Pure Opioid Agonists Morphine Agonist-Antagonist Opioids Pentazocine Pure Opioid Antagonists Naloxone
Basic Pharmacology of the Opioids
Morphine
Morphine is the prototype of the strong opioid analgesics and remains the standard by which newer opioids are measured. Morphine has multiple pharmacologic effects, including analgesia, sedation, euphoria, respiratory depression, cough suppression, and suppression of bowel motility.
Overview of Pharmacologic Actions
Morphine has multiple pharmacologic actions. In addition to relieving pain, the drug causes drowsiness and mental clouding, reduces anxiety, and creates a sense of well-being. Through actions in the CNS and periphery, morphine can cause respiratory depression, constipation, urinary retention, orthostatic hypotension, emesis, miosis, cough suppression, and biliary colic. With prolonged use, the drug produces tolerance and physical dependence.
Individual effects of morphine may be beneficial, detrimental, or both. For example, analgesia is clearly beneficial, whereas respiratory depression and urinary retention are clearly detrimental. Certain other effects, such as sedation and reduced bowel motility, may be beneficial or detrimental, depending on the circumstances of drug use.
Therapeutic Use: Relief of Pain
The principal indication for morphine is relief of moderate to severe pain. The drug can relieve postoperative pain, pain of labor and delivery, and chronic pain caused by cancer and other conditions.
Morphine relieves pain without causing loss of consciousness. The drug is more effective against constant, dull pain than against sharp, intermittent pain. However, even sharp pain can be relieved by large doses. The ability of morphine to cause mental clouding, sedation, euphoria, and anxiety reduction can contribute to relief of pain.
The use of morphine and other opioids to relieve pain is discussed further in this chapter and in Chapter 83.
Adverse Effects
Respiratory Depression
Respiratory depression is the most serious adverse effect. At equianalgesic doses, all of the pure opioid agonists depress respiration to the same extent. Death after an overdose is almost always from respiratory arrest. Opioids depress respiration primarily through activation of mu receptors, although activation of kappa receptors also contributes.
The time course of respiratory depression begins up to 90 minutes after PO ingestion. With prolonged use of opioids, tolerance develops to respiratory depression. Huge doses that would be lethal to a nontolerant individual have been taken by opioid addicts without noticeable effect. Similarly, tolerance to respiratory depression develops during long-term clinical use of opioids (e.g., in patients with cancer). Certain patients, including the very young, older adults, and those with respiratory disease (e.g., asthma, emphysema), are especially sensitive to respiratory depression and hence must be monitored closely. Outpatients should be informed about the risk for respiratory depression and instructed to notify the prescriber if respiratory distress occurs.
Pronounced respiratory depression can be reversed with naloxone [Narcan], an opioid antagonist. However, dosing must be carefully titrated because excessive doses will completely block the analgesic effects of morphine, causing pain to return.
Black Box Warning
Opioids
Opioid medications can cause respiratory arrest in both opioid-naïve and opioid-tolerant patients. Monitor for respiratory depression, especially during new-onset therapy or after escalation of dose.
Constipation
Opioids promote constipation through actions in the CNS and gastrointestinal (GI) tract. Specifically, by activating mu receptors in the gut, these drugs can suppress propulsive intestinal contractions, intensify nonpropulsive contractions, increase the tone of the anal sphincter, and inhibit secretion of fluids into the intestinal lumen. As a result, constipation can develop after a few days of opioid use. Potential complications of constipation include fecal impaction, bowel perforation, rectal tearing, and hemorrhoids.
Opioid-induced constipation can be managed with a combination of pharmacologic and nonpharmacologic measures. The goal is to produce a soft, formed stool every 1 to 2 days. Principal nondrug measures are physical activity and increased intake of fiber and fluids (for prevention) and enemas (for treatment). Most patients also require prophylactic drugs: a stimulant laxative, such as senna, is given to counteract reduced bowel motility; a stool softener, such as docusate [Colace], plus polyethylene glycol (an osmotic laxative) can provide additional benefit. If these prophylactic drugs prove inadequate, the patient may need rescue therapy with a strong osmotic laxative, such as lactulose or sodium phosphate. As a last resort, patients may be given methylnaltrexone [Relistor], an oral drug that blocks mu receptors in the intestine. As discussed later in the chapter, methylnaltrexone can’t cross the blood-brain barrier and hence does not reverse opioid-induced analgesia.
Because of their effects on the intestine, opioids are highly effective for treating diarrhea. In fact, antidiarrheal use of these drugs preceded analgesic use by centuries. The impact of opioids on intestinal function is an interesting example of how an effect can be detrimental (constipation) or beneficial (relief of diarrhea) depending on who is taking the medication. Opioids employed specifically to treat diarrhea are discussed in Chapter 64.
Orthostatic Hypotension
Morphine-like drugs lower blood pressure by blunting the baroreceptor reflex and by dilating peripheral arterioles and veins. Peripheral vasodilation results primarily from morphine-induced release of histamine.
Urinary Retention
Morphine can cause urinary hesitancy and urinary retention. Three mechanisms are involved. First, morphine increases tone in the bladder sphincter. Second, morphine increases tone in the detrusor muscle, thereby elevating pressure within the bladder, causing a sense of urinary urgency. Third, in addition to its direct effects on the urinary tract, morphine may interfere with voiding by suppressing awareness of bladder stimuli. To reduce discomfort, patients should be encouraged to void every 4 hours. Urinary hesitancy or retention is especially likely in patients with benign prostatic hypertrophy. Drugs with anticholinergic properties (e.g., tricyclic antidepressants, antihistamines) can exacerbate the problem.
In addition to causing urinary retention, morphine may decrease urine production largely by decreasing renal blood flow, and partly by promoting release of antidiuretic hormone.
Emesis
Morphine promotes nausea and vomiting through direct stimulation of the chemoreceptor trigger zone of the medulla. Emetic reactions are greatest with the initial dose and then diminish with subsequent doses. Nausea and vomiting are uncommon in recumbent patients but occur in 15% to 40% of ambulatory patients, suggesting a vestibular component. Nausea and vomiting can be reduced by pretreatment with an antiemetic (e.g., prochlorperazine) and by having the patient remain still.
Euphoria and Dysphoria
Euphoria is defined as an exaggerated sense of well-being. Morphine often produces euphoria when given to patients in pain. Although euphoria can enhance pain relief, it also contributes to the drug’s potential for abuse. Euphoria is caused by activation of mu receptors.
In some individuals, morphine causes dysphoria (a sense of anxiety and unease). Dysphoria is uncommon among patients in pain but may occur when morphine is taken in the absence of pain.
Sedation
When administered to relieve pain, morphine is likely to cause drowsiness and some mental clouding. Although these effects can complement analgesic actions, they can also be detrimental. Outpatients should be warned about CNS depression and advised to avoid hazardous activities (e.g., driving) if sedation is significant. Sedation can be minimized by taking smaller doses more often or using opioids that have short half-lives.
Neurotoxicity
Opioid-induced neurotoxicity can cause delirium, agitation, myoclonus, hyperalgesia, and other symptoms. Primary risk factors are renal impairment, preexisting cognitive impairment, and prolonged, high-dose opioid use. Management consists of hydration and dose reduction. For patients who must take opioids long term, opioid rotation (periodically switching from one opioid to another) may reduce neurotoxicity development.
Pharmacokinetics
With oral morphine therapy, duration of action depends on the formulation. For example, with immediate-release (IR) tablets, effects last 4 to 5 hours, whereas with extended-release (ER) capsules, effects last 24 hours.
To relieve pain, morphine must cross the blood-brain barrier and enter the CNS. Because the drug has poor lipid solubility, it does not cross the barrier easily. Consequently, only a small fraction of each dose reaches sites of analgesic action. Because the blood-brain barrier is not well developed in infants, these patients generally require lower doses than do older children and adults.
Morphine is inactivated by hepatic metabolism. When taken by mouth, the drug must pass through the liver on its way to the systemic circulation. Much of an oral dose is inactivated during this first pass through the liver. In patients with liver disease, analgesia and other effects may be intensified and prolonged. Accordingly, it may be necessary to reduce the dosage or lengthen the dosing interval.
Tolerance and Physical Dependence
With continuous use, morphine can cause tolerance and physical dependence. These phenomena, which are generally inseparable, reflect cellular adaptations that occur in response to prolonged opioid exposure.
Tolerance
Tolerance can be defined as a state in which a larger dose is required to produce the same response that could formerly be produced with a smaller dose. Alternatively, tolerance can be defined as a condition in which a particular dose now produces a smaller response than it did when treatment began. Because of tolerance, dosage must be increased to maintain analgesic effects.
Tolerance develops to many—but not all—of morphine’s actions. With prolonged treatment, tolerance develops to analgesia, euphoria, and sedation. As a result, with long-term therapy, an increase in dosage may be required to maintain these desirable effects. Fortunately, as tolerance develops to these therapeutic effects, tolerance also develops to respiratory depression. As a result, the high doses needed to control pain in the tolerant individual are not associated with increased respiratory depression.
Very little tolerance develops to constipation and miosis. Even in highly tolerant addicts, constipation remains a chronic problem, and constricted pupils are characteristic.
Cross-tolerance exists among the opioid agonists (e.g., oxycodone, methadone, fentanyl, codeine, heroin). Accordingly, individuals tolerant to one of these agents will be tolerant to all the others. No cross-tolerance exists between opioids and general CNS depressants (e.g., barbiturates, ethanol, benzodiazepines, general anesthetics).
Physical Dependence
Physical dependence is defined as a state in which an abstinence syndrome will occur if drug use is abruptly stopped. Opioid dependence results from adaptive cellular changes that occur in response to the continuous presence of these drugs. Although the exact nature of these changes is unknown, it is clear that, after these compensatory changes have taken place, the body requires the continued presence of opioids to function normally. If opioids are withdrawn, an abstinence syndrome usually will follow.
The intensity and duration of the opioid abstinence syndrome depends on two factors: the half-life of the drug being used and the degree of physical dependence. With opioids that have relatively short half-lives (e.g., morphine), symptoms of abstinence are intense but brief. In contrast, with opioids that have long half-lives (e.g., methadone), symptoms are less intense but more prolonged. With any opioid, the intensity of withdrawal symptoms parallels the degree of physical dependence.
For individuals who are highly dependent, the abstinence syndrome can be extremely unpleasant. Initial reactions include yawning, rhinorrhea, and sweating. Onset occurs about 10 hours after the final dose. These early responses are followed by anorexia, irritability, tremor, and “gooseflesh”—hence the term cold turkey. At its peak, the syndrome manifests as violent sneezing, weakness, nausea, vomiting, diarrhea, abdominal cramps, bone and muscle pain, muscle spasm, and kicking movements—hence the term kicking the habit. Giving an opioid at any time during withdrawal rapidly reverses all signs and symptoms. Left untreated, the morphine withdrawal syndrome runs its course in 7 to 10 days. It should be emphasized that, although withdrawal from opioids is unpleasant, the syndrome is rarely dangerous. In contrast, withdrawal from general CNS depressants (e.g., barbiturates, alcohol) can be lethal (see Chapter 27).
To minimize the abstinence syndrome, opioids should be withdrawn gradually. When the degree of dependence is moderate, symptoms can be avoided by administering progressively smaller doses over 3 days. When the patient is highly dependent, dosage should be tapered more slowly—over 7 to 10 days. With a proper withdrawal schedule, withdrawal symptoms will resemble those of a mild case of flu—even when the degree of dependence is high.
It is important to note that physical dependence is rarely a complication when opioids are taken acutely to treat pain. Hospitalized patients receiving morphine 2 to 3 times a day for up to 2 weeks show no significant signs of dependence. If morphine is withheld from these patients, no significant signs of withdrawal can be detected. The issue of physical dependence as a clinical concern is discussed further later in the chapter.
Infants exposed to opioids in utero may be born drug dependent. If the infant is not provided with opioids, an abstinence syndrome will ensue. Signs of withdrawal include excessive crying, sneezing, tremor, hyperreflexia, fever, and diarrhea. The infant can be weaned from drug dependence by administering dilute paregoric in progressively smaller doses.
Cross-dependence exists among pure opioid agonists. As a result, any pure agonist will prevent withdrawal in a patient who is physically dependent on any other pure agonist.
Abuse Liability
Morphine and the other opioids are subject to abuse, largely because of their ability to cause pleasurable experiences (e.g., euphoria and sedation). Physical dependence contributes to abuse: when dependence exists, the ability of opioids to ward off withdrawal serves to reinforce their desirability in the mind of the abuser.
The abuse liability of the opioids is reflected in their classification under the Controlled Substances Act. (The provisions of this act are discussed in Chapter 30.) As shown in Table 22.3, morphine and all other strong opioid agonists are classified under Schedule II. This classification reflects a moderate to high abuse liability. The agonist-antagonist opioids have a lower abuse liability and hence are classified under Schedule IV (butorphanol, pentazocine) or Schedule III (buprenorphine), or have no classification at all. Health care personnel who prescribe, dispense, and administer opioids must adhere to the procedures set forth in the Controlled Substances Act.
TABLE 22.3
Interactions of Morphine-Like Drugs With Other Drugs
| Interacting Drugs | Outcome of the Interaction |
| ADVERSE INTERACTIONS | |
| Increased respiratory depression and sedation | |
| Agonist-antagonist opioids | Precipitation of a withdrawal reaction |
| Increased constipation and urinary retention | |
| Hypotensive agents | Increased hypotension |
| Monoamine oxidase inhibitors | Hyperpyrexic coma |
| BENEFICIAL INTERACTIONS | |
| Amphetamines | Increased analgesia and decreased sedation |
| Antiemetics | Suppression of nausea and vomiting |
| Naloxone | Suppression of symptoms of opioid overdose |
| Dextromethorphan | Increased analgesia; possible reduction in tolerance |
Fortunately, abuse is rare when opioids are employed to treat pain. The issue of abuse as a clinical concern is addressed in depth later in the chapter.
Precautions
Some patients are more likely than others to experience adverse effects. Common sense dictates that opioids be used with special caution in these people. Conditions that can predispose patients to adverse reactions are discussed next.
Decreased Respiratory Reserve
Because morphine depresses respiration, it can further compromise respiration in patients with impaired pulmonary function. Accordingly, the drug should be used with caution in patients with asthma, emphysema, kyphoscoliosis, chronic cor pulmonale, and extreme obesity. Caution is also needed in patients taking other drugs that can depress respiration (e.g., barbiturates, benzodiazepines, general anesthetics).
Other Precautions
Infants and older-adult patients are especially sensitive to morphine-induced respiratory depression. In patients with inflammatory bowel disease, morphine may cause toxic megacolon or paralytic ileus. Because morphine and all other opioids are inactivated by liver enzymes, effects may be intensified and prolonged in patients with liver impairment. Severe hypotension may occur in patients with preexisting hypotension or reduced blood volume. In patients with benign prostatic hypertrophy, opioids may cause acute urinary retention; repeated catheterization may be required.
Drug Interactions
The major interactions between morphine and other drugs are shown in Table 22.3. Some interactions are adverse, and some are beneficial.
Toxicity
Clinical Manifestations
Opioid overdose produces a classic triad of signs: coma, respiratory depression, and pinpoint pupils. Coma is profound, and the patient cannot be aroused. Respiratory rate may be as low as 2 to 4 breaths/minute. Although the pupils are constricted initially, they may dilate as hypoxia sets in (secondary to respiratory depression). Hypoxia may cause blood pressure to fall. Prolonged hypoxia may result in shock. When death occurs, respiratory arrest is almost always the immediate cause.
Treatment
Treatment consists primarily of ventilatory support and giving an opioid antagonist. Naloxone [Narcan] is the traditional antagonist of choice. The pharmacology of the opioid antagonists is discussed later.
Preparations
Morphine Alone
Morphine sulfate, by itself, is available in eight nonparenteral formulations:
• Controlled-release tablets (15, 30, 60, 100, and 200 mg) sold as MS Contin
• ER tablets (20, 30, 50, 60, 80, and 100 mg)
• Sustained-release capsules (10, 20, 30, 40, 50, 60, 70, 80, 100, 130, 150, and 200 mg) sold as Kadian and Morphine SR 
• ER capsules (10, 30, 45, 60, 75, 90, 100, 120, and 200 mg) sold as M-Eslon 
• Standard oral solution (10 and 20 mg/5 mL) sold as MSIR
• Concentrated oral solution (100 mg/5 mL) sold as MSIR
• Rectal suppositories (5, 10, 20, and 30 mg) sold as Statex 
Morphine and Naltrexone [Embeda]
In 2010, the U.S. Food and Drug Administration (FDA) approved Embeda, a fixed-dose combination of morphine and naltrexone, an opioid antagonist (see later). The product is designed to discourage morphine abuse. Embeda capsules are filled with tiny pellets that have an outer layer of ER morphine and an inner core of naltrexone. When the capsules are swallowed intact, only the morphine is absorbed. However, if the pellets are crushed, the naltrexone will be absorbed too, thereby blunting the effects of the morphine. As a result, potential abusers cannot get a quick high by crushing the pellets to release all of the morphine at once. However, abusers can still get high by simply taking a large dose. Embeda capsules are more expensive than other ER morphine products and should be prescribed only when abuse appears likely.
Alcohol can accelerate release of morphine from Embeda pellets. As a result, the entire dose can be absorbed quickly—rather than over 24 hours—thereby causing a potentially fatal spike in morphine blood levels. Accordingly, patients should be warned against alcohol consumption.
Embeda capsules are available in six morphine/naltrexone strengths: 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, and 100 mg/4 mg. Dosing is done once or twice daily. Patients can swallow Embeda capsules whole, or they can open the capsules and sprinkle the pellets on applesauce, which must be ingested without chewing.
Dosage and Administration
General Guidelines
Dosage must be individualized. High doses are required for patients with a low tolerance to pain or with extremely painful disorders. Patients with sharp, stabbing pain need higher doses than patients with dull pain. Older adults generally require lower doses than younger adults. Neonates require relatively low doses because their blood-brain barrier is not fully developed. For all patients, dosage should be reduced as pain subsides. Outpatients should be warned not to increase dosage without consulting the prescriber.
Routes and Dosages
Oral
Oral dosing is generally reserved for patients with chronic, severe pain, such as that associated with cancer. Because oral morphine undergoes extensive metabolism on its first pass through the liver, oral doses are usually higher than parenteral doses. A typical dosage is 10 to 30 mg repeated every 4 hours as needed. However, oral dosing is highly individualized, and some patients may require 75 mg or more. Controlled-release formulations may be administered every 8 to 12 hours, and the ER formulation [Kadian] is given every 12 to 24 hours. Patients should be instructed to swallow these products intact, without crushing or chewing. Also, warn patients using Kadian or Embeda capsules not to drink alcohol, which can accelerate release of morphine from these products.
Other Strong Opioid Agonists
In an effort to produce a strong analgesic with a low potential for respiratory depression and abuse, pharmaceutical scientists have created many new opioid analgesics. However, none of the newer pure opioid agonists can be considered truly superior to morphine; these drugs are essentially equal to morphine with respect to analgesic action, abuse liability, and the ability to cause respiratory depression. Also, to varying degrees, they all cause sedation, euphoria, constipation, urinary retention, cough suppression, hypotension, and miosis. However, despite their similarities to morphine, the newer drugs do have unique qualities. Hence one agent may be more desirable than another in a particular clinical setting. With all of the newer pure opioid agonists, toxicity can be reversed with an opioid antagonist (e.g., naloxone). Important differences between morphine and the newer strong opioid analgesics are discussed later. Table 22.4 shows dosages, routes, and time courses for morphine and the newer agents.
TABLE 22.4
Clinical Pharmacology of Pure Opioid Agonists
| Time Course of Analgesic Effects | ||||
| Drug and Route* | Equianalgesic Dose (mg)† | Onset (min) | Peak (min) | Duration (hr) |
| Codeine | ||||
| PO | 200 | 30-45 | 60-120 | 4-6 |
| Fentanyl | ||||
| Transdermal | — | Delayed | 24-72 | 72 |
| Transmucosal‡ | — | 10-15 | 20 | 1-2 |
| Nasal spray | — | 10-15 | 15-20 | 1-2 |
| Hydrocodone | ||||
| PO | 30 | 10-30 | 30-60 | 4-6 |
| Hydromorphone | ||||
| PO (IR) | 7.5 | 30 | 90-120 | 4 |
| PO (ER) | 7.5 | — | 360-480 | 18-24 |
| Levorphanol | ||||
| PO | 4 | 10-60 | 90-120 | 6-8 |
| Meperidine | ||||
| PO | 300 | 15 | 60-90 | 2-4 |
| Methadone | ||||
| PO | 20 | 30-60 | 90-120 | 4-6§ |
| Morphine | ||||
| PO (IR) | 30 | — | 60-120 | 4-5 |
| PO (ER) | 30 | — | 420 | 8-12 |
| Oxycodone | ||||
| PO (IR) | 20 | 15-30 | 60 | 3-4 |
| PO (CR) | 20 | — | 120-180 | Up to 12 |
| Oxymorphone | ||||
| PO (IR) | 10 | — | — | 4-6 |
| PO (ER) | 10 | — | — | Up to 12 |
| Rectal | 10 | 15-30 | 120 | 3-6 |
| Tapentadol | ||||
| PO | 100 | 45-60 | 90-120 | 4-8 |
Fentanyl
Fentanyl [Duragesic, Abstral, Actiq, Fentora, Onsolis, Lazanda, Subsys] is a strong opioid analgesic with a high milligram potency (about 100 times that of morphine). Eight formulations are available for administration by four different routes: parenteral, transdermal, transmucosal, and intranasal. Depending on the route, fentanyl may be used for surgical analgesia, chronic pain control, and control of breakthrough pain in patients taking other opioids. All preparations are regulated under Schedule II of the Controlled Substances Act.
Fentanyl, regardless of route, has the same adverse effects as other opioids: respiratory depression, sedation, constipation, urinary retention, and nausea. Of these, respiratory depression is the greatest concern. Signs of toxicity can be reversed with an opioid antagonist (e.g., naloxone).
Fentanyl is metabolized by CYP3A4 (the 3A4 isoenzyme of cytochrome P450), and hence fentanyl levels can be increased by CYP3A4 inhibitors (e.g., ritonavir, ketoconazole). Patients taking these inhibitors should be closely monitored for severe respiratory depression and other signs of toxicity.
Transdermal System
The fentanyl transdermal system [Duragesic] consists of a fentanyl-containing patch that is applied to the skin of the upper torso. The drug is slowly released from the patch and absorbed through the skin, reaching effective levels in 24 hours. Levels remain steady for another 48 hours, after which the patch should be replaced. If a new patch is not applied, effects will nonetheless persist for several hours, owing to continued absorption of residual fentanyl remaining in the skin.
Transdermal fentanyl is indicated only for persistent severe pain in patients who are already opioid tolerant. Use in nontolerant patients can cause fatal respiratory depression. The patch should not be used in children younger than 2 years or in anyone younger than 18 years who weighs less than 110 pounds. Also, the patch should not be used for postoperative pain, intermittent pain, or pain that responds to a less powerful analgesic.
Like other strong opioids, fentanyl overdose poses a risk for fatal respiratory depression. If respiratory depression develops, it may persist for hours after patch removal, owing to continued absorption of fentanyl from the skin.
Fentanyl patches are available in five strengths, which deliver fentanyl to the systemic circulation at rates of 12.5, 25, 50, 75, and 100 mcg/hour. The smallest effective patch should be used. If a dosage greater than 100 mcg/hour is required, a combination of patches can be applied. After placing a fentanyl patch, it must not be exposed to direct heat (e.g., heating pads, hot baths, electric blankets) because doing so can accelerate fentanyl release, as can fever, sunbathing, and strenuous exercise. Because full analgesic effects can take up to 24 hours to develop, PRN therapy with a short-acting opioid may be required until the patch takes effect. As with other long-acting opioids, if breakthrough pain occurs, supplemental dosing with a short-acting opioid is indicated. For most patients, patches can be replaced every 72 hours, although some may require a new patch in 48 hours. Used or damaged patches should be folded in half with the medication side touching and flushed down the toilet. Unused patches should be stored out of reach of children.
Transmucosal
Fentanyl for transmucosal administration is available in four formulations: lozenges on a stick [Actiq], buccal tablets [Fentora], sublingual spray [Subsys], and sublingual tablets [Abstral]. All five products are approved only for breakthrough cancer pain in patients at least 18 years old who are already taking opioids around-the-clock and have developed some degree of tolerance, defined as needing, for 1 week or longer, at least: 60 mg of oral morphine a day, or 30 mg of oral oxycodone a day, or 25 mg of oral oxymorphone a day, or 8 mg of oral hydromorphone a day, or 25 mcg of fentanyl per hour, or an equianalgesic dose of another opioid. Transmucosal fentanyl must not be used for acute pain, postoperative pain, headache, or athletic injuries. Furthermore, it is essential to appreciate that the dose of fentanyl in these formulations is sufficient to kill nontolerant individuals—especially children. Accordingly, these products must be stored in a secure, child-resistant location.
All fentanyl transmucosal formulations are regulated as Schedule II products. Owing to risks of misuse, abuse, and overdose, all transmucosal fentanyl products are available only through a restricted distribution program, called the Transmucosal Immediate Release Fentanyl Risk Evaluation and Mitigation Strategy (TIRF REMS) Access program. The patient must enroll in this program to receive these products, and they are available only through pharmacies enrolled in the TIRF REMS program.
Adverse effects of transmucosal fentanyl are like those of other opioid preparations. The most common are dizziness, anxiety, confusion, nausea, vomiting, constipation, dyspnea, weakness, and headache. The biggest concerns are respiratory depression and shock.
Because of differences in bioavailability, transmucosal fentanyl products are not interchangeable on a microgram-for-microgram basis. For example, a 100-mcg buccal tablet produces about the same fentanyl blood level as does a 200-mcg lozenge. Accordingly, if a patient switches from one transmucosal product to another, dosage of the new product must be titrated to determine a strength that is safe and effective.
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