leading to risk for delirium and seizures. Instead, the most common use for meperidine is to interrupt the severe shivering with chills (also known as rigors) that may occur postoperatively in clients who received general anesthesia.
Methadone
Methadone is a synthetic opioid that is most frequently used to treat opioid use disorders. Because of its long half-life, up to 59 hours, it persists in the body longer than many other opioids. This long half-life helps prevent the opioid withdrawal symptoms that can occur when individuals stop using opioids entirely. Methadone’s long half-life also means that it has utility in providing long-lasting pain relief in clients with chronic pain. In addition, it has some efficacy in treating neuropathic pain because it can block the reuptake of the neurotransmitters norepinephrine and serotonin, which helps reduce painful signals from being transmitted to the brain.
Morphine
Morphine is a naturally occurring opioid that has been in widespread use since its discovery in the 1800s. It is considered to be the prototypical opioid to which all others are compared. It is used to treat both acute and chronic types of pain and is available in a wide variety of dosage forms, including intravenous and oral options. Oral forms come in immediate and extended-release formulations, making morphine suitable for breakthrough and around-the-clock types of pain. Because of its high degree of efficacy, morphine is used for moderate to severe pain.
Oxycodone
Oxycodone is a semisynthetic opioid commonly used orally to treat moderate to severe pain. It is frequently used because of its favorable side effect profile compared with other agents such as morphine (for instance, oxycodone causes less itching).
Oxycodone comes in a variety of dosage forms, including immediate- and extended-released preparations, making it useful for acute and chronic pain therapy in outpatient settings. The extended-release formulation, sold under the brand names OxyContin and Xtampza ER, is used to provide around-the-clock pain relief. Clients with chronic pain often need long-acting medications for their basal levels of pain (i.e., the baseline level of pain that is always present) as well as short-acting agents for breakthrough episodes of pain (i.e., pain above the basal level brought on by injury or activity).
Oxycodone is often coformulated with acetaminophen, which nurses should consider when totaling a client’s total daily acetaminophen intake.
Table 14.4 lists common opioid agonists and typical routes and dosing for adult clients.
| Drug | Routes and Dosage Ranges |
|---|---|
| Codeine | Pain: 15–60 mg orally every 4 hours as needed; maximum dose: 360 mg/day. |
|
Fentanyl
( Sublimaze , Duragesic , Actiq ) |
Acute severe pain:
25–50 mcg every 30–60 minutes intravenously (IV) or intramuscularly as needed.
Chronic pain: Transdermal patch; initial fentanyl transdermal dose (25–100 mcg/hour) based on prior 24-hour oral morphine requirement. |
|
Hydromorphone
( Dilaudid ) |
Acute pain:
Intravenous: 0.2–1 mg IV every 2–3 hours as needed. Oral: 2–4 mg orally every 4–6 hours as needed. |
|
Meperidine
( Demerol ) |
Acute pain: 50–150 mg intramuscularly/subcutaneously every 3–4 hours as needed; maximum dose: 600 mg/day. |
|
Methadone
( Dolophine ) |
Chronic pain: Dosing is individualized; typical dose: 2.5–5 mg orally every 8–12 hours. |
|
Morphine
( Duramorph , MS Contin ) |
Acute pain:
Intravenous: 0.1–0.2 mg/kg IV every 1–4 hours as needed. Oral: 15–30 mg orally every 4 hours as needed. |
|
Oxycodone
( Roxicodone , OxyContin ) |
Immediate-release for acute pain:
5–15 mg orally every 4–6 hours as needed.
Extended-release for chronic pain : 10 mg orally every 12 hours. |
Adverse Effects and Contraindications
Adverse effects of opioid therapy can range from general gastrointestinal upset to life-threatening respiratory depression. The most common are gastrointestinal effects, including nausea, vomiting, and constipation. Nearly all clients receiving chronic opioid therapy will develop constipation, so nurses should assess for this to help determine which type of constipation treatment (laxatives, stool softeners, stimulants, fiber supplements) the client needs to ensure regular bowel movements. A handy mnemonic for adverse effects is NARCS U : nausea, acute toxicity/addiction, respiratory depression, constipation, sedation, and urinary retention.
Morphine is known to cause significant histamine release in susceptible clients and may manifest as flushing, pruritis, and hypotension. This situation is normally managed by using an alternative opioid that does not cause histamine release (e.g., hydromorphone or oxycodone) or treating the client with an antihistamine such as diphenhydramine to combat the actions of histamine release. (Antihistamines are discussed in Upper Respiratory Disorder Drugs.)
In overdose or in combination with other CNS depressants (e.g., benzodiazepines, muscle relaxants, alcohol), the most dangerous effects seen with opioids include CNS and respiratory depression. The individual may appear sedated or can be completely unresponsive, and their breathing may be slow, shallow, or absent. These signs constitute a medical emergency and necessitate the use of an opioid antagonist such as naloxone hydrochloride (discussed in the following section) along with the response of emergency medical services.
Opioids should be avoided in clients with any known hypersensitivities to them or to any of their constituent components. Clients with documented allergies to naturally occurring opioids such as morphine are generally able to safely receive synthetic opioids such as fentanyl because the chemical structures differ enough that there is low cross-sensitivity between these agents. Clients with significant respiratory depression or gastrointestinal obstruction should also avoid opioids because these conditions can worsen when opioids are present in the body.
Clinical Tip
Assess for Constipation
Opioid agonists are well known to cause significant constipation when taken chronically. Constipation can cause or worsen abdominal pain and may distress the client. The nurse should recommend to most clients that they consume more water and fiber in their diet. Many clients will need to use laxatives such as senna and docusate to ensure normal stooling habits.
Table 14.5 is a drug prototype table for opioid agonists featuring morphine. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.
|
Drug Class
Opioid analgesic Mechanism of Action Activates opioid receptors to modulate and reduce incoming painful signals to reduce pain perception |
Drug Dosage
Intravenous: 0.1–0.2 mg/kg IV every 1–4 hours as needed. Oral: 15–30 mg orally every 4 hours as needed. |
|
Indications
Moderate to severe pain Therapeutic Effects Reduced pain perception |
Drug Interactions
Alprazolam Diphenhydramine Cyclobenzaprine Food Interactions Alcohol |
|
Adverse Effects
Edema Flushing Hypotension Tachycardia Rash Central nervous system depression Respiratory depression Dizziness Drowsiness Euphoria Miosis Blurred vision |
Contraindications
Hypersensitivity Respiratory depression Severe asthma Paralytic ileus Caution: CNS depression Hypotension Abdominal conditions Hepatic impairment Renal impairment Thyroid dysfunction Mental health conditions |
Nursing Implications
The nurse should do the following for clients who are taking an opioid:
- Assess the client’s pain before and after administering an opioid to determine its efficacy in treating the client’s pain.
- Watch for adverse effects, including sedation, ataxia, slurred speech, and shallow breathing, which could require the use of antidotal therapy or respiratory support.
- With chronic use of opioids, ask about the client’s bowel movements because constipation is very common with these medications and could be a source of abdominal pain.
- Ensure that naloxone is readily available in the event of opioid toxicity or overdose.
- Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.
Safety Alert
Opioid Agonists
Although respiratory depression is rare when opioid agonists are used in therapeutic doses, nurses should instruct clients not to mix opioids with other CNS depressants, including sedatives, alcohol, and muscle relaxants, because this interaction will increase the risk for potentially fatal respiratory failure. Naloxone hydrochloride should be coprescribed to clients who are at greater risk for opioid overdose.
Client Teaching Guidelines
The client taking an opioid agonist should:
- Alert their health care provider before starting opioid agonist therapy if they have any breathing difficulties, asthma, or sleep apnea.
- Alert their health care provider about any signs or symptoms of allergic reactions, including throat swelling, severe itching, rash, or chest tightness.
- Take the lowest dose needed, if prescribed as as-needed (prn) use, to control pain to reduce the risk of dependence.
- Alert all health care providers that they are taking opioids, including the dose and frequency.
- Take a missed dose as soon as they remember it; however, they should not take double doses.
- Keep all medication out of the reach of children and pets.
The client taking an opioid agonist should not:
- Crush or chew the product if taking an extended-release drug.
- Mix opioids with other CNS depressants, including sedatives, alcohol, and muscle relaxants, because their interaction increases the risk for potentially fatal respiratory failure.
- Share opioids with family or friends because this practice can lead to harm or even death.
FDA Black Box Warning
Opioid Agonists
Opioid agonists expose clients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each client’s risk prior to prescribing and reassess all clients regularly for the development of these behaviors and conditions.
Serious, life-threatening, or fatal respiratory depression may occur with use of opioid agonists. Monitor for respiratory depression, especially during initiation of opioid agonists or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of opioid agonists is essential.
Accidental ingestion of opioid agonists, especially by children, can be fatal.
Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of tramadol and benzodiazepines or other CNS depressants for use in clients for whom alternative treatment options are inadequate. Limit treatment to the minimum effective dosages and durations. Follow clients for signs and symptoms of respiratory depression and sedation.
Prolonged use of opioid agonists during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant client, advise the client of the risk for neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Tolerance and Addiction
Tolerance and addiction are two important topics concerning the use of opioid medications. Clients and health care professionals can misunderstand the definitions of these terms and how likely the conditions are to occur. It is important for nurses to understand these terms and how they apply to clients using opioids.
Tolerance
Tolerance is a phenomenon that occurs in clients taking opioid agonists chronically. As the body adapts to the presence of the drug, the client will become accustomed to some of the side effects, including sedation, and it may appear as if the dose that previously treated the client’s pain is no longer adequate. Therefore, the opioid dose may need to be increased to treat the client’s pain adequately. In fact, clients can develop so much tolerance that the dose that is appropriate for them would be potentially dangerous to someone who has never taken an opioid agonist. This tolerance is a normal phenomenon that occurs in nearly all clients receiving chronic opioid agonists and should not be confused with addiction.
Clients who have developed a significant amount of tolerance to the effects of opioids are at risk for developing withdrawal symptoms when the medication is discontinued. Opioid withdrawal can be extremely distressing to the client and may result in agitation, sweating, diarrhea, and severe dysphoria. Fortunately, opioid agonist withdrawal is not associated with significant mortality, in contrast to withdrawal from CNS depressants such as alcohol or benzodiazepines, which can cause seizures and is associated with greater mortality risk.
Addiction
Opioid addiction (also called opioid use disorder ) is a condition characterized by compulsive use of opioids, increased opioid tolerance, and withdrawal symptoms if the client does not continue taking an opioid agonist. This compulsion can be so strong in susceptible individuals that they will continue using opioids despite the known physical, financial, and social harms that it may be causing. It is estimated that in the United States, 2.1 million individuals have opioid use disorders and 47,000 deaths are attributable to opioid agonists each year (Wilson et al., 2020).
Addiction typically occurs as a result of dopamine release in the reward pathway of the brain, also known as the dopaminergic pathway. This causes an intense euphoria that often leaves the client wanting more opioids to feel that same elation repeatedly. Risk factors for developing an opioid use disorder include genetic and environmental factors. Clients with a history of certain mental health disorders, such as post-traumatic stress disorder and depression, have been shown to be at risk for various substance use disorders as well (National Institute on Drug Abuse, 2022).
It is important to determine how clients are obtaining their opioids because not all opioids are obtained legally. Nurses also should ask about the illicit use of opioids, such as heroin, that may not be documented in the medical chart.
Not all clients who use opioids will develop opioid use disorders; however, this possibility is a concern for many clients who may have pain but refuse all opioids based on the small risk of addiction. It is important to counsel clients about the differences between tolerance and addiction to ensure they feel comfortable getting the best care that is right for them. Tolerance and physical dependence will occur in nearly all clients receiving chronic opioid therapy, but only some will go on to develop an opioid use disorder.
Unfolding Case Study
Part B
Read the following clinical scenario to answer the questions that follow. This case study is a follow-up to Unfolding Case Study Part A.
Two months after the last encounter, Maria Vega presents to the emergency department following a fall at home. She rates her right ankle pain as 6/10 on a 0- to 10-point pain scale. She is diagnosed with a right ankle fracture.
History
Coronary artery disease
Osteoarthritis
Current Medications
Aspirin 81 mg orally once daily
Metoprolol 50 mg orally twice daily
Over-the-counter ibuprofen 400 mg orally every 4–6 hours as needed for joint pain
| Vital Signs | Physical Examination | |
|---|---|---|
| Temperature: | 97.4°F |
|
| Blood pressure : | 146/66 mm Hg | |
| Heart rate : | 93 beats/min | |
| Respiratory rate: | 18 breaths/min | |
| Oxygen saturation: | 96% on room air | |
| Height : | 5'3" | |
| Weight: | 122 lb |
Based on the information above, which medication does the nurse anticipate the provider will order for the client’s pain?
- Answer
-
Hydromorphone
The health care provider prescribes hydromorphone for the client’s ankle pain. Which information will the nurse give the client about this drug?
- Answer
-
“Do not drink alcohol while you’re taking this medication.”
Opioid Antagonists
Opioid analgesics are extremely effective when used to manage moderate to severe forms of pain but can cause potentially life-threatening CNS and respiratory depression when the recommended dosage is exceeded or when individuals use them along with other CNS depressants (e.g., alcohol). It is critical that agents are available to reverse the effects of opioids to avoid severe injury and potential death. This section will cover these opioid antagonist s.
Naloxone Hydrochloride
Naloxone hydrochloride is an opioid receptor antagonist that is used as an antidote in people experiencing signs and symptoms of opioid agonist overdose, including severe CNS and respiratory depression. Overdose may present as shallow or absent breathing, and the person may be unresponsive to any type of stimuli. Naloxone works by blocking the opioid receptors, thus causing a rapid reversal of opioid agonist effects. Because the individual will be too sedated to administer the medication themselves, it will often be given by emergency medical services, law enforcement officers, or bystanders with access to naloxone. Naloxone can be given intravenously, intramuscularly, or intranasally.
Importantly, naloxone has a duration of action of only approximately 20–30 minutes. This short duration means the individual may resedate because many opioids have a longer duration of action than naloxone does. This is why it is critical that those who respond to naloxone receive medical care as quickly as possible to prevent delaying more definitive therapy. The only major adverse effect of naloxone is that it can induce severe opioid withdrawal in individuals who chronically use opioids; they may become very agitated, develop diarrhea, and experience intense dysphoria. To avoid these consequences of sudden withdrawal, smaller doses may be administered in quick succession until the individual is able to breathe on their own.
Naltrexone Hydrochloride
Naltrexone hydrochloride is an opioid receptor antagonist. It is not often given for emergency reversal of opioid intoxication but is instead used for clients who want to abstain from opioid use. It is orally bioavailable, and when a client has been taking it orally, it will blunt the effects of opioids if the client relapses and begins to use opioids again. Long-acting formulations of naltrexone can also be administered intramuscularly every 4 weeks to ensure client compliance during this period. Adverse effects of naltrexone are similar to those of naloxone in that it can induce opioid withdrawal in clients who are actively using opioids.
Recent research suggests that naltrexone can be used in combination with other medications to treat a variety of addictive conditions, such as eating disorders (Stancil et al., 2019). See Substance Use Disorder Treatment Drugs for more information on naltrexone.
Nalbuphine Hydrochloride
Nalbuphine is a mixed opioid agonist/antagonist. On its own, it can serve as an alternative to other opioid agonists when treating pain. At lower doses, it acts as an antagonist and can reverse the depressant effects of other opioid agonists.
Table 14.7 lists common opioid antagonists and typical routes and dosing for adult clients.
| Drug | Routes and Dosage Ranges |
|---|---|
|
Naloxone hydrochloride
( Narcan ) |
Opioid overdose (known or suspected):
0.4–2 mg as needed. Intranasal spray: 4–8 mg in one nostril every 2–3 minutes until medical assistance is available. |
|
Naltrexone hydrochloride
( Vivitrol ) |
Treatment of opioid dependence:
Oral: 25–50 mg daily. Intramuscular: 380 mg every 4 weeks. |
|
Nalbuphine
hydrochloride
( Nubain ) |
Acute pain: 10 mg subcutaneously/intramuscularly/IV every 3–6 hours as needed. |
Table 14.8 is a drug prototype table for opioid antagonists featuring naloxone. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.
|
Drug Class
Opioid antagonist Mechanism of Action Competitively antagonizes opioid receptors to reverse the depressant effects of opioids |
Drug Dosage
Opioid overdose (known or suspected): IV: 0.4–2 mg as needed. Intranasal spray: 4–8 mg in one nostril every 2–3 minutes until medical assistance is available. |
|
Indications
Opioid overdose Therapeutic Effects Reversal of opioid effects |
Drug Interactions
Opioid agonists Food Interactions No significant interactions |
|
Adverse Effects
Flushing Hypotension Tachycardia Diaphoresis Abdominal cramps Diarrhea Agitation Disorientation Dizziness |
Contraindications
Hypersensitivity Caution: Acute opioid withdrawal |
Trending Today
Over-the-Counter Naloxone
In March 2023, the U.S. Food and Drug Administration approved naloxone hydrochloride nasal spray to be sold over the counter to increase access to this life-saving medication (U.S. Food and Drug Administration, 2023). This change in the status of naloxone has paved the way to making it available in a variety of locations outside of pharmacies, including Internet retailers, gas stations, and grocery stores. This change is a crucial step to address the number of opioid overdose deaths that occur in the United States every year, as getting naloxone even a few minutes before emergency medical services arrive could mean the difference between life and death. A New York Times podcast describes the importance of naloxone becoming available over the counter.